Synthesis, quantum chemical study, AIM simulation, in silico ADMET profile analysis, molecular docking and antioxidant activity assessment of aminofuran derivatives

Synthesis, quantum chemical study, AIM simulation, in silico ADMET profile analysis, molecular docking and antioxidant activity assessment of aminofuran derivatives

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Journal Pre-proof Synthesis, quantum chemical study, AIM simulation, in silico ADMET profile analysis, molecular docking and antioxidant activity assessment of aminofuran derivatives Iqbal Azad, Yusuf Akhter, Tahmeena Khan, Mohammad Irfan Azad, Subhash Chandra, Praveer Singh, Durgesh Kumar, Malik Nasibullah PII:

S0022-2860(19)31394-8

DOI:

https://doi.org/10.1016/j.molstruc.2019.127285

Reference:

MOLSTR 127285

To appear in:

Journal of Molecular Structure

Received Date: 20 April 2019 Revised Date:

22 October 2019

Accepted Date: 23 October 2019

Please cite this article as: I. Azad, Y. Akhter, T. Khan, M.I. Azad, S. Chandra, P. Singh, D. Kumar, M. Nasibullah, Synthesis, quantum chemical study, AIM simulation, in silico ADMET profile analysis, molecular docking and antioxidant activity assessment of aminofuran derivatives, Journal of Molecular Structure (2019), doi: https://doi.org/10.1016/j.molstruc.2019.127285. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V.

1

Synthesis, quantum chemical study, AIM simulation, in silico ADMET profile

2

analysis, molecular docking and antioxidant activity assessment of

3

aminofuran derivatives

4

Iqbal Azad1, Yusuf Akhter2, Tahmeena Khan1, Mohammad Irfan Azad3, Subhash

5

Chandra4, Praveer Singh5, Durgesh Kumar6, Malik Nasibullah1*

6 7

1

Department of Chemistry, Integral University, Dasauli, P.O. Bas-ha, Kursi Road, Lucknow-226026, U.P., India.

8

2

Department of Biotechnology, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow,

9

Uttar Pradesh 226025, India.

10

3

Department of Chemistry, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.

11

4

Department of Chemistry, IIT BHU, Varanasi 221005, India.

12

5

Department of Chemistry, University of Lucknow, Lucknow 226007, India.

13

6

Department of Chemistry, University of Delhi, New Delhi 110007, India.

14 15

*[email protected], [email protected]

16 17

Abstract

18

Quantum computational investigations and in silico biological evaluation of substituted

19

aminofuran derivatives are described in this study. The synthesized compounds were

20

characterized by 1H NMR,

21

Experimental observations were compared with the theoretical data generated by quantum

22

chemical calculations. Computational quantum chemical evaluations were done through ab-initio

23

density function theory (DFT) using Becke’s three parameters hybrid functional (B3LYP) with

24

6-311++G(d,p) level of theory, to study the molecular structural properties, thermodynamic

25

properties, nonlinear optical properties (NLO) and natural bond order (NBO). NBO exploration

26

was also done to study the intermolecular interactions and their stabilization energies with the

27

help of a molecular electrostatic potential map (MEP). Mulliken population and NBO correlated

28

the charge distributions within the molecule. Topological parameters at the bond critical point

29

(BCP) were studied by the quantum theory of atoms in molecules (QTAIM). VEDA4 program

30

was used to evaluate the potential energy distribution (PED). The molecular docking

31

investigation was done with three human targets viz. coronin 1C (Cor1C), eukaryotic elongation

32

factor 1A (eEF1A) and villin found in various carcinoma cells. The molecular docking

13

C NMR, FTIR, UV-Vis and ESI-MS spectroscopic techniques.

1

33

interactions of the compounds revealed a good interaction profile with cytoskeletal targets

34

Furthermore, pharmacological absorption, distribution, metabolism, excretion and toxicity

35

(ADMET) properties along with druglikeness were also assessed. The synthesized compounds

36

were also evaluated for their antioxidant activity and were shown to possess potential antioxidant

37

activity.

38 39

Keyword: Synthesis; Quantum analysis; Chemical reactivity; Molecular Docking; Molecular

40

Dynamic

41 42

Highlights: •

43

Synthesis and characterization of aminofuran derivatives by 1H NMR,

13

C NMR, FTIR,

UV-Vis and Mass spectroscopic techniques was done.

44



45

Computational quantum chemical studies were performed to evaluate NPO, NLO, NBO, FMO, MEP and global reactivity descriptors.

46 47



in silico pharmacological and druglikeness evaluation was also perfomed.

48



QTAIM methods were used to evaluate intramolecular interaction.

49



Molecular docking was done to explore the biological significance.

50 51

1.

Introduction

52

Substituted furans are widely distributed in a large number of natural products and synthetic

53

compounds of biological and synthetic importance [1]. The utilization of furan-based moieties in

54

electronic devices especially optoelectronic and their applications in conductive polymers has

55

increased their importance [2,3]. In this paper, two tetra-substituted aminofuran derivatives

56

(dimethyl 2-(cyclohexyl-amino)-5-phenylfuran-3,4-dicarboxylate (I) and dimethyl 2-(tert-butyl-

57

amino)-5-phenylfuran-3,4-dicarboxylate (II) have been synthesized following a one-step

58

isocyanide based multi-component strategy and characterized by various spectroscopic

59

techniques. Density functional theory (DFT) was used for the evaluation and validation of

60

molecular descriptors, AIM simulation and for molecular dynamic analysis [4]. Nonlinear

61

optical (NLO) materials are important for diverse optical phenomena such as the generation of 2

62

innovative light frequencies. Many organic molecules possess NLO properties in the presence of

63

the π-conjugated system [5,6]. The synthesized aminofuran derivatives were subjected to the

64

evaluation of spectroscopic parameters. Obtained experimental data were correlated with the

65

theoretically generated data. The NBO analysis was also carried out for interpreting the

66

molecular wave-function in relation to charge, bond order, bond type, hybridization, resonance,

67

and donor-acceptor interactions etc. [7,8]. In eukaryotic cells the cytoskeleton is involved in the

68

longitudinal association of the cells and dynamic relations with other cell types as well as their

69

aptitude to develop, split, and adapt to altering situations. The cytoskeleton also has an acute

70

function in mitotic assembly and disassembly, cell division, cytokinesis and apoptosis [9,10].

71

However these cytoskeletal fibers function on their own and necessitate the occurrence of a huge

72

quantity of accessory and regulatory proteins. It is assumed that the transformation of actin

73

cytoskeleton may assist cancer cells in eluding apoptotic signaling [11,12]. Coronin 1C (Cor1C),

74

eukaryotic elongation factor 1A (eEF1A) and villin are some cytoskeletal fibers involved in

75

various types of cancers [13,14]. Coronins have been evolved as regulatory protein for actin

76

dependant processes such as cell motility. Cor1C is a transcriptionally dynamic gene that is up-

77

regulated in several aggressive cancers. Cor1C has also been found to meditate miR-206

78

regulatory mechanism. Cor1C belongs to the coronin family of actin-binding proteins which are

79

imperative for the control and remodeling of the actin filaments network [15,16]. It has been

80

found to reduce cell invasion and metastasis in many rapidly dividing cancer cells [17,18]. The

81

elongation factor eEF1A has a vital role in protein synthesis. eEF1A is associated with transfer

82

of tRNAs to ribosomes [19,20]. Two isomeric forms are known viz. eEF1A1 and eEF1A2 which

83

are approximately 92% similar in their respective amino acid sequencing and have similar

84

functions [21,22]. It was found to be overexpressed in 30% of ovarian, 30-60% of breast and

85

80% of pancreatic cancers [23,24]. In non-small cell lung cancer eEF1A2 was overexpressed in

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28% of the observed cases [25]. eEF1A2 is also involved in cell multiplication, migration and

87

invasion with the help of actin remodeling [26] and phosphatidylinositol signaling [27]. Villin is

88

also a cytoskeletal protein that is necessary for the development of brush‐border microvilli in

89

small intestine and colon epithelium [28].

90 91

2.

Experimental and computational methods

92

Synthesis 3

93

The synthetic route of the target compounds I and II and the proposed synthetic mechanism is

94

presented as scheme I and II. A mixture of Ph3P 3 (0.33g, 1.25 mM) and cyclohexyl isocyanide 2

95

(0.14 g, 1.25 mM) in dry dichloromethane (DCM) (5 ml) was added drop wise in the solution of

96

benzoic acid 1 (0.12 g, 1 mM) and dimethyl acetylenedicarboxylate 4 (DMAD) (0.14 g, 1 mM)

97

in dry DCM (10 ml) at room temperature. The contents were refluxed for 16 h and the reaction

98

was monitored with the help of TLC. The solvent was removed under reduced pressure and the

99

viscous filtrate was purified by column chromatography using ethyl acetate (EtOAc) and hexane

100

(2:8) mixtures as eluent to give I and II in appreciable yield.

101 102

dimethyl 2-(cyclohexylamino)-5-phenylfuran-3,4-dicarboxylate (I): Viscous pale yellow oil,

103

67% yield. IR (KBr) (vmax/cm-1): 3364 (-NH), 1736 (C=O), 1670 (C=O), 1557, 1446 (Ph), 1251,

104

1180, 1153, 1037; 1H-NMR (400 MHz, CDCl3): δ 1.41-1.68 (m, 10H, 5xCH2, c-hex), 3.15 (m,

105

1H, CHNH), 3.92 (s, 3H, OCH3), 3.93 (s, 3H,OCH3), 6.79 (d, J = 8.1 Hz, 1H, NH) 7.46-7.83 (m,

106

5H, ArH);

107

24.81(C25H2, c-hex), 31.16(C22H2, c-hex), 33.53(C26H2, c-hex), 51.44 (OC13H3), 52.45

108

(OC14H3), 52.94 (C21HN), 88.98 (C2Furan), 113.45 (C3Furan), 121.94 (o-C16HPh), 125.32 (o-

109

C20HPh), 129.58 (m-C18HPh), 129.58 (m-C17HPh), 130.21 (p-C19HPh), 138.01 (C15ipso),

110

155.22 (C4Furan), 161.87 (C1Furan), 163.99 (C6OOCH3), 165.20 (C7OOCH3); ESI-HRMS calcd

111

for C20H23NO5 (M + H+): 358.21. Found: 357.42; Anal. Calc. C, 67.21; H, 6.49; N, 3.92.

13

C-NMR (300 MHz, CDCl3): δ 19.92 (C24H2, c-hex), 19.92(C23H2, c-hex),

112 113

dimethyl 2-(tert-butylamino)-5-phenylfuran-3,4-dicarboxylate (II): Viscous colorless oil,

114

52% yield. IR (KBr) (vmax/cm-1): 3326 (-NH), 1701 (C=O), 1665 (C=O), 1567, 1433 (Ph), 1271,

115

1194, 1151, 1099, 1021; 1H-NMR (400 MHz, CDCl3): δ 1.48 (s, 9H, 3xCH3, t-but), 3.85 (s, 3H,

116

OCH3), 3.96 (s, 3H, OCH3), 7.11 (s, 1H, NH) 7.37-7.39 (t, 1H, ArH), 7.62-7.64 (d, J = 8.1 Hz,

117

2H, ArH), 7.80-7.82 (t, 2H, ArH);

118

(C(CH3)3), 50.89 (OCH3), 52.42 (OCH3), 84.38 (C2Furan), 117.36 (C3Furan), 124.60 (o-C16HPh),

119

126.37 (o-C20HPh), 127.08 (m-C18HPh), 129.38 (m-C17HPh), 130.20 (p-C19HPh), 132.51

120

(C15ipso), 138.22 (C4Furan), 162.10(C1Furan), 165.13 (C6OOCH3), 167.38 (C7OOCH3); ESI-

121

HRMS calcd for C20H23NO5 (M + H+): 332.15. Found: 331.14; Anal. Calc. C, 65.24; H, 6.39; N,

122

4.23.

13

C-NMR (300 MHz, CDCl3): δ 29.87 (C(CH3)3), 50.29

4

123 124

Scheme I. Synthesis scheme of aminofuran derviratives I and II

125

Scheme II. Proposed Mechanistic pathway

126 127 128 129

2.1. Experimental details

5

130

All the reagents were purchased from Sigma-Aldrich and utilized without further purification.

131

The progress of the reaction was monitored with the help of thin layer chromatography (TLC).

132

TLC plates were prepared using silica Gel ‘G' (Merck, India). Electro-thermal melting point

133

apparatus was used to assess the melting points (°C) by open capillary method and were

134

uncorrected. The FT-IR spectra (4000-450 cm-1) of the compounds were recorded using KBr

135

pellets method on Agilent Cary 630 FT-IR spectrometer. UV-Visible spectra (200-400 nm) were

136

recorded on ELICO SL-160 double beam, UV-Visible spectrophotometer equipped with a 10

137

mm quartz cell in ethanol. 1H-NMR and 13C-NMR spectra were recorded on Bruker Avance (FT-

138

NMR) instrument (400 MHz) in CDCl3 using TMS as an internal reference. Mass spectrometric

139

analysis was performed on Agilent 6520 Q-TOF mass spectrometer with electro spray ionization

140

(ESI) probe.

141 142

2.2. Density Functional Theory (DFT) Calculations

143

The geometry optimization of the molecules and all other calculations (vibrational frequencies,

144

nuclear magnetic resonance, electronic absorption, optimized geometric parameters, natural bond

145

orbital, global reactivity and etc) were done by GaussView and Gaussian 09W program package.

146

The quantum calculations were done with the help of IA32W-G09RevD.01 program. GaussView

147

was used to define the primary atomic coordinates and for the optimization of the molecular

148

structure. In the ground state (gaseous and solvent phase) the molecular structure was optimized

149

using DFT/HF with B3LYP method with STO-3G, 6-31G, 6-31+G(d), 6-31G(d,p), 6-31+G(d,p),

150

6-311G(d,p) and 6-311++G(d,p) basis set. The calculated vibrational frequencies were scaled by

151

a factor of 0.9679 for 6-311++G(d,p) level. VEDA4 program was used to analyze the calculated

152

vibrational frequencies by potential energy distribution (PED). The energies and the strengths of

153

the lowest energy spin permitted electronic excitations were calculated with the help of time-

154

dependent DFT (TD-DFT) using B3LYP method in vacuum and solvent phase by polarized

155

continuum model (PCM). 1H-NMR and

156

independent atomic orbital (GIAO) method. QTAIM methods have been used to achieve a

157

deeper understanding of the intra and intermolecular interactions as well as to assess the strength

158

of hydrogen bonding.

159

The energy of highest occupied molecular orbital (EHOMO), lowest unoccupied molecular orbital

160

(ELUMO), the band gap energy (EGAP or ELUMO-HOMO), chemical softness (σ), global softness (S),

13

C-NMR analyses were carried out using the Gauge

6

161

absolute electronegativity (), chemical potential (CP), chemical hardness (η), electrophilicity

162

index (ω), nucleophilicity index (N), additional electronic charges (∆N) and optical softness (σ˳)

163

were calculated with the help of Eq. (1)-(12) and the scale factor (Average) between the observed

164

and the theoretical frequencies was calculated by Eq. (13)-(14). Furthermore, DFT/B3LYP 6-

165

311++G(d,p) level theory was used to perform the natural bond order (NBO) and non-linear

166

optical (NLO) calculation. NBO 3.0 program was used to recognize the inter and intramolecular

167

delocalization or hyperconjugation and strength of delocalization interaction with the help of Eq.

168

(26). NLO parameters such as static dipole movement (µ), mean polarizability (α), anisotropy of

169

polarizability (∆α) and first hyperpolarizability (β) were calculated with the help of Eq. (15)-(18)

170

[29,30]. Molecular electrostatic potential surfaces (MEP) of the compounds were analyzed with

171

the help of GaussView tool.

172

 = −

(1)

173

= − 

(2)

174

 =  −

(3)

175

 = − ( +  ) =

176

 = − = ( +  )

177

 = ( −  ) =

 

| | 

=

|   | 

 

 

 

=

(5)   

(6)

 

178

=

179

! =

180

" =

181

$ =

182

∆$&' = −

(7)



(8)



=

#

(9)



 "

(10) # (

(11)

  

183

)

184

*=

185

* /0120 =

(4)

(12)

+ '.

(13)

+#-.. * * *3 ⋯*$

(14)

$

7



186

5 = (5' + 56 + 57 )

187

8 = (8'' + 866 + 877 )

188

∆8 =

189

= = (=' + =6 + =7 )/

190

Where βx = βxxx + βxyy + βxzz, βy = βyyy + βyzz + βyxx, βz = βzzz + βzxx + βzyy

(15)



(16)

3



√



:(8'' − 866 ) + (866 − 877 ) + (877 − 8'' ) + ;8'7 + ;8'6 + ;867 <

(17) (18)

191 192

2.3. Molecular docking simulation

193

2.3.1. Ligand preparation

194

The 2D structures of compound I and II were drawn in ChemDraw Professionals (Perkin Elmer

195

15.1) and ChemDraw 3D was used to prepare .mol files. Structure optimization was done using

196

the MMFF94 method. For greater accuracy, the optimized structure was further subjected to

197

energy minimization using the DFT/B3LYP/6-311++G(d,p) basis set through Gaussian 09W and

198

Gauss View v6.0. Optimized structures of the compounds are presented in Figure 1.

199 200

Figure 1. Optimized structure of compound I and II with DFT-B3LYP/6-311++G(d,p) level

201 202

2.3.2. Homology modeling

203

The crystal structure of villin was available (PDB ID: 3FG7). Homology modeling is a potential

204

tool to prepare the 3D structure models of the protein molecule, required for the interaction

205

analysis. Since the 3D structures of human eukaryotic elongation factor 1A2 (eEF1A2) and

206

coronin-1C (Cor1C) could not be retrieved from the Protein Data Bank (http://www.rcsb.org),

207

they were generated with the help of homology modeling. The sequences of amino acids of

208

human eEF1A2 and Cor1C were obtained from universal protein knowledge database

209

(UniProtKB) having IDs Q05639 and Q9ULV4, respectively. ExPASy Molecular Biology

210

Server was used to set the amino acid sequence into FASTA format to build homology models. 8

211

Phyre2 (Protein homology/analog recognition engine 2.0) server was used to generate the 3D

212

structure of query proteins with the help of FASTA sequence. The server used 1G7C and 2AQ5

213

as a template to produce a working model of human eEF1A2 and Cor1C through one-to-one

214

threading method. The query proteins contained 442 and 394 amino acids. The pockets and

215

cavities were attained by CASTp server. BDSV 2017R was used to visualize the protein’s

216

structure.

217 218

2.3.3. Verification of homology modeling

219

The model generated with the help of 3D modeling was validated with the help of Molprobity

220

(http://molprobity.biochem.duke.edu/) which is an online server used for the structure evaluation.

221

The confirmation was done with the calculation of H atoms, total atoms, Ramachandran,

222

interaction analysis, rotamer analysis and covalent-geometry analysis.

223 224

2.3.4. Receptor preparation

225

The target proteins were exposed to structural optimization. Polar hydrogen atoms, non-polar

226

hydrogen atoms and Kollman charges were added. The receptor macromolecule was subjected to

227

energy minimization through the default RMSD and AMBER force field 14SB with the help of

228

Chimera 1.12. Energy predictions were completed after structural procurement and eliminating

229

structural conflicts. Optimization was executed by MMTK which is encompassed with Chimera

230

and visualized by BDS visualizer 2017R (Figure 2).

9

231 232

Figure 2. Electrostatic potential surface structure and pocket sites of eEF1A2 (I), Cor1C (II) and

233

villin (III) with the amino acid sequence.

234 235

2.3.5. AutoDock

236

Molecular docking is used to calculate the binding energy upon protein-ligand interaction and to

237

detect the probable ligand binding sites. The docking investigations were accomplished by

238

AutoDock 4.2 and AutoDock Tools (ADT) through the Lamarckian Genetic Algorithm (LGA).

239

The scoring function in AutoDock is based on the hydrogen bonding, van der Waals interaction,

240

electrostatic interaction, entropy change upon ligand binding and solvation [31]. The grid

241

parameter file (GPF) was set at 32×32×32 Å, 30×30×30 Å and 30×30×30 Å along, x, y, z axes

242

with grid arrangement and grid center which was set at 28.10, 35.10 and 48.10 Å for eEF1A2,

243

4.70, 41.10 and 21.10 Å for Cor1C and 14.93, 16.47 and 13.91 Å for villin respectively. Firstly

244

.gpf was run to produce the grid map of the protein and ligand complex. Flexible docking

245

simulation was executed through 500 runs, 27000 generations, 50 GA populations and 2.5×106

246

energy evaluations. RMS cluster tolerance was set to 2.0 Å per run and 10 most stable

10

247

conformations were selected on the basis of scoring and position. Confirmation of the ligand

248

having the minimum energy was selected for the docking evaluation. AutoDock estimated free

249

binding energy scoring function as presented by Eq. (19)–(20):

250

H100 IJKLJK2 0K126 = H + HM + MH − N

(19)

251

H = /LO + IPKL + -0.. + L0QP-/.

(20)

252

Where FIM = Final inter molecular energy, FTI = Final total internal energy, TF =

253

Torsional free energy, US = Unbound system’s energy, vdW = van der Waals energy, H bond =

254

Hydrogen bonding energy, Elec = Electrostatic energy, Edesolv = Disolvation energy

255 256

2.3.6. AutoDock Vina

257

Molecular docking validation was performed with the help of AutoDock Vina which runs the

258

PDBQT file that is prepared through MGL tools. Protein and ligand files were prepared using

259

AutoDock tools and grid box size was set at 32×32×32 Å, 30×30×30 Å and 30×30×30 Å along

260

the x, y, and z axes respectively. The grid center was set at 28.10, 35.10 and 48.10 Å for eEF1A2,

261

4.70, 41.10 and 21.10 Å for Cor1C and 14.93, 16.47 and 13.91 Å for villin respectively. The

262

docking calculations produced ten poses. The identification of the final pose was done on the

263

basis of interaction profile of the protein ligand complex. AutoDock Vina estimated scoring

264

function as given by Eq. (21):

265

∆(IJKLJK2) = ∆(/LO) + ∆( IPKL) + ∆( -0.. ) + ∆( L0QP-/. ) + ∆(RP1Q) (21)

266

Where ∆S = Gibbs’s free energy, ∆G (tors) = Torsional free energy

267 268

2.3.7. iGEMDOCK

269

iGEMDOCK is a graphical docking, screening and post-screening evaluation tool. During

270

docking simulation by iGEMDOCK, accurate docking parameters were set as, numbers of runs:

271

80, maximum interactions: 8000, population size: 800 with an energy threshold of 100. Docking

272

outcome was obtained in the form of the lowest binding energy confirmation [32,33]. The

273

hydrophobic and electrostatic preferences were set at 1.00. The binding site of the receptor was

274

recognized at a distance of 8 Å. iGEMDOCK empirical scoring function is given by Eq. (22):

275

TUVWXYY = Z[\ + ] ^_W[ + `aXb.

(22)

276 277 11

278

2.4. PreADMET

279

PreADMET is a web-based tool for evaluating the ADMET properties. The input of PreADMET

280

is .mol file. Synthesized compounds were assessed for blood brain barrier penetrability (BBB),

281

Caco-2 cell permeability, human intestinal absorption, Madin-Darby, canine kidney cell

282

permeability, plasma protein binding distribution and skin permeability [34] using PreADMET.

283 284

2.5. Druglikeness

285

The druglikeness was assessed on Lipinski's, Veber’s and Ghose filters [35-37].

286 287

Free radical scavenging or antioxidant activity by DPPH Assay

288

Antioxidant activity was assessed through (diphenylpicrylhydrazide) DPPH method at different

289

concentrations viz. 25, 50, 75 and 100 µL in freshly prepared DPPH as described earlier [38].

290

The scavenging the DPPH radical was measured by the following Eq. (23):

291

c Q./0K2JK2 0dd0.R (% JKfJIJRJPK) = g

#  N h×

#

))

(23)

jℎlml; op = oqrsmqtuvl sw xℎl vsuxmsy mltvxzsu ({||} rsy~xzsu) o = oqrsmqtuvl sw xℎl vs€s~u‚r

292 293

3.

Results and discussion

294

3.1. Geometry optimization

295

The target molecules, C20H23NO5 (I) and C18H21NO5 (II) were exposed to geometry optimization

296

using DFT/B3LYP/6-311++G(d,p) method. Geometry optimization involves the calculation of

297

wave-function, energy of the molecule and works to find the most stable conformation of the

298

molecule having minimum energy. The calculated bond lengths, bond angles and dihedral angles

299

are given in Table 1 and optimized molecular structures of the compounds are given as Figure 1.

300

The calculated bond lengths for C1-C2, C2-C3, C3-C4, C4-O5 and O5-C1 were 1.390, 1.448,

301

1.364 1.402 and 1.347 Å in compound I and 1.391, 1.447, 1.364 1.402 and 1.347 Å in compound

302

II for the furan ring, out of which C1-C2 and C3-C4 possessed double bond character. For the

303

carboxylate group, C2-C6, C6-O9, C6-O10, O10-C13 and C3-C7, C7-O11, C1-O12, O12-C14

304

bond lengths were calculated to be 1.447, 1.212, 1.378, 1.438 and 1.487, 1.210, 1.342, 1.439 Å

305

in compound I whereas 1.448, 1.212, 1.378, 1.478 and 1.488, 1.210, 1.342 and 1.439 Å in

306

compound II. Due to the presence of double bond character the contraction in the bond length 12

307

was found between C6-O9 and C7-O11 in both the compounds. Calculated bond lengths of the

308

amine group, C1-N8, N8-C21 were 1.346 and 1.465 Å in compound I whereas 1.347 and 1.485

309

Å in compound II. Within the aromatic group, bond lengths have been calculated between 1.390-

310

1.407 Å for I and between 1.390-1.407 Å for compound II, respectively. The ring size in both the

311

compounds showed that substitution changes do not influence the aromatic ring system. The

312

bond length of C-C for the cyclohexyl group was found between 1.535-1.540 Å in compound I

313

and the bond length of C-C for the tertbutyl group was between 1.536-1.540 Å in compound II.

314

The bond angle of phenyl ring system was found approximately near ~120.3° and the bond angle

315

of cyclohexyl group was found near ~111.5°. The bond angles of C1-N8-C21, N8-C21-C22 of

316

compounds I and II were 125°, 109.5° and 128°, 105.5° respectively. These variations in the

317

bond angles were due to the substitutions at C21 position. Cyclohexyl substitution (C21, tertiary)

318

enhanced the strain in the bond angle as compared to the tertbutyl substitution (C21, quaternary).

319

In furan region, the bond angles of C1-C2-C3, C2-C3-C4, C3-C4-O5, C4-O5-C1 and O5-C1-C2

320

were 105.3°, 107.8°, 108.6° and 110.2°, respectively for compound I and 105.4°, 107.8°, 108.2°,

321

108.7° and 110.0°, respectively for compound II.

322

The dihedral angles in furan region viz. C1-C2-C3-C4, C2-C3-C4-O5, C3-C4-O5-C1, C4-O5-

323

C1-C2 and O5-C1-C2-C3 displayed low bond angles viz. 0.1°, -0.8°, 1.2°, -1.2° and 0.7° in

324

compound I and 1.6°, -1.1°, 1.1°, -0.7° and 0.04°, respectively in compound II. The major

325

variations between the dihedral angles of C1-N8-C21-C22, C2-C1-N8-C21 and O5-C1-N8-C21

326

were observed to be -150.6°, -175.2° and 8.0° in compound I and -173.8°, 166.5° and -13.8° in

327

compound II respectively. C21 quaternary carbon was more stable as compared to the tertiary

328

carbon leading to the distortion in the dihedral angles of the ring system. Some minor variations

329

were also observed between the dihedral angles of C3-C2-C1-N8, C4-O5-C1-N8 and C6-C2-C1-

330

N8 viz. -176.3°, 176.3° and 177.6° in compound I and 179.8°, 179.5° and -7.2° in compound II

331

respectively. These variations were observed due to the weak internal hydrogen bonding between

332

N8-H----O10-C6 influencing the C21 position. The calculated geometrical parameters were in

333

good agreement with the single-crystal X-ray analyses reported by the researchers [39,40] (Table

334

1).

335 336 337

13

338

Table 1. Selected optimized geometrical parameters using DFT-B3LYP/6-311++G(d,p) Bond length (Å) Comp. I Comp. II Bond angle (°) Comp. I

Comp. II

Dihedral angle (°)

Comp. I Comp. II

C1-C2

1.390

1.391

C1-C2-C3

105.285

105.401

C1-C2-C3-C4

0.094

0.638

C2-C3

1.448

1.447

C2-C3-C4

107.803

107.782

C2-C3-C4-O5

-0.797

-1.057

C3-C4

1.364

1.364

C3-C4-O5

108.151

108.165

C3-C4-O5-C1

1.236

1.101

C4-O5

1.402

1.402

C4-O5-C1

108.571

108.651

C4-O5-C1-C2

-1.191

-0.693

O5-C1

1.347

1.347

O5-C1-C2

110.175

109.989

O5-C1-C2-C3

0.682

0.043

C2-C6

1.447

1.448

C2-C6-O9

126.649

126.513

C1-C2-C6-O10

10.822

10.790

C6-O9

1.212

1.212

C2-C6-O10

111.600

111.781

C1-C2-C6-O9

-168.279

-168.213

C6-O10

1.378

1.378

C6-O10-C13

115.371

115.417

C1-C2-C3-C7

-175.219

-175.034

O10-C13

1.438

1.438

C6-C2-C3

126.921

126.489

C1-O5-C4-C15

178.000

178.080

C3-C7

1.487

1.488

C6-C2-C1

127.422

127.707

C1-N8-C21-C22

-150.630

-173.836

C7-O11

1.210

1.210

C2-C3-C7

125.112

125.107

C1-N8-C21-C23

-

-55.078

C7-O12

1.342

1.342

C2-C1-N8

132.233

131.271

C1-N8-C21-C24

-

68.030

O12-C14

1.439

1.439

C3-C7-O11

125.437

125.414

C1-N8-C21-C26

85.506

-

C1-N8

1.346

1.347

C3-C7-O12

110.724

110.710

C2-C3-C7-O11

-125.150

-125.133

N8-C21

1.465

1.485

C7-O12-C14

115.972

115.981

C2-C3-C7-O12

55.145

55.730

C21-C22

1.535

1.536

C7-C3-C4

126.899

126.952

C2-C3-C4-C15

-176.511

-177.070

C22-C23

1.536

-

C3-C4-C15

136.785

136.647

C2-C6-O10-C13

-178.650

-178.625

C23-C24

1.535

-

C3-C4-O5

108.151

108.165

C2-C1-N8-C21

-175.197

166.482

C24-C25

1.535

-

C4-O5-C1

108.571

108.651

C3-C7-O12-C14

-170.257

-173.641

C25-C26

1.536

-

C4-C15-C16

119.895

120.003

C3-C2-C6-O9

3.271

3.410

C26-C21

1.540

-

C4-C15-C20

121.502

121.404

C3-C2-C6-O10

-177.630

-177.587

C4-C15

1.458

1.458

C15-C16-C17

120.672

120.685

C3-C2-C1-N8

-176.301

179.821

C15-C16

1.407

1.407

C16-C17-C18

120.340

120.329

C3-C4-C15-C20

-27.441

-28.323

C16-C17

1.390

1.390

C17-C18-C19

119.389

119.398

C3-C4-C15-C16

153. 394

152.397

C17-C18

1.394

1.394

C18-C19-C20

120.735

120.721

C4-C3-C7-O11

62.381

60.026

C18-C19

1.394

1.394

C19-C20-C15

120.258

120.270

C4-C3-C7-O12

-119.271

-119.112

C19-C20

1.391

1.391

C20-C15-C16

118.598

118.590

C4-C3-C2-C6

-173.285

-172.496

C20-C15

1.406

1.406

C1-N8-C21

125.045

128.099

C4-O5-C1-N8

176. 290

179.497

C21-C23

-

1.540

N8-C21-C22

109.463

105.472

C4-C15-C16-C17

179.809

179.828

C21-C24

-

1.539

N8-C21-C26

112.272

-

C4-C15-C20-C19

179.753

179.704

C21-C22-C23

111.496

-

O5-C1-C2-C6

174.017

173.065

C22-C23-C24

111.816

-

O5-C1-N8-C21

7.996

-13.756

C23-C24-C25

111.321

-

O5-C4-C15-C16

-22. 114

-23.420

C24-C25-C26

111.531

-

O5-C4-C15-C20

157.051

155.860

14

C25-C26-C21

111.396

-

O5-C4-C3-C7

174.408

174.512

N8-C21-C23

-

110.910

C6-C2-C3-C7

11.402

11.832

N8-C21-C24

-

110.301

C6-C2-C1-N8

177.573

-7.157

C6-C2-C1-O5

174.017

173.065

C7-C3-C4-C15

-1.306

-1.501

N8-C21-C22-C23

-179.406

-

N8-C21-C26-C25

178.150

-

C15-C16-C17-C18

0.153

0.185

C15-C20-C19-C18

0.761

0.781

C16-C17-C18-C19

-0.481

-0.426

C16-C15-C20-C19

-1.071

-1.005

C17-C18-C19-C20

0.024

-0.056

C17-C16-C15-C20

0.620

0.528

C21-C22-C23-C24

54.689

-

C21-C26-C25-C24

-55.201

-

C22-C23-C24-C25

-54.349

-

C22-C21-C26-C25

55.201

-

339 340

3.2. Infrared Spectroscopy

341

The experimental FT-IR spectra of compound I and II were compared with the calculated spectra

342

as presented in Table 2. Scaled (calculated) harmonic vibrational frequencies using DFT-B3LYP

343

method and observed vibrational frequencies with comprehensive detailed PED assignments are

344

given in Supplementary Table 4 using vibrational energy distribution analysis (VEDA) program

345

[41]. The experimental and theoretical vibrational analyses were performed between 4000-450

346

cm-1 and represented graphically in Figure 4. The harmonic frequencies were calculated in the

347

gaseous phase. However, the experimental values were obtained in the solid phase. The

348

calculated vibrations were scaled down through a single scaling factor 0.9679 to discard any

349

harmonicity found in the real system [42]. Compounds I and II consisted of 49 and 45 atoms, and

350

had 141 and 129 fundamental vibrations modes. The optimized molecular structures of the

351

compounds were subjected to energy and harmonic vibrational frequencies calculation through

352

DFT/B3LYP/6-311++G(d,p) method. The correlation graph showed good agreement between

353

experimental and theoretical vibrational spectra (r2= 0.9996) for both the compounds as shown in

354

Figure 3 and 4.

15

355 356

Figure 3. Observed and calculated IR spectra of compound I and II

357 358

N-H group vibrations

359

The N–H stretching vibrations commonly occur in the region 3500-3300 cm-1 [43]. Secondary

360

amines give a broad band at ~1500 cm-1 and an out of plane bending at ~800 cm-1. The N–H

361

stretching vibrations of compounds I/II were calculated at 3480/3476 cm-1 and observed at

362

3349/3326 cm-1. Stretching (N–H), in-plane (N–H) and out-plane (N–H) deformation bands were

363

observed at 3480, 1588, 678/ 3476, 1580, 679 cm-1 and calculated at 3349, 1606, 677/ 3326,

364

1567, 675 cm-1 for the two derivatives. The experimental values were in good agreement with the

365

theoretical values.

366

Carbonyl group (C=O) vibrations

367

The stretching vibration of ester C=O group with conjugated arene ring has been reported as a

368

strong band between 1740-1715 cm-1. The calculated C=O stretching vibration was observed as a

369

strong band at 1710 and 1702 cm-1 for compounds I/II. The calculated peaks were observed at

370

1736 and 1670 cm-1 for compound I and 1701 and 1665 cm-1 for compound II. The vibrational

371

frequency of C–O bands was found between 1300-1000 cm-1. The stretching vibrations for ester 16

372

C–O group for compound I and II were calculated at 1186, 1052, 868, 817 cm-1 and 1166, 1013,

373

825, 792 cm-1 showing correlation with the observed vibrations at 1181, 1053, 856, 804 cm-1 for

374

compound I and 1161, 1020, 804, 787 cm-1 for compound II.

375

CH3 group vibrations

376

The C-H stretching vibrations generally lie between 3000-3100 cm-1. The stretching vibrations of

377

C–H, linked with OCH3 groups were observed at 2983 and 2942 cm-1 for compound I/II while

378

the calculated values were found at 2973 and 2954 cm-1. The in-plane deformations of OCH3

379

were observed at 1446 and 1433 cm-1 for compound I and II whereas the calculated bands were

380

found at 1447 and 1432 cm-1 respectively.

381

CH2 group vibrations

382

Methylene group has its characteristic bending absorption at ~1465 cm-1. Scissoring vibration of

383

the CH2 group was observed at 1461 cm-1 which was in good agreement with the calculated

384

value at 1460 cm-1. The stretching symmetric and anti-symmetric vibrations for C–H were

385

observed at 2933 and 2910 cm-1 for compound I, whereas the calculated values were 2951 and

386

2913 cm-1.

387

C–N vibrations

388

The amine (C–N) stretching vibrations are observed between 1350-1000 cm-1 [44] as medium to

389

strong intensity bands. Due to the conjugation of the aromatic ring and the attached nitrogen

390

atom of the amine group, aromatic amines absorb at a higher frequency between 1350-1250 cm-1.

391

The experimental spectra showed only two bands at 1606, 1557 and 1601, 1469 cm-1 for

392

compound I and II respectively corresponding to the C–N symmetrical and anti-symmetrical

393

stretching.

394

Phenyl ring vibrations

395

The C-H stretching vibrations in the phenyl ring occur between 3100-3000 cm-1 [45]. The

396

experimental spectra showed four medium-weak intensity bands at 3119, 3078, 3069 and 2968

397

cm-1 for compound I and 3083, 3081 and 3060 cm-1 for compound II which were in agreement

398

with the C-H stretching of the phenyl ring. Theoretically these bands were observed between

399

3097-3061 cm-1 for compound I and 3096-3061 cm-1 for compound II. The in-plane aromatic C-

400

H bending vibrations are found in the range 1465-1000 cm-1 [43,44]. 17

These bands were

401

observed at 1475, 1461, 1369, 1306, 1091 and 996 cm-1 for compound I and 1433, 1313, 1271,

402

1099, 999 cm-1 for compound II. The calculated bands were found at 1462, 1460, 1351, 1209,

403

1165, 1138, 1020, 1013 and 981 cm-1 for compound I and 1432, 1319, 1288, 1076 and 982 cm-1

404

for compound II showing good agreement with the experimental data. The in-plane bending

405

vibrations were mixed with ring C-C stretching vibrations. The C-H out-of-plane deformations

406

were observed at 947, 799, 759 and 712 cm-1 and calculated at 960, 792, 758 and 740 cm-1 for

407

compoundI and for compound II, they were observed at 999, 908, 787, 755 and 743 cm-1 and

408

calculated at 982, 910, 792, 751 and 748 cm-1, respectively. The most prominent C-C stretching

409

bands of furan ring were observed at 1621, 1606, 1572 and 1557 cm-1 for compound I. While for

410

compound II they were observed at 1601, 1567 and 1469 cm-1. C-C stretching bands of the

411

hetero-ring were found at 1602, 1588, 1579 and 1555 cm-1 for compound I and 1595, 1580 and

412

1465 cm-1 for compound II. The characteristic C-C stretching of phenyl ring is expected in the

413

range 1650-1200 cm-1. Experimentally these bands were observed at 1602, 1579, 1475, 1432 cm-

414

1

415

overlap with the C-H in-plane deformation. Theoretically calculated bands were obtained at

416

1621, 1572, 1486, 1428 cm-1 for compound I and 1601, 1582, 1513, 1313 cm-1 for compound II

417

representing a good agreement between the theoretical and experimental data.

for compound I and 1595, 1588, 1555, 1319 cm-1 for compound II. Generally these bands

418 419

Table 2. Experimental and calculated vibrational wave numbers (cm-1) at B3LYP/6-311

420

G++(d,p) level Comp. I

Comp. II

IRUnscale IRScale IRObserv IRUnscale IRScale

Vibration Modes (I/ II)

IRObserv

3596

3480

3349

3591

3476

3326

[STRE-(N8H27)]/ [STRE-(N8H25)]

3214

3110

3119

3213

3110

3083

[STRE-(C20H38)]/ [STRE-(C20H36)]

3186

3084

3078

3186

3084

3081

3172

3071

3069

3162

3061

3060

3071

2973

2983

3052

2954

2942

3010

2913

2910

3026

2928

2901

[STRE-(C17H35), (C18H36) and (C19H37)]/ [STRE(C16H32), (C17H33) and (C18H34)] [STRE-(C17H35) and (C19H37)]/ [STRE-(C17H33), (C16H32), (C18H34) and (C19H35)] [STRE-C13H28) and (C13H30)]/ [STRE-(C14H29), (C14H30) and (C14H31)(49)] [STRE-(C22H41) and (C24H44)]/ [STRE-(C22H37), (C22H38), (C22H39) and (C23H42)]

18

1767

1710

1736

1767

1710

1701

[STRE-(O11C7)]/ [STRE-(O11C7)]

1759

1702

1670

1758

1702

1665

[STRE-(O9C6)]/ [STRE-(-(O9C6)] [STRE-(C16C17), (C20C19) and (C3C4)]/ (BEND-

1656

1602

1621

1641

1588

1582

H32C16C17), (H33C17C18), (H34C18C19)-(H35C19C20), (H36C20C15)]

1641

1588

1606

1632

1580

1567

1632

1579

1572

1607

1555

1513

[STRE-(C2C1) and (N8C1)]/ [STRE-( (C3C4), (C4C15)] [STRE-(C3C4), (C19C18) and (C15C20)]/ [STRE-C3C4), (C4C15), (C16C17), (C20C19) and (C15C20)] [BEND-(H34C16C17), (H35C17C18), (H37C19C20) and

1524

1475

1486

1527

1478

1483

(H38C20C19)]/ [STRE-H37C22)(17), (H38C22), (H39C22), (H40C23), (H41C23), (H42C23), (H43C24), (H44C24) and (H45C24)]

1511

1462

1475

-

-

-

1495

1447

1446

1480

1432

1433

1475

1427

1426

1475

1428

1426

1462

1415

1412

1363

1319

1313

1451

1405

1393

1262

1221

1227

[BEND-(H43C23H42), (H45C24H44), (H47C25H46) and (H49C26H48)]/[BEND-(H32C14H31), (H33C14H32) and TORS(H32C14O12C7)]/ [BEND-H27C14H26), (H28C14H27)] [BEND-(H29C13H28) and (H30C13H29)]/ [BEND(H26C13H28) and (H31C14H30)] [BEND-(H39C21C26) and (C2C1O5)]/ [BENDH36C20C15), (H32C16C15) and (H34C18C19)] [BEND-(H39C21C26) and (C2C1O5)]/ [STRE-(N8C21), BEND-(H25N8C21) and (H40C23C21)] [BEND-(H44C24C25), TORS-H42C23C24C25),

1395

1351

1369

1233

1194

1194

(H43C23C24C25) and (H44C24C25C26)]/ [BEND(H44C24C21), (H45C24C21), (H43C24C21) and (TORE(H41C23C21C24)] [STRE-(C4C15) and (O5C4)]/ [STRE-(O10C6) and TORE-

1289

1248

1251

1205

1166

1161

1273

1232

1230

-

-

-

[STRE-(O12C7)]/-

1226

1186

1181

1167

1130

1110

[TORE-(H45C24C25C26)]/ [BEND-(H31C14H30)]

(H26C13O10C6)]

[STRE-(O5C1), (N8C21) and BEND-(C16C17C18)]/ 1117

1081

1091

1092

1057

1070

[BEND-(H44C24C21), TORE-(H41C21N8C1), (H26C13O10C6)] [STRE-(O5C4)]/ [STRE-(O5C4), (O10C13), TORE-

1087

1052

1053

1046

1013

1020

1073

1039

1038

-

-

-

[STRE-(O12C14)]/-

952

921

930

-

-

-

[v-(C23C24)(11)-v-(C22C23)(12)-v-(C25C26)(15)]/-

(C17C18C19C20)]

19

897

868

856

852

825

[STRE-(O10C6), (O12C7), BEND-(O9C6O10) and

804

(O11C7O12)]/ [STRE-(O10C13), (O12C14)] [(TORE-(O9C2O10C6) and (C6C1C3C2)]/ [STRE-(

845

817

804

818

792

787

(O11C7), TORE-(H34C16C17C18), (H36C18C19C20) and (H38C20C19C18)(10)]

798

772

777

787

761

[TORE-(O9C2O10C6) and (O11C3O12C7)]/ [TORE-

763

(O10C6C2C3)] [BEND-(C19C18C17), (C2C1O5C4) and (N8C2O5C1)]/

764

740

712

759

735

718

[TORE-(H45C24C21CN8), (H26C13O10C6) and (H42C23C21N8)]

700

678

677

701

679

675

[TORE-(H27N8C1C2)]/ [STRE-(C2C1)(17) and (C1N8)]

683

661

650

-

-

-

[BEND-(C23C24C25) and (C25C26C21)]/-

421

422 423

Figure 4. The correlation graph between experimental and calculated wave numbers for

424

compound I and II

425 426

3.3. 1H and 13C NMR spectra

427

The chemical shifts for the optimized structure have been computed with the help of DFT-

428

B3LYP method with 6-311++G(d,p) as a basis set, using the GIAO approach. The IEFPCM

429

model with chloroform solvent (relative permittivity (ε) 46.7) was used to study the solvent-

430

induced and temperature effects. Linear scaling approach is most applicable, the slope and

431

intercept from the fittest line agrees for the direct calculation of the empirically scaled chemical

432

shifts (Eq. 24) [46].

433

ƒQ.-0L = .-.

434

Where σ is the calculated isotropic shielding value for a particular nucleus or the average of

435

several symmetry associated nuclei.

(JKR01.0R  )

(24)

Q-P0

20

436

The experimental and calculated chemical shifts are shown in Table 3. In the 1H NMR spectrum

437

of compound I, a multiplet for ten protons of the cyclohexyl group was observed between 1.25-

438

1.67 ppm and a singlet for nine protons of the tertbutyl group was observed 1.48 ppm,

439

respectively. A doublet for NH proton was observed at 2.17 ppm for compound I and singlet was

440

observed at 7.11 ppm for compound II while a one proton multiplet for the CHNH proton was

441

observed at 3.15 ppm for compound I, this peak was absent in the compound II, due to the

442

presence of quaternary tertbutyl carbon, directly attached with the NH group. A singlet for three

443

methyl protons of the –COOCH3 groups was observed at 3.92 and 3.93 ppm for compound I and

444

3.85 and 3.96 ppm for compound II, respectively. Furthermore, additional support for the

445

characterization of the structure of aminofuran derivatives was obtained by their

446

spectra. The peaks of the carboxylate carbon (-COO; C6=O9 and C7=O11) were observed at

447

163.99 and 165.20 ppm for compound I and 165.73 and 167.38 ppm for compound II,

448

respectively. The peak due to the carbon attached to the amine nitrogen, C1-N8 was found at

449

161.87 and 162.10 ppm for compound I and compound II, respectively, as reported in the

450

literature (Table 3; Figure 5 and 6).

451 452

Figure 5. 1H NMR spectra of compound I and II

21

13

C NMR

453

Figure 6. 13C NMR spectra of compound I and II

454 455 456

The correlation coefficient for 1H NMR (r2=0.970 and 0.983) for compound I and II and

13

457

NMR (r2=0.998 and 0.998) exhibited sufficient agreement between the experimental and

458

calculated findings (Figure 7). The radar graphs were also prepared to explore the correlation of

459

13

460

calculated values (Figure 8). The 1H and 13C NMR results were supported by the presence of a

461

molecular ion peak at 357.21 and 332.15 in the mass spectra of the two derivatives I and II

462

confirming the molecular formula of the two compounds to be C20H23NO5 and C18H21NO5,

463

respectively.

C

C NMR values and interesting agreement was obtained between the experimental and

464 22

465

Figure 7. Correlation between the experimental and calculated 1H and 13C chemical shifts at

466

DFT-B3LYP/6-311G++(d,p) level

467

Table 3. Calculated and experimental 1H and 13C NMR chemical shift („/€) in CDCl3 Atoms

Comp. I Exp. value Calc. value

Comp. II ∆



Exp. value Calc. value





Position

C1

161.87

162.52

-0.65

0.996

162.10

163.59

-1.49

0.991

IC, Furan C-NH

C2

88.98

91.72

-2.74

0.970

84.38

92.90

-8.52

0.908

IC, Furan C-CO

C3

113.45

121.10

-7.65

0.937

117.36

120.85

-3.49

0.971

IC, Furan C-CO

C4

155.22

148.84

6.38

1.043

138.22

149.71

-11.49

0.923

IC, Furan C-Ph

C6

163.99

165.90

-1.91

0.988

165.13

165.73

-0.6

0.996

IC, COOCH3

C7

165.20

171.18

-5.98

0.965

167.38

171.30

-3.92

0.977

IC, COOCH3

C13

51.44

50.10

1.34

1.027

50.29

50.15

0.14

1.003

IC,OCH3

C14

52.76

51.97

0.79

1.015

50.89

52.00

-1.11

0.979

IC,OCH3

C15

138.01

134.10

3.91

1.029

132.51

134.01

-1.51

0.989

IC, Ph C

C16

121.94

127.76

-5.82

0.954

124.60

128.32

-3.72

0.971

IC, Ph CH

C17

129.58

131.20

-1.62

0.988

129.38

131.15

-1.77

0.987

IC, Ph CH

C18

130.21

130.22

-0.01

0.999

127.08

130.37

-3.29

0.975

IC, Ph CH

C19

129.58

131.47

-1.89

0.986

130.20

131.47

-1.27

0.990

IC, Ph CH

C20

125.32

129.67

-4.35

0.966

126.37

130.06

-3.69

0.972

IC, Ph CH

C21

52.94

53.15

-0.21

0.996

52.42

56.09

-3.67

0.935

IC, c-hex CHN

C22

33.53

34.08

-0.55

0.984

-

-

-

-

IC, c-hex CH2

-

-

-

29.87

29.53

0.34

1.012

IC, t-but CH3

24.81

27.17

-2.36

-

-

-

-

IC, c-hex CH2

-

-

-

29.87

24.62

5.25

1.213

IC, t-but CH3

19.92

26.36

-6.44

-

-

-

-

IC, c-hex CH2

-

-

-

29.87

26.80

3.07

1.115

IC, t-but CH3

C25

19.92

26.50

-6.58

0.752

-

-

-

-

IC, c-hex CH2

C26

31.16

35.81

-4.65

0.870

-

-

-

-

IC, c-hex CH2

C23

C24

2

0.913 0.756 -

R

0.998

0.998

…†‡ˆ‰Š‡

0.957

0.995

H1

6.88

5.61

1.27

1.226

7.11

6.03

1.08

1.179 s, 1H, N-H

H2, H3, H4

3.92

3.53

0.39

1.110

3.85

3.55

0.3

1.085 s, 3H, OCH3

H5, H6 H7

3.93

3.64

0.29

1.080

3.96

3.65

0.31

1.085 s, 3H, OCH3

7.46-7.83

7.23-8.33

-

0.983

7.37-7.82

7.25-8.35

-

0.968 m, 5H, ArH

H8, H9, H10, H11,

23

H12 H13 H14, H15,

3.15

3.53

-0.38

0.892

-

-

-

-

m, 1H, NCH

1.41-1.68

1.02-1.94

-

1.047

-

-

-

-

m, 10H, CH2

-

-

-

1.48

1.01

0.47

H16, H17, H18, H19, H20, H21, H22, H23 H13, H14,

1.465 s, 9H, C(CH3)3

H15, H16, H17, H18, H19, H20, H21 R2

0.970

0.983

…†‡ˆ‰Š‡

1.057

1.156

468

469 470

Figure 8. 13C NMR values of synthesized compounds in the form of radar presentation to

471

showing a correlation between experimental and calculated values

472 473

3.4. Electronic absorption spectra

474

The electronic spectra were computed and TD-DFT excitations were calculated in the gaseous

475

phase. The PCM model was used to observe the transitions in the solvent phase. The predicted

476

UV-Vis spectra and electronic transitions of high oscillatory strength in gaseous phase, ethanol

477

and chloroform are shown in Table 4 and displayed good agreement with the observed spectra in

478

ethanol [47]. The weak and broad absorption bands were obtained at 359 and 282 nm for 24

479

compound I and at 353 and 271 nm for II showed satisfactory correlation with the TD-DFT

480

calculated transitions at 361 and 287 nm, with oscillator strength (f) of 0.3367 and 0.2285 for I

481

and II, 350 and 266 nm with 0.4423 and 0.0035 oscillator strength (f). These excitations

482

generally correspond to H→L and H→L+2 for compound I whereas H→L and H→L+4

483

electronic transitions for compound II (Table 4).

484

Table 4. Electronic transition calculated by TDDFT using B3LYP/CPCM method in gaseous

485

phase, ethanol and chloroform solvents Name

Phase

Gas

Comp. I

EtOH

CHCl3

Gas

Comp. II

EtOH

CHCl3

EExcitation

Osc. strength Calc. Excitation

Coefficient

Major transition

Assignment

Cont.*

(eV)

(f)

(nm)

%

3.6099

0.3152

343.45

0.70156

H(95) → L(96)

π → π*

98.44

4.1476

0.0032

298.93

0.67088

H(95) → L(97)

π → π*

90.02

4.3231

0.0015

286.79

0.67414

H(95) → L(99)

π → π*

90.89

3.4361

0.3367

360.83

0.70186

H(95) → L(96)

π → π*

98.52

4.1948

0.0064

295.56

0.63200

H(95) → L(98)

π → π*

79.88

4.3213

0.2285

286.92

0.64353

H(95) → L(97)

π → π*

82.83

3.4648

0.3635

357.84

0.70252

H(95) → L(96)

π → π*

98.71

4.3296

0.2387

286.36

0.60674

H(95) → L(97)

π → π*

73.63

4.8267

0.0008

256.87

0.68096

H(95) → L(101)

π → π*

92.74

3.7210

0.4037

333.20

0.69937

H(88) → L(89)

π → π*

97.82

4.6887

0.0639

264.43

0.66459

H(88) → L(95)

π → π*

88.34

4.7864

0.0011

259.04

0.67751

H(88) → L(93)

π → π*

91.80

3.5384

0.4423

350.40

0.70042

H(88) → L(89)

π → π*

98.12

4.6532

0.0035

266.45

0.65014

H(88) → L(93)

π → π*

84.54

5.0412

0.0037

245.94

0.64291

H(88) → L(94)

π → π*

82.67

3.5620

0.4735

348.08

0.70127

H(88) → L(89)

π → π*

98.36

4.5938

0.0206

269.89

0.58210

H(88) → L(92)

π → π*

67.78

4.9806

0.0002

248.94

0.69402

H(88) → L(94)

π → π*

96.33

486 487

3.5. FMO (Frontier Molecular Orbital)

488

The HOMO and LUMO are involved in the chemical stability of the molecule [43,45]. The

489

HOMO signifies the aptitude to donate an electron and LUMO signifies the tendency to gain

490

electron. The HOMO and LUMO energies have been computed using TD-DFT/B3LYP/6-

491

311++G(d,p) method. In the favor of the chemical hardness, the large HOMO-LUMO difference 25

492

represents a hard molecule and small HOMO-LUMO difference signifies a soft molecule. The

493

molecule with least HOMO-LUMO variations indicates its high reactivity. The HOMO-LUMO

494

energy difference was calculated in gaseous phase, in EtOH and CHCl3 respectively to present

495

the reactivity and kinetic stability of the molecules. The calculated energies were predicted by

496

the PCM model by TD-DFT/B3LYP method with 6-311++G(d,p) level. The HOMO-LUMO

497

energy difference computed by quantum chemical analysis revealed the chemical reactivity of

498

the compounds and defined the combined charge transfer interaction within the molecule, which

499

is necessary for the biological activity of a molecule. The positive and negative phases are

500

denoted by red and green colors respectively. HOMO-LUMO plots are shown in Figure 9. The

501

HOMO was delocalized on the furan and phenyl rings, carboxylate and amine group, whereas

502

the LUMO in compound II was mainly localized on the furan and phenyl rings and on the

503

carboxylate group (Table 5; Figure 9).

504 505

Table 5. HOMO-LUMO energies with HOMO-LUMO energy gap Comp. I (eV)

Comp. II (eV)

Activity ranking

Gaseous

Solvent

Solvent

Gaseous

Solvent

Solvent

(in Gas phase,

phase

(EtOH)

(CHCl3)

phase

(EtOH)

(CHCl3)

EtOH and CHCl3)

EHOMO

-5.3746

-5.5676

-5.5117

-5.4230

-5.5944

-5.5380

II > I

ELUMO

-1.3281

-1.6361

-1.5450

-1.2971

-1.5876

-1.4100

I > II

EGAP

4.0464

3.9315

3.9667

4.1328

4.0069

4.0380

II > I

506

26

507 508

Figure 9. Atomic orbital composition of the FMOs and their energy gap obtained from TD-

509

DFT/B3LYP/6-311++G(d,p) level in ethanol using PCM model

510 511

3.6. MEP (Molecular electrostatic potential) and MR (Molar refractivity)

512

The MEP recognizes the electrophilic and nucleophilic sites in a molecule and explains the

513

charge distribution on the basis of polarity in the molecular system depicted by the color

514

variations and offers findings in a pictorial form describing the virtual polarity of the molecule

515

[46]. The red and blue colors depict electrophilic and nucleophilic sites as displayed in the Figure

516

11. The color code was found in the range -9.812 (red) to +9.812 a.u. (blue) and -9.394 (red) to

517

+9.394 a.u. (blue) for compounds I and II. Electrostatic potential decreased in the order; blue >

518

green > yellow > orange > red. A high electropositive potential was observed in the vicinity of

519

the –COO group and a low electropositive potential was found near the nitrogen atom. The MEP

520

findings confirmed the occurrence of an intramolecular hydrogen bond between N8-H27····O10

521

in compound I and N8-H25····O10 in II (Figure 10).

27

522 523

Figure 10. MEP plot (A = 3D surface, B = transparent 3D surface and C = contour map) of the

524

synthesized compounds showing total density mapped with ESP

525 526

MR is another essential parameter used to analyze the polarizability of a material. It is

527

determined by molecular weight, refractive index, and density of the substance and represents

528

the interaction profile and lipophilicity of the system [7]. It is a constitutive-chemical parameter

529

and presented by the Lorenz-Lorentz Eq. (25). MR =

530

n2 n2

1 2

MW

ρ

= 1.333πN α

‹

(25)

531

where n is the refractive index; ρ is the density; MW is the molecular weight; (MW/ρ) is the

532

molar volume; N is the Avogadro number; α is the polarizability of the molecular system

533

depending on the wavelength of the light used to measure n. The values of MR were found to be

534

97.93 (I) and 88.98 (II) esu respectively.

535 536

Mulliken population analysis (MPA)

537

Mulliken atomic charge is a vital parameter for the theoretical prediction of the effect of atomic

538

charge in the molecular coordination, which is responsible for regulating structural confirmation

539

and bonding aptitudes. Mulliken atomic charge values were analyzed with the help of MPA

540

which was calculated with the help of DFT- B3LYP method using 6-311++G(d,p) as the basis

541

set and presented in Supplementary Table 1. All the carbon atoms were negatively charged

542

except C1 (0.17942), C2 (0.106861), C3 (0.286459), C15 (0.758823), C16 (0.116305) and C26

28

543

(0.244105) in compound I and C1 (0.030229), C3 (0.310579), C15 (0.793326) and C16

544

(0.248352) in compound II. These variations were due to the attachment with electronegative

545

atoms. All the hydrogens possessed positive charge between 0.13-0.20 in both the compounds

546

except H34 (0.06645) and H32 (0.49064) which possessed minimum positive charge because of

547

the attachment with positively charged ring C16 and H27 (0.412204) and H38 (0.23620) in

548

compound I, similarly H25 (0.489847) and H36 (0.227824) in compound II had highest positive

549

charge due to the involvement in the hydrogen bonding between N8 and O10. Furan ring O5

550

retained positive charge viz. 0.046307 for I and 0.07009 for compound II. Similarly ester (COO)

551

oxygen atoms had high negative charge O9 (-0.24503/-0.24577), O10 (-0.21049/-0.20442) and

552

O11(-0.19059/-0.19085) except O12 (0.011129/0.013615) in both the compounds. These

553

variations were observed due to resonance as well as hydrogen bonding but in case of O12

554

resonating effect was very low and hydrogen bonding was not observed. Furthermore, N8 had

555

positive charge 0.080607 (I) and 0.08116 (II). The occurrence of negative charge on oxygen

556

atoms and a positive charge on hydrogen atoms, nitrogen and oxygen (O12) may propose

557

intramolecular interaction.

558 559

3.7. Quantum chemical parameters

560

According to Koopman’s theorem [48], quantum chemical calculations can be done with the

561

energies of FMOs (HOMO and LUMO) such as the band gap energy (EGAP or ELUMO-HOMO).

562

Absolute electronegativity (), chemical potential (CP), chemical hardness (η), global softness

563

(S), electrophilicity index (ω), nucleophilicity index (N), chemical softness (σ), additional

564

electronic charges (∆N) and optical softness (σ˳) were calculated with the help of Eq. (1)-(12)

565

and given in Table 6. According to Parr et al. [49] ω is a global reactivity index related to the

566

chemical hardness and chemical potential of the molecule. HOMO is directly associated with the

567

ionization potential (I), higher the value of EHOMO higher would be the ionization and molecules.

568

Biological interactions increase with the increasing energy of HOMO. On the other hand energy

569

of LUMO is directly linked with the electron affinity (A) of the molecule, lower value of ELUMO

570

shows high electron accepting power. In terms of biological reactivity low value of ELUMO

571

displays high biological activity. EGAP is also a significant parameter to understand the biological

572

reactivity spectrum. Chemical hardness (η) and softness (σ) are used to analyze the behavior of

573

molecule within a biological system. Absolute electronegativity () and chemical potential (CP) 29

574

give significant information about the molecular system. Low value of absolute electronegativity

575

as well as high value of chemical potential denotes the delocalization of electrons in the

576

molecular system. Electrophilicity index (EI, ω) and nucleophilicity indexes (NI, N) are also

577

associated with the biological activity of a molecule. The reactivity of a molecule increases with

578

increased nucleophilicity index. Additional electronic charge (∆Nmax) and global softness (σ˳) are

579

other important parameters to predict the molecular behavior [50] (Table 6).

580

Table 6. Calculated quantum chemical parameters at B3LYP/6-311++G(d, p) level.

581

a

b

c

d

d’

Inter-I

Inter-II

Inter-III

Inter-IV

PPh3O

Comp. I

Comp. II

EHOMOI

-5.8993

-8.1330

-7.5176

-8.1029

-6.0232

-4.3875

-3.9780

-4.4465

-6.5413

-7.1328

-5.3746

-5.4230

ELUMOI

-1.1132

-2.8136

-1.7007

-0.4239

-2.3004

-1.9649

-2.9031

-3.4256

-1.5227

-1.2735

-1.3281

-1.2971

EGAPI

4.7861

5.3195

5.4569

7.6789

3.7227

2.4226

1.0748

1.0210

5.0185

5.8593

4.1097

4.1328



3.5063

5.4734

4.6091

4.2634

4.1618

3.1762

3.4406

3.9361

4.0320

4.2031

3.3397

3.3636

-3. 5063

-5.4734

-4.6091

-4.2634

-4.1618

-3.1762

-3.4406

-3.9361

-4.0320

-4.2031

-3.3397

-3.3636

I I

CP I

2.3931

2.6597

2.7284

3.8395

1.8614

1.2113

0.5374

0.5105

2.5093

2.9297

2.0548

2.0664

I

0.4179

0.3760

0.3665

0.2605

0.5372

0.8256

1.8608

1.9589

0.3985

0.3413

0.4867

0.4839

SII

0.2089

0.1880

0.1833

0.1302

0.2686

0.4128

0.9303

0.8267

0.1993

0.1707

0.2433

0.2420

I

2.5687

5.6318

3.8930

2.3671

4.6526

4.1642

11.0135

15.1749

3.2394

3.0150

2.7140

2.7376

II

0.3893

0.1776

0.2569

0.4225

0.2149

0.2401

0.0908

0.0659

0.3087

0.3317

0.3685

0.3653

1.4652

2.0579

1.6893

1.1104

2.2358

2.6221

6.4023

7.7102

1.6068

1.4347

1.6253

1.6278

η σ

ω N

∆NmaxI

582

I

583

II

584

a = Triphenylphosphine (PPh3),

585

b = Dimethyl acetylene-dicarboxylate (DMAD),

586

c = Benzoic acid

587

d = Cyclohexyl isocyanide

588

d’ = Tertbutyl isocyanide

in Ev; in eV-1

589 590

The interaction profile of the reacting groups with the intermediates and the target molecule on

591

the basis of quantum chemical parameters are shown in Figure 11.

592

The electrophilic and the nucleophilic behavior depend upon the values of EI and electrophilic

593

charge transfer (ECT). ECT is signified by the variance of the ∆Nmax of the interacting

594

molecules. When two molecules, 1 and 2 interact with each other, two conditions may arise: (i)

595

ECT > 0 then charge flows from 2 to 1 (ii) ECT < 0 then charge flows from 1 to 2.

30

596

Reactant a and b interacted together and the calculated value of ECT was -0.5928 eV,

597

showing that the mean charge flows from molecule a to b. Reactant a possessed a lower (2.5592

598

eV) value of EI as compared to the reactant b (5.6108 eV), showing its nucleophile nature upon

599

the generation of intermediate I. Reactant c attacks the intermediate I indicating the charge flow

600

form reactant c to intermediate I. Hence, reactant c is an electron donor while intermediate I

601

behaves as an electron acceptor to give highly unstable intermediate II which is converted to

602

intermediate III and Ph3PO. Reactant d attacks the intermediate III and charge flows from

603

reactant d to intermediate III producing intermediate IV. Reactant d shows high nucleophilicity.

604

At the end intermediate IV undergoes tautomerization followed by the aromatization to give the

605

final product. The energy gap between LUMO and HOMO represents the reactivity of the

606

interacting molecules. Intermediates were highly reactive as compared to the attacking reagents.

607

Intermediate IV was less reactive as compared to the final product, favoring the conversion

608

under the tautomerization with aromatization. From the above findings it is very clear that

609

quantum chemical parameters favor the proposed mechanism and additionally provide the

610

chemical reactivity profile of the target molecule to understand the behavior of molecule with

611

respect to biological targets (Figure 11).

612

31

613 614

Figure 11. 3D schematic representation of global electrophilicity index or global reactivity index

615

(ω) and additional electronic charge (∆N) from the surroundings

616 617 618 32

619

3.8. Natural population analysis (NPA)

620

The NPA reveals the stability of the compound and also depicts the electron distribution. The

621

natural charge from NPA and MPA were calculated using the DFT-B3LYP/6-311G++(d,p) data

622

set as displayed in Supplementary Table 1. The analysis showed that carbon atoms had a

623

negative charge except C1(0.60175/0.60256), C4(0.31368/0.30440), C6(0.78506/0.78493) and

624

C7 (0.81666/0.81611) in both the synthesized drivatives out of which C7 in both compounds

625

carried a highest positive charge showing greatest electropositive nature. Similarly, N8 (-

626

0.61315/-0.63172) displayed highest negative charge. O5(-0.49443/-0.49522), O9(-0.60603/-

627

0.60598), O10(-0.59651/-0.59640), O11(-0.59451/-0.59285) and

628

possessed negative charge but showed less electronegative nature as compared to N8 in both the

629

compounds. C7 in compound I, possessed slightly greater positive charge and N8 in compound II

630

possessed greater negative charge. All the hydrogen atoms in the compounds had positive charge

631

among which H27 (I) and H25 (II) acquired highest positive charge viz. 0.42156 and 0.42526,

632

due to the N8 atom and hydrogen bonding with O10.

O12(-0.53308/-0.53292)

633 634

3.10. Natural bond orbital analysis (NBO)

635

The NBO analysis has been performed to quantify resonance structure contributions to molecules

636

and provides an efficient method to study intramolecular charge transfer interactions and

637

delocalization of electron density within the molecule. The NBO analysis was carried out using

638

Gaussian NBO 3.1. The details are given in Supplementary Table 3. Through NBO complete

639

quantum mechanical description of the molecular structure can be predicted by a set of localized

640

bonds, antibonds and Rydberg extra valence natural atomic orbitals. The strength of hydrogen

641

bond can also be ascertained by using the second order perturbation theory. The NBO analysis

642

was performed at the DFT/B3LY/6-311++G(d,p) level.

643

The larger value of E(2) (stabilization energy or energy of hyper conjugative interaction),

644

shows the stronger donor-acceptor interaction. Consequently E(2) values can represent the bond

645

strength. The strength of delocalization interaction (or stabilization energy) for each donor

646

NBO(i) and the acceptor NBO(j) and E(2) associated with electron delocalization between the

647

donor and the acceptor is predicted by the second order energy Eq. (26):

648

() = −K

(HJŒ)

(26)

(Œ) (J)

33

649

Where Fij is the off-diagonal Fock-matrix elements, E(j)−E(i) is the difference in orbital energies

650

of the donor and the acceptor NBO orbitals and nσ is the population of the donor orbital.

651

The π-conjugation/resonance due to π-electron delocalization is complicated due to π→

652

π* interactions. However, the primary hyper-conjugation interaction is due to orbitals overlaps

653

like σ→π*, π→σ*, n→σ* and secondary hyper-conjugation interaction is due to the overlapping

654

of σ→σ* orbital. The electron density at the conjugated π bonds and π* bonds of phenyl ring

655

shows strong π-electron delocalization inside the ring, which is prominently represented by a

656

maximum stabilization energy (55.47 kcal/mol). The values of occupancy for σ and π bonding

657

NBOs are 1.94936-1.99500, 1.62506-1.98595 for compound I and 1.94949-1.99498, 1.62568-

658

1.98601 for compound II, respectively. The donor capacity of π bonding NBOs is considerably

659

higher than those of σ bonding. The π bonding NBO at C15-C20 has the lowest occupancy of

660

1.62506 and 1.62568 for both the compounds thereby retaining the strongest donor capacity

661

among all the bonding NBOs. Similarly higher occupancies of the anti-bonding NBOs lead to

662

stronger acceptor capacity. A significant interaction, associated with the resonance in the

663

molecule is the electron donation from oxygen atom n(2)O12 to π*C7-O11, important for the

664

high stabilization energy of 47.00 and 45.66 kcal/mol for both the compounds. This higher

665

energy displays hyper-conjugation inside the COO group. The atoms n(2)O9 share the energies

666

of 32.91 and 103.42 kcal/mol to σ* C6-O10 bonds. Similarly the atoms n(1)O10 and n(1)O12

667

share the energies of 3.33, 8.56, 7.15 and 3.78, 6.05, 6.36 kcal/mol to σ*N8-H28/N8-H25, σ*C6-

668

O9 and σ*C7-O11 bonds for compound I and II, respectively. The weak intra-molecular C-

669

H····O hydrogen bond is formed due to the orbital overlap between LP1 (O10) with σ*(N8-

670

H27/N8-H25) and LP1 (O11) with σ*(C20-H38/C20-H36) which increases ED that weakens the

671

particular bond leading to stabilization and resulting in energy viz. 3.33/3.78 kcal/mol and

672

7.15/6.36 kcal/mol for both the compounds. The increased electron density at the oxygen atoms

673

(O10 and O11) ultimately increases the elongation of the particular bond length and reduction of

674

consistent stretching in the vibration. Correspondingly LP1 (N8) does not undergo intra-

675

molecular interaction but it undergoes resonance which ultimately stabilizes the system by 58.31

676

and 54.26 kcal/mol for the two compounds. The hyper-conjugative interaction energy E(2) was

677

assumed to be calculated from the second-order perturbation method and is chemically important

678

for quantifying numerous intramolecular interactions (Table 7).

679

34

680

Table 7. Second order perturbation theory analysis of Fock matrix using NBO analysis for the

681

selected donor (Lewis) and acceptor (non-Lewis) orbitals.

Donor NBO (i)

Occupancy

Acceptor NBO (j)

Occupancy

(E2)a

E(j)-E(i)b

F (i,j)c

(kcal/mol)

(a.u.)

(a.u.)

D···A(Å)

A-H(Å)

D-H(Å)

D-H···A(°)

Comp. I (within unit 1) n(2)O9

1.83585

σ*O12-C14

0.01733

1.72

0.47

0.026

2.96652

1.43930

1.21160

92.17086

n(1)O10

1.96195

σ*N8-H27

0.02232

3.33

0.93

0.021

2.12455

1.01095

1.37836

109.12462

n(1)O11

1.97749

σ*C20-H38

0.01653

15.97

1.17

0.122

2.25925

1.08148

1.20961

100.90681

Comp. II (within unit 1) n(2)O9

1.83568

σ*O12-C14

0.01730

3.22

0.35

0.031

2.96733

1.43942

1.21166

92.28536

n(1)O10

1.96059

σ*N8-H25

0.02161

3.78

0.99

0.055

2.07619

1.01092

1.37827

108.23665

n(1)O11

1.97719

σ*C20-H36

0.01641

1.12

0.41

0.019

2.26477

1.08154

1.20955

101.07097

n(1)O5

1.96847

σ*C24-H45

0.00679

43.88

0.32

0.106

2.49149

1.08992

1.34730

99.14141

682 683

3.11. Thermodynamic calculations

684

Thermodynamic quantities were calculated with the help of vibrational frequency at ambient

685

temperature (298.15 K) and one atmospheric pressure. Evaluation of the spontaneity of the

686

reaction in the form of entropies (S), heat capacities (C), enthalpies (H), Gibbs free energies (G),

687

zero-point energy, entropy change of the reaction (∆SReaction) Gibbs free energy change

688

(∆GReaction) and enthalpy change (∆HReaction) were calculated (Table 8). For the reaction, the

689

Gibbs free energy change (∆GReaction), enthalpy change (∆HReaction) and entropy change

690

(∆SReaction) were negative predicting the spontaineity of the reaction (Table 8 and 9) [7,42].

691 692

Table 8. Calculated thermodynamic parametors Parameter

ZPV (Kcal/Mol) RC (GHZ)

RT (Kelvin)

a

b

170.90218 71.66053

c

d

d’

Ph3PO

Comp. I

Comp. II

71.89719 105.66239 82.31068 170.04524 252.55348 228.28996

0.35724

4.55114

3.77255

4.30349

6.25931

0.32736

0.22207

0.26485

0.34834

0.47076

1.21449

1.45994

3.88538

0.31803

0.15040

0.20235

0.20797

0.42900

0.97215

1.17559

2.65334

0.18725

0.09537

0.12192

0.01715

0.21842

0.18105

0.20653

0.30040

0.01571

0.01066

0.01271

0.01672

0.02259

0.05829

0.07007

0.18647

0.01526

0.00722

0.00971

0.00998

0.02059

0.04666

0.05642

0.12734

0.00899

0.00458

0.00585

129.228

101.541

83.714

76.911

71.269

129.999

176.710

170.941

S (Cal/MolKelvin) Total

35

Translational

42.590

40.764

40.312

39.977

39.165

42.767

43.513

43.287

Rotational

33.784

28.860

28.669

28.167

26.013

34.066

35.866

35.152

Vibrational

52.853

31.918

14.733

8.767

6.091

53.166

97.331

92.502

Total

62.361

35.486

27.174

23.642

17.599

71.757

92.823

90.346

Translational

2.981

2.981

2.981

2.981

2.981

2.981

2.981

2.981

Rotational

2.981

2.981

2.981

2.981

2.981

2.981

2.981

2.981

Vibrational

56.399

29.524

21.212

17.681

11.638

65.795

86.861

84.385

Total

180.753

78.327

76.321

109.259

85.328

180.830

268.175

243.679

Translational

0.889

0.889

0.889

0.889

0.889

0.889

0.889

0.889

Rotational

0.889

0.889

0.889

0.889

0.889

0.889

0.889

0.889

Vibrational

178.976

76.549

74.544

107.482

179.052

266.398

CV (Cal/MolKelvin)

E (KCal/Mol)

693

a = Triphenylphosphine (PPh3),

694

b = Dimethyl acetylene-dicarboxylate (DMAD),

695

c = Benzoic acid

696

d = Cyclohexyl isocyanide

697

d’ = Tertbutyl isocyanide

83.551

241.901

698 699

Table 9. Calculated thermodynamic properties Parameters

Gibbs free energy Enthalpy (H)

Entropy (S)

(G) (kcal/mol)

(kcal/mol)

(a.u.)

a

-650260.9945

-650222.4659

-1036.222790

b

-334557.1169

-334526.8423

-533.119525

c

-264085.0981

-264060.1392

-420.818954

d

-205840.1712

-205817.2403

d’

-156996.0649

PPh3O

∆G Reaction ∆H Reaction ∆S Reaction (kcal/mol)

(kcal/mol)

(a.u.)

-328.000711

-3.8958/

-29.1447/

-0.047532/

-156974.8158

-250.163626

-275.7271

-301.014

-0.48134

-697435.5186

-697396.7596

-1111.402076

Comp. I

-757311.7582

-757259.0731

-1206.807436

Comp. II

-708739.4825

-708688.5174

-1129.404159

700

a = Triphenylphosphine (PPh3),

701

b = Dimethyl acetylene-dicarboxylate (DMAD),

702

c = Benzoic acid

703

d = Cyclohexyl isocyanide

704

d’ = Tertbutyl isocyanide

36

705 706

3.12. Non-linear Optical Properties

707

DFT has been used to study the Non-Linear Optical (NLO) properties of organic materials.

708

Theoretical analysis of hyper-polarizability is a measure to assess the NLO properties. NLO

709

parameters such as static dipole moment (µ0), mean polarizability (α0), anisotropy of

710

polarizability (∆α) and first hyper-polarizability (β0) were calculated for the aminofuran

711

derivatives for exploring their NLO properties as they have a proton acceptor carboxylate group

712

(COO) and the proton donor amine group (NH). The values are given in Table 10. The α0, ∆α,

713

and β0 values were 3.1991×10-23, 1.2289×10-22, and 1.0175×10-29 esu. for compound I and

714

3.1368×10-23, 1.1119×10-22, and 1.8767×10-29 esu. for compound II. The calculated results

715

indicated that the aminofuran derivatives might possess appreciable NLO properties (Table 10).

716 717

Table 10. Calculated NLO of the synthesized compounds, urea and 4-aminosalicylic acid (ASA) Comp. I

Comp. II

Urea

esu (x10 )

a.u.

esu (x10 )

a.u.

esu (x10 )

a.u.

esu (x10-24)

µx

5.3429

-

3.7076

-

0.0016

-

0.3872

-

µy

1.1767

-

-2.3728

-

-4.6790

-

4.8909

-

µz

2.1709

-

-1.1310

-

0.0441

-

0.1011

-

I

5.8859

-

4.5448

-

4.6793

-

4.9073

-

αxx

316.840

46.9557

322.059

47.7291

20.5379

3.0438

57.450

8.5141

αyy

-12.5921

-1.8661

24.6035

3.6424

-0.0005

-7.41

0.5032

0.0746

αzz

343.334

50.8821

288.320

42.7290

21.270

3.1522

86.68

12.8460

αxy

7.9104

1.1723

-8.73025

-1.2938

0

0

0

0

αyz

1.9944

0.2956

12.2443

1.8146

0

0

0

0

αzx

177.717

26.3377

163.164

24.1809

17.3283

2.5681

39.6086

5.8700

α0

215.861

31.9906

211.6608

31.3681

13.9361

2.0653

48.211

7.1449

∆α

829.2487

122.8947

750.2383

111.1853

76.4347

11.3276

184.3937

27.3271

-33

-24

ASA

a.u.

µ0

-24

-33

esu (x10 )

-24

-33

esu (x10 )

esu (x10-33)

esu (x10 )

βxxx

561.665

4852.2239

-1921.13

-16596.642

-0.0509

-0.4397

344.66

2977.5177

βxyy

588.575

5084.6994

-369.268

-3190.1063

13.8407

119.5698

-232.14

-2005.4575

βxzz

1101.39

9514.9082

181.931

1571.7019

0.0690

0.5961

387.71

3349.4267

βyyy

415.307

3587.8372

472.860

4085.0375

-47.993

-414.6115

-1209.58

-10449.5616

βyzz

58.4713

505.1336

-18.7979

-162.3951

0.0157

0.1356

0.2549

2.2021

βyxx

4.2944

37.0992

66.0369

570.4928

0.0817

0.7058

-0.0210

-0.1814

37

βzzz

44.2845

382.5738

63.2461

546.3831

0.1557

1.3451

-0.4821

-4.1649

βzxx

14.1331

122.0959

14.8382

128.1872

-0.0058

-0.0501

136.412

1178.4633

βzyy

53.3204

460.6349

-55.6560

-480.8122

-39.512

-341.3442

-133.792

-1155.8291

18767.2245

63.525

548.7925

925.856

7998.4700

-

0.1862

-

0.3121

-

β0˳ σ˳

2304.5339 19908.8684 2172.3839

II

0.2471

-

0.2420

718 719

3.13. AIM analysis

720

The presence of hydrogen bond could be reinforced by Koch and Popelier principles based on

721

‘Atoms in Molecules’ theory [51]. The point with the lowest value of the electron density

722

(minimum along the path) on the bond path at a particular point is known as the bond critical

723

point (BCP). (i) The presence of a bond critical point for the proton (H)-acceptor (A) interaction

724

acts as a validation for the presence of hydrogen bonding interaction; (ii) The assessment value

725

of electron density ρ (H····A) should be in the range of 0.002-0.040 a.u. and (iii) the

726

corresponding Laplacian ∇2ρ(BCP) should be within the range of 0.024-0.139 a.u. if the

727

hydrogen bond is formed. The H-bond interactions rendering may be categorized as follows: (1)

728

Strong H bonds are considered by ∇2ρ(BCP) < 0; H(BCP) < 0; ε HB > 24.0 kcal/mol and their

729

conventional covalent character; (2) Average H-bonds are considered by ∇2ρ(BCP) > 0; H(BCP)

730

< 0; 12.0 < εHB < 24.0 kcal/mol and their partially conventional covalent character; (3) Weak H-

731

bonds are classified by ∇2ρ(BCP) > 0; H(BCP) > 0; εHB > 12.0 kcal/mol and they are generally

732

electrostatic and the distance between interacting atoms is greater than the sum of their van der

733

Waals radii. ∇2ρ(BCP) is associated with the energy of bond interaction by the Virial theorem

734

Eq. (27):

735 736

 Ž

  (1‘# ) = (1‘# ) + ’(1‘# ) = (1‘# )

(27)

Where G(rBCP) is the kinetic energy density, ρ(rBCP) the electron density, H(rBCP) the total

737

electron density and V(rBCP) potential energy density at the bond critical point (BCP).

738

Table 11. Geometrical parameters (bond length) and topological parameters for bonds of

739

interacting atoms: ellipticity (“ ), electron density ”(BCP), Laplacian of electron density ∇2ρ(BCP),

740

electron kinetic energy density G(BCP), electron potential energy density V(BCP), total electron

741

energy density H(BCP) at bond critical point (BCP) and estimated interaction energy (Eint.)

742

(kcal/mol) of the synthesized compounds Interaction BLa (Å) Ellipticity

ρ (BCP)

∇2ρ BCP)

G(BCP)

38

V(BCP)

K(BCP)

L(BCP)

H(BCP)

Eint

(Ɛ)

(a.u.)

(a.u.)

O11····H38 2.25925 0.014249 0.048996 0.010514 Comp. I

(a.u.)

743

(a.u.)

O10····H27 2.12455 0.045038 0.018669 0.072952 -0.072286 -0.013359 -0.002440 -0.018238 O9····O12

a

(a.u.)

-0.00878 -0.072286 -0.001735 -0.012249

2.96652 0.456419 0.009331 0.032323

-0.0074

(a.u.)

(Kcal/mol)

-0.081066 -22.67984 -0.085645

-4.19141

-0.00672 -0.000681 -0.008081

-0.01412

-2.10841

-0.0087

-0.001709 -0.012117

-0.019108

-2.72964

O10····H25 2.07619 0.045038 0.018669 0.072952 -0.015798 -0.013359 -0.002440 -0.018238

-0.029157

-4.19141

O9····O12

-0.01412

-2.10841

O11····H36 2.26477 0.075231 0.014134 0.048467 -0.010408 Comp. II

(a.u.)

2.96733 0.456419 0.009331 0.032323

-0.0074

-0.00672 -0.000681 -0.008081

BL = Bond length

744 745

The molecular graph using AIM program at DFT-B3LYP/6–311++G(d,p) method is presented in

746

Figure 12. Geometrical and topological factors for H-bonds among interacting atoms are shown

747

in Table 11. The different interactions envisioned in the molecular graph are categorized by

748

geometrical, topological and energetic properties. Here the QTAIM theory has been applied to

749

assess hydrogen bond energy (E). The proportionality between E and VBCP at H···O contact is E

750

= ½(VBCP). The calculated interaction energy at BCP shows that three intermolecular H-bonds

751

O11····H38, O10····H27 and O9····O12. On the basis of these parameters, O11····H38 and

752

O10····H27 are considered as medium hydrogen bonds (Table 11; Figure 12).

753 754

Figure 12. Molecular graph of compounds at DFT-B3LYP/6-311G++(d,p) method using AIM

755

program: bond critical points (small green spheres), ring critical points (small red sphere), bond

756

paths (dark grey lines).

757 758

3.14. Theoretical IC50 % values calculated by quantum chemical parameters (QCPs)

759

Quantum chemical parameters can be used to evaluate the biological activity with the help of the

760

energies of FMOs (HOMO and LUMO), energy gap (EGAP or ELUMO-EHOMO), absolute

761

electronegativity (), chemical potential (CP), chemical hardness (η), global softness (S),

762

electrophilicity index (ω), nucleophilicity index (N), chemical softness (σ), additional electronic

763

charges (∆N), optical softness (σ˳), total negative charge of heteroatoms (TNC) and total energy 39

764

(ETotal) [30,50,52]. Theoretical IC50 % values of the synthesized derivatives were calculated with

765

the help of QCPs using the DFT-B3LYP/6-311G++(d,p) method in gaseous phase as given in the

766

Table 6. Both derivatives were active against A549 with the IC50% of 6.07 and 6.28 respectively.

767 768

3.15. Molecular Docking analysis

769

AutoDock 4.2.6, AutoDock Vina 1.1.2 and iGEMDOCK 2.1 were used to study the interaction

770

profile of synthesized compounds with the cytoskeleton target proteins. Results of molecular

771

docking are summarized in Table 12. Against the three target proteins Cor1C, eEF1A2 and villin

772

docking results were obtained with respect to the binding energy and dissociation constant (Kd).

773

Physiological ligands such as ATP (Adenosine triphosphate), PDS-4-P (Phosphatidylinositol-4-

774

phosphate) and SLS (Sodium lauryl sulfate) were selected for comparing the binding modes.

775

Docking results showed that compound I showed good interaction as compared to compound II

776

against all the targets. 2cHAPF exhibited minimum binding energy (-5.04, -7.5 and -112.77

777

kcal/mol) with respect to Cor1C. Compound I and II had Kd values equal to 203.21 µM and

778

635.47 µM respectively as predicted by AutoDock.

779

ATP showed the minimum binding energy viz. -7.8 and -168.9 against Cor1C, -7.6 and -

780

131.79 against eEF1A2 and -6.4 and -130.36 kcal/mol against villin. PDS-4-P and SLS exhibited

781

comparatively low binding affinity (PDS-4-P: -6.5 and -91.85 against Cor1C, -7.1 and -113.20

782

against eEF1A2, -5.1 and -113.76 kcal/mol against villin; SLS: -5.1 and -91.71 against Cor1C, -

783

5.0 and -86.44 kcal/mol against eEF1A2, -5.2 and -66.28 kcal/mol against villin). Docking

784

results showed that the compounds possessed good interaction ability which were lower than

785

ATP and higher than PDS-4-P and SLS. The results have been given in Table 12; Figure 13.

40

786 787

Figure 13. Schematic representation of ligand target interactions obtained from AutoDock Vina

788 789

Table 12. Binding energies obtained from various docking tools with suitable interacting amino

790

acids of the synthesized compounds and physiological ligands Comp.

Target

Comp. I

AutoDock Vina BEa

Kib

-

203.2

5.04

1

-

635.4

4.36

7

BE

-7.5

iGEMDOCK

Interacting amino acids

TEc VDWd HBe Ele.f 112.77

-99.17

13.59

0

HB

VAL41, TYR319

-6.6

102.27

-79.42

22.85

Other

SER37, CYS39, ASN42, ASP87,

ALA40, PRO90,

TRP88, PHE272, TYR273, ASP274, MET320, PRO321, PRO275

Cor-1C Comp. II

VDW

ALA40, VAL41, ASN42, ASP87, 0

TYR319

TRP88, TYR273, ASP274, PRO275, GLY318, LYS322, ARG323

41

LYS322 PRO90, MET320, PRO321

ATP

-

-

-7.8

-168.9

-

-

108.49 60.94

0.53

GLN22, LEU63,

VAL18, TYR24, HIS64, THR66,

GLY324, LEU325,

ARG323, VAL327, PHE336,

ARG334, LEU390,

PRO345, HIS392, GLY393, TYR394,

LYS391

PDS-4-P

-

SLS

-

Comp. I

Comp. II

ATP

eEF1α2

PDS-4-P

-

-

-

391.5

4.65

6

-

522.0

4.48

9

-

-

-

-

-6.5

-5.1

-7.0

-6.8

-7.6

-7.1

-91.85 -84.56 -7.29 0

-91.71 -65.79 -18.9

-

-

107.93 104.14 105.49 131.79

-

7.02

-

113.20 105.86

-

-

-5.0

ARG184, ALA366

-

Comp. II

720.9

4.29

2

-

806.3

4.22

6

-6.1

-3.79 0

51.08

0.6

-7.34 0

-86.44 -72.78 -10.5 -3.2

-5.5

101.80 101.73

-95.88 -5.92 0

-76.90

-

GLY318, PRO321, ARG323

ASP93, ASP274, PRO275, ASP276,

-

TYR319, LYS322, ARG323, THR365

PHE190, LYS215,

24.83

0

TYR167, ASP168, SER175, PRO185, VAL171, TRP210

TRP214

VAL188, PHE211, LYS212, GLY213

SER175, ALA186,

TYR167, LYS172, VAL188,

VAL171, PRO185, PHE190

LYS215

PRO189, TRP214, VAL216, GLU217

HIS7, ASN9, SER107,

LEU77, LYS79, TYR86, THR88,

GLN108, ARG240,

THR106, GLY305, ASP306,

ARG266, ARG423

ASN307, PRO420

HIS7, ASN9, SER107,

ILE8, GLY105, THR106, GLN108,

ARG240, ARG266,

ASP110, PRO241, PRO304, GLY305,

GLU268, ARG423

PRO420

GLN108, ARG266, ARG423

Comp. I

PRO90, ASP93, PHE272, MET317,

CYS42, TRP88, CYS89, PRO90,

ASN9, SER107, SLS

CYS39, ASN42, ILE86, TRP88,

ALA186, PRO189,

-98.55 -6.95 0

-81.34

PRO396

SER37, ALA40, VAL41, CYS89, TYR319

-

ARG620

ARG620

ASP110, GLU268

-

THR106, LEU143, PRO241, PRO419,

-

PRO420

ILE617, THR618, ASP653, ARG689

ILE617, THR618, ASP653

LEU615, TRP655, PRO686 LEU615, TRP655, PRO686

ILE617, THR618, ATP

Villin

-

-

-6.4

130.36

-75.84

-

-

44.92 9.60

ARG620, PRO637, ASP638, ASP653,

VAL616, PRO619, LEU621, ILE636, GLU635, PRO686, PHE639, TRP655

ARG689

TYR681 PDS-4-P

-

-

-5.1

SLS

-

-

-5.2

113.76

-85.73

-66.28 -66.28

28.03 0

0

0

PHE631, ALA633,

PHE622, LEU632, THR634,

THR677

GLU635, ALA678, TYR681, HIS685

TYR681, PRO686,

LEU615, VAL616, ILE617, THR618,

ARG689

PRO619, ASP653, VAL654

GLU680

ARG620, TRP655

791

a

BE (Kcal/Mol) = Binding Energy, bKd (µM) = Estimated dissociation constant, cTE (Kcal/Mol) = total binding

792

energy, dVDW (Kcal/Mol) = Van Der Waals force energy, eHB (Kcal/Mol) = Hydrogen bond energy, fEle.

793

(Kcal/Mol) = Electrostatic interection enrgy, PDS-4-P = Phosphatidylinositol-4-phosphate, SLS = Sodium lauryl

794

sulfate,

795 796

3.16. ADMET and druglikeness

42

797

ADMET profile of amino furan derivatives I and II and standard reference drug regorafenib was

798

assessed using PreADMET database. The compounds were predicted to have mild blood brain

799

barrier crossing ability and Caco-2 permeability. They were found to have good human intestinal

800

absorption ability, whereas the reference drug had low HIA ability. Plasma protein binding

801

(PPB) ability of the compounds was strong, whereas the standard drug had low PPB ability. The

802

compounds obeyed the drug filter rules. Buffer solubility of the compounds was higher than the

803

reference drug. Synthesized compounds possessed good druglikeness as well as ADMET

804

properties.

805 806 807 808

Table 13. Shows the relative ADMET profiles of the synthesized compounds (as obtained from

809

PreADMET server). ADMET Properties

Comp. I

Comp. II

Regorafenib

0.0595959

1.14661

1.31554

24.0348

25.1779

22.4366

96.746707

96.456056

93.518216

2.96938

19.5756

0.0796041

95.701004

96.762436

-2.49797

-3.2424

-2.62538

91.051013

0.783468

6.86863

0.205199

BS

6.20128

21.229

2.68205

CYP-2C19 inhibition

Non

Non

Non

CYP-2C9 inhibition

Non

Non

Inhibitor

CYP-2D6 inhibition

Non

Non

Non

CYP- A4 inhibition

Non

Non

Non

CYP-2D6 substrate

Non

Non

Non

CYP-3A4 substrate

Non

Inhibitor

Weakly

Carcinogenicity in Rat

Positive

Positive

Negative

Positive

Positive

medium_risk

medium_risk

BBB

a

Caco2

b

HIA%

c

MDCK PPB%

d

e

SPf PWS

g

i

Carcinogenicity in Mouse Negative j

hERG (Inhibition) k

medium_risk Qualified

Qualified

Qualified

Drug like

Mild

Mild

Suitable

Suitable

Suitable

WDI like rule

In 90% cutoff

In 90% cutoff

In 90% cutoff

Ghose Filter

Qualified

Qualified

2 Violations

Veber’s rule

Suitable

Suitable

Suitable

CMC-50 like rule MDDR like rule Lipinski’s rule m

l

43

Bayer filter

Qualified

Qualified

Qualified

810 811

3.17. Free radical scavenging activity

812

The radical-scavenging aptitude of an antioxidant is assumed to be linked with its hydrogen

813

donating capacity [53,54]. NBO analysis provides an insight to the possible sites in the molecular

814

system where radical formation is possible [55,56]. The prediction of bond dissociation energies

815

(BDE) of existing –OH/-NH groups supports the antioxidant potential of the molecular system.

816

Minimum BDE favors the maximum antioxidant property. BDE of NH was observed to be 24.81

817

and 24.63 kcal/mol for compound I and II respectively with the bond order 0.96676 and 0.96642.

818

To validate the docking results experimental free radical scavenging activity was also evaluated

819

at different concentrations (25, 50, 75 and 100 µM). Both compounds exhibited significant

820

antioxidant activity in the tested range of 25-100 µM. The compound compound I showed the

821

highest scavenging activity 39% at 100 µM concentration (Table 14; Figure 15).

822 823

Table 14. Free radical scavenging or antioxidant activity of the synthesized compounds

824 Compounds

%age Inhibition

%age Inhibition

%age Inhibition

%age Inhibition

(25 µM)

(50 µM)

(75 µM)

(100 µM)

Comp. I

12

21

28

39

Comp. II

11

19

27

37

825

44

826 827

Figure 15. Free radical scavenging dose response curves of synthesized compounds in the range

828

25-100 µM. Results were expressed as mean ± SD of treatments done in triplicates.

829 830

4.

Conclusion

831

The aminofuran derivatives (dimethyl 2-(cyclohexyl-amino)-5-phenylfuran-3,4-dicarboxylate (I)

832

and dimethyl 2-(tert-butyl-amino)-5-phenylfuran-3,4-dicarboxylate (II) were synthesized and

833

structural characterization was done through various spectroscopic techniques. DFT was used to

834

optimize the structure of the compounds and to validate the experimental spectral data. The

835

charge distribution analysis and molecular electrostatic potential depiction of compounds showed

836

the intramolecular N-H····O and C-H····O interactions within the molecule. The NBO

837

investigation supported the inter charge transmission in the synthesized compounds. The first

838

hyperpolarizability specified that compounds may find applicability as NLO material. Small

839

HOMO-LUMO energy gap (∆E) and theoretical IC50 % values against the A549 cancer cell line

840

exhibited the bioactivity of the compounds. QTAIM method exposes the weak molecular

841

interactions and π-character of bond in aromatic rings. The lower value of ellipticity showed

842

strong delocalization of electrons within the molecular system. In silico ADMET and

843

druglikeness evaluation revealed the drug like the behavior of the compounds. Docking results

844

showed the biological interaction of comp. I and II with the target proteins. The compounds

845

showed good but lower interactions as compared to the physiological ligand ATP whereas better 45

846

interaction was obtained as compared to the other physiological ligands PDS-4-P and SLS.

847

Druglikeness was evaluated using different rules to calculate oral which can lead to a path of

848

development of novel and safe drugs.

849 850

Acknowledgements

851

The authors are thankful to Dr. Syed Mohd. Danish Rizvi and YA lab for helping in data

852

analysis. We thank the Bioinformatics Resources & Applications Facility, at CDAC. The authors

853

are also thankful to the R & D wing of Integral University, Lucknow, India and Department of

854

Chemistry, University of Lucknow, Lucknow, India for the facilities to carry out research work.

855 856

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Reference#: MOLSTRUC-D-19-01277 Submission Title: Synthesis, quantum chemical study, AIM simulation, in silico ADMET profile analysis, molecular docking and antioxidant activity assessment of aminofuran derivatives The authors declare they have no competing interests. Dr. Malik Nasibullah Corresponding author