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Letters in Drug Design & Discovery, 2016, 13, 982-991

RESEARCH ARTICLE

Design, Synthesis and Molecular Docking Studies of 2-Aryl/HeteroarylEthyl 6-Chloroquinoline-4-Carboxylates as Potential Antimalarial Agents Thamatakallu O. S. Kumara, Kittappa M. Mahadevana,*, Pasura S. Sujanganapathyc and Manikyanahally N. Kumarad a

Department of Post Graduate Studies and Research in Chemistry, School of Chemical Science, Kuvempu University, Shankaraghatta-577451, Karnataka, India; bCentre for Advanced Studies in Biosciences, Jain University, Bangalore560024, Karnataka, India; cDepartment of Chemistry, Yuvaraja’s College, University of Mysore, Mysore-570005, Karnataka, India

ARTICLE HISTORY Received: August 10, 2015 Revised: July 03, 2016 Accepted: July 14, 2016 DOI: 10.2174/1570180813666160722112 725

Abstract: In an effort to develop a lead antimalarial compounds, a series of novel 2-aryl/heteroaryl-ethyl-6-chloroquinoline-4-carboxylate derivatives (2a-j) were obtained by using quinoline-4-carboxylic acid derivatives which were produced by a simple one-pot synthesis of Pfitzinger reaction of isatin with Arylketones as intermediates which were finally esterified with ethanol in the presence of concentrated sulfuric acid to get the expected ethyl-6-chloro-2-(furan-2-yl)quinoline-4carboxylates (2a-j) with good to excellent yields. All the crude products were purified by column chromatography using silica gel (60-120 mesh, petroleum ether: ethyl acetate, 9:1 v/v), to furnish analytically pure 2-aryl/heteroaryl-ethyl-6K. M. Mahadevan chloroquinoline-4-carboxylates (2a-j). Additionally, the structures of the products were confirmed by spectral analysis such as 1H NMR, 13C NMR and LCMS analysis. As Molecular docking results illustrates, the most potent ligands among the synthesized compounds are 2j and 2h. The ligand Ethyl-2-(anthracen-9-yl)-6-chloroquinoline-4-carboxylate (2j) derivative interacts with FTase receptor at the binding sites located within the active site amino acids such as ARG291, LYS294 with binding energy -10.11 kcal/mol, docking energy -11.78 kcal/mol and inhibition constant Ki= 3.88e-008 M respectively. The another ligand 2h was also shown strong binding interaction with active site HIS248, ARG291and ARG291 with binding energy of -9.81 kcal/mol docking energy -11.27 kcal/mol and inhibition constant Ki=6.5e-008 mM respectively. In the same way ligands 2a, 2b, 2d and 2i forms four hydrogen bonding interaction with amino acids having binding energy -6.72, -6.54, -6.87 and-8.02 kcal/mol respectively, indicates more potent inhibitors of farnesyltransferase receptor. With this it was concluded that the compounds 2a-j were found to be a potent and selective FTase antagonist inhibitors.

Keywords: 2-aryl/heteroaryl-ethyl6-chloroquinoline-4-carboxylates, antimalarial, molecular docking, farnesyltransferase, lipinski, ADMET. 1. INTRODUCTION Quinoline has become the most prevalent N-hetero aromatic compound possessing significant pharmaceutical and pharmacological activities [1-6]. The structural modifications on the quinoline scaffolds are known to possess antimalarial properties; few are chloroquine and amodiaquine, which are well-known antimalarial drugs (Fig. 1) [7]. There are several 7-chloroquinolines [8, 9] and analogues of quinolyhydrazones, hydrazides and sulfonylhydrazides [10] exhibited higher potency of antimalarial activity against both chloroquine-resistant and chloroquine-sensitive strain of P. falciparum parasite. Moreover, the 7-chloroquinolinyl derived amides, sulfonamides, ureas and thioureas [11] were found to be potent

*Address correspondence to this author at the Department of Chemistry, Kuvempu University, P.O. Box: 577-451, Shankaraghatta, India; Tel: +919164621170; E-mail: [email protected] 1570-1808/16 $58.00+.00

antimalarial agents. Hence, due to their biological significance, a number of methods for the synthesis of quinolines have been reported [12-15]. Hence, the Pfitzinger reaction of 5-chloroisatin with various substituted acetophenones was used for the synthesis of some novel 2-aryl/heteroaryl-6-chloroquinoline-4carboxylic acids [16]. These 2-aryl/heteroaryl-6-chloroquinoline-4-carboxylic acids were found to be useful precursors to obtain corresponding 2-aryl/heteroaryl-6-chloroquinoline-4-carboxylates by esterification reaction using concentrated sulphuric acid with ethanol. In testimony of our study on 6-chloroquinoline-4-carboxylates, we found that the various 6-chloroquinolines were also reported as most active against falciparum (Fig. 2) [17]. Hence, based on the wider application of chloroquinoline moieties and in continuation of our effort to identify new quinoline based therapeutic agents [18-29], in the present investigation we report one pot synthesis of novel 2aryl/heteroaryl-ethyl-6-chloroquinoline-4-carboxylates (2a-j) ©2016 Bentham Science Publishers

Design, Synthesis and Molecular Docking Studies

Letters in Drug Design & Discovery, 2016, Vol. 13, No. 9

H3C H3C

983

OH

CH3 N NH

HN N

Cl

N chloroquine

Cl

N

CH3

CH3

amodiaquine

Fig. (1). Chemical structure of well-known anti-malarial drugs. Ph Cl

CO2Et

N

R=

R

CH3

N ,

Fig. (2). 6-Chloroquinolins falciparum inhibitors.

by esterification of 2-aryl/heteroaryl-6-chloroquinoline-4carboxylic acids (1a-j) using concentrated sulphuric acid in ethanol. We also performed molecular docking studies in order to understand how various 2-aryl/heteroaryl-ethyl-6chloro-quinoline-4-carboxylates interact with farnesyltransferase (FTase) receptor protein which enables to explain the differences in their activity. The characterization data of various 2-aryl/heteroaryl-ethyl-6-chloroquinoline-4carboxylates (2a-j) are presented in spectral data section. 2. MATERIALS AND METHODS The TLC was performed to monitor the progress of reactions using on alumina silica gel 60 F254 (Merck). The mobile phase was hexane and ethyl acetate (9:1 v/v) and detection was made using UV light (254 nm). Melting points of the synthesized compounds were determined by electrothermal apparatus in open capillaries and are uncorrected. The 1 H NMR and 13C NMR spectra were recorded on Brucker (Bangalore, India) AM 400 (at 400 and 100 MHz, respectively) model spectrophotometer in CDCl3 or DMSO-d6 as solvent. Chemical shifts were expressed as  values relative to TMS as internal standard. Mass spectra was recorded on a Jeol SX 102=DA-6000(10 kV) mass spectrometer. 2.1. Chemistry Typical Procedure for the Synthesis of ethyl-6-chloro-2(furan-2-yl)quinoline-4-carboxylate (2a) A mixture of 6-chloro-2-(furan-2-yl)quinoline-4carboxylic acid (1.0g, 0.003 mol) and absolute EtOH (15 ml) was stirred at 0-5oC. The concentrated sulfuric acid (2-3ml) was added drop wise into the flask until the powdered 6chloro-2-(furan-2-yl)quinoline-4-carboxylic acid was completely dissolved and the solution was then refluxed for 15 hr. The completion of the reaction was monitored by thin layer chromatography [hexane and ethyl acetate (9:1 v/v)]. The reaction mixture was poured into crushed ice (100 mL),

the precipitate was collected by filtration, washed with water and EtOH, dried under vacuum to afford crude product. The crude product was purified by column chromatography using silica gel (60-120 mesh, petroleum ether: ethyl acetate, 9:1 v/v) furnished analytically with pure ethyl-6-chloro-2-(furan2-yl) quinoline-4-carboxylate (2a), yield 80%. All other derivatives (2b-j) were obtained similiarly. 2.2. Spectral Data Ethyl-6-chloro-2-(furan-2-yl)quinoline-4-carboxylate (2a) Elution from silica using 10% ethyl acetate in hexane afforded the title compound (2a) as a brown solid, Yield= 85%. MP=115-120oC. 1H NMR (400 MHz, DMSO-d6): =8.62 (d, J=2.40 Hz, 1H), 8.31 (s,1H), 8.06(d, J=8.80 Hz,1H), 7.99 (d, J=1.20 Hz, 1H), 7.83 (ddd, J=2.40, 9.20, Hz, 1H), 7.45(d, J=3.20 Hz,1H), 6.75-6.76 (m, 1H), 4.48 (q, J=7.20 Hz, 2H), 1.41 (t, J=6.80 Hz, 3H) ppm. 13C NMR (100 MHz, DMSO-d6) =13.93 (CH3), 62.00 (CH2), 111.75 (CH), 112.82 (CH), 119.02 (CH), 123.62 (CH), 124.08 (C), 130.86 (CH), 131.26 (CH), 132.31 (C), 134.69 (C), 145.71 (C), 146.76 (CH), 148.27 (C), 151.92 (C), 164.81 (C=O) ppm. MS. m/z =301.90 (M+). Ethyl-6-chloro-2-(5-methylfuran-2-yl)quinoline-4carboxylate (2b) Elution from silica using 10% ethyl acetate in hexane afforded the title compound (2b) as a pale yellow solid, Yield= 90%. MP=95-100oC. 1H NMR (400 MHz, CDCl3): =8.73 (d, J=2.40 Hz, 1H), 8.22 (s, 1H), 8.03 (d, J=8.80 Hz, 1H), 7.62 (d, J=2.40 Hz, 1H), 6.83 (d, J=2.00 Hz, 1H), 6.24 (d, J=1.20 Hz, 1H), 4.51 (q, J=7.60 Hz, 2H), 4.17 (s, 3H), 1.48 (t, J=7.20 Hz, 3H) ppm. 13C NMR (100 MHz, DMSO-d6) =13.98 (CH3), 13.55 (CH3) 62.04 (CH2), 111.55 (CH), 112.89 (CH), 119.34 (CH), 124.42 (C), 125.13 (CH), 130.32 (CH), 131.02 (CH), 132.31 (C), 134.59 (C), 135.67 (C), 148.38 (C), 151.92 (C), 155.54 (C), 168.93 (C=O) ppm. MS. m/z =315.09 (M+). Ethyl-6-chloro-2-(1,-methyl-1H-pyrrol-2-yl)quinoline-4carboxylate (2c) Elution from silica using 10% ethyl acetate in hexane afforded the title compound (2c) as a pale yellow solid, Yield= 90%. MP=125-130oC. 1H NMR (400 MHz, DMSO-d6): =8.87 (s, 1H), 8.64 (s, 1H), 8.55 (d, J=7.60 Hz, 1H), 8.49 (dd, J=1.60, 8.60 Hz, 1H), 8.23 (d, J=8.40 Hz, 1H), 8.098.11 (m, 2H), 7.99-8.00 (m, 1H), 7.87-7.87 (m, 1H), 7.73 (t, J=8.40 Hz, 1H), 7.59-7.60 (m, 2H), 4.53 (q, J=7.20 Hz, 2H), 1.45 (t, J=7.20 Hz, 3H) ppm. 13C NMR (100 MHz, DMSOd6) =14.02 (CH3), 30.45 (CH3), 61.85 (CH2), 108.73 (CH),

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Letters in Drug Design & Discovery, 2016, Vol. 13, No. 9

111.55 (C), 112.89 (CH), 119.25 (CH), 123.07 (CH), 124.34 (C), 125.02 (CH), 130.28 (CH), 132.94 (CH), 133.57 (C), 135.05 (C), 148.31 (C), 155.50 (C), 168.85 (C=O) ppm. MS. m/z =328.98 (M+). Ethyl-2-(4-bromophenyl)-6-chloroquinoline-4-carboxylate (2d) Elution from silica using 10% ethyl acetate in hexane afforded the title compound (2d) as a pale brown solid, Yield= 90%. MP=105-110oC.1H NMR (400 MHz, DMSO-d6): =8.65 (d, J=2.00 Hz, 1H), 8.54 (s, 1H), 8.18-8.20 (m, 3H), 7.90 (dd, J=2.40, 9.20 Hz, 1H), 7.76-7.77 (m, 2H), 4.50 (q, J=7.20 Hz, 2H), 1.43 (t, J=7.20 Hz, 3H) ppm. 13C NMR (100 MHz, DMSO-d6) =13.95 (CH3), 62.06 (CH2), 120.08 (C), 123.91 (C), 124.01 (CH), 124.09 (CH), 129.19 (CH), 130.94 (CH), 131.81 (CH), 131.92 (CH), 132.80 (CH), 135.44 (C), 136.40 (C), 146.71 (C), 155.04 (C), 165.12 (C=O) ppm. MS. m/z =391.13 (M+1). Ethyl-6-chloro-2-[(E)-2-phenylethenyl]quinoline-4carboxylate (2e) Elution from silica using 10% ethyl acetate in hexane afforded the title compound (2e) as a yellow solid, Yield= 85%. MP=75-80oC. IR (KBr):  2979.52(ArH), 1716.34(C=O) cm-1.1H NMR (400 MHz, DMSO-d6): =8.83 (s, 1H), 8.62 (s, 1H), 8.57 (d, J=7.20 Hz, 1H), 8.41 (d, J=2.40 Hz, 1H), 8.27 (d, J=7.60 Hz, 1H), 8.05-8.17 (m, 1H), 8.05 (q, J=3.40 Hz, 1H), 7.83 (t, J=7.60 Hz, 2H), 7.34-7.35 (m, 1H) 7.52-7.65 (m, 1H), 4.52 (q, J=7.20 Hz, 2H), 1.43 (t, J=7.20 Hz, 3H) ppm. 13C NMR (100 MHz, DMSO-d6) =14.05 (CH3), 61.87 (CH2), 119.27 (CH), 123.82 (CH), 126.58 (CH), 127.10 (C), 127.95 (CH), 128.48 (CH), 128.83 (CH), 130.34 (CH), 132.98 (CH), 133.63 (C), 135.13 (C), 148.32 (C), 155.57 (C), 165.89 (C=O) ppm. MS. m/z =338.10 (M+1). Ethyl-6-chloro-2-[(E)-2-(4-chlorophenyl)ethenyl]quinoline-4-carboxylate (2f) Elution from silica using 10% ethyl acetate in hexane afforded the title compound (2f) as a bright yellow solid, Yield= 85%. MP=80-85oC. IR (KBr):  2927.32(ArH), 1716.59(C=O) cm-1. 1H NMR (400 MHz, DMSO-d6): =8.87 (s, 1H), 8.64 (s, 1H), 8.55 (d, J=7.60 Hz, 1H), 8.49 (d, J=6.80 Hz, 1H), 8.23 (d, J=8.00 Hz, 1H), 8.09-8.11 (m, 1H), 8.00 (q, J=3.60 Hz, 1H), 7.89 (t, J=6.80 Hz, 1H), 7.73 (t, J=7.20 Hz, 1H), 7.59-7.60 (m, 1H), 4.54 (q, J=7.20 Hz, 2H), 1.45 (t, J=7.20 Hz, 3H) ppm. 13C NMR (100 MHz, DMSOd6) =14.02 (CH3), 61.85 (CH2), 119.25 (CH), 123.07 (CH), 126.53 (CH), 127.13 (CH), 127.89 (CH), 128.41 (CH), 128.79 (CH), 129.78 (CH), 130.28 (CH), 132.94 (CH), 133.57 (C), 135.05 (C), 148.31 (C), 155.50 (C), 165.85 (C=O) ppm. MS. m/z =372.06 (M+).

Kumar et al.

Hz, 2H), 3.97 (d, J=5.20 Hz, 6H), 3.88 (s, 3H), 1.47 (t, J=7.20 Hz, 3H) ppm. 13C NMR (100 MHz, DMSO-d6) =13.23 (CH3), 55.23 (CH3), 55.71 (CH3), 55.86 (CH3), 60.77 (CH2), 101.94 (CH), 113.43 (CH), 115.5 (C), 118.20 (CH), 123.87 (C), 124.22 (CH), 125.27 (CH), 131.48 (CH), 133.74 (C), 134.25 (C), 143.18 (C), 146.93 (C), 151.50 (C), 150.84 (C), 152.47 (C), 165.13 (C=O) ppm. MS. m/z =402.12 (M+1). Ethyl-6-chloro-2-(naphthalen-2-yl)quinoline-4-carboxylate (2h) Elution from silica using 10% ethyl acetate in hexane afforded the title compound (2h) as a yellow solid, Yield= 90%. MP=100-105oC. 1H NMR (400 MHz, CDCl3): =8.83 (d, J=2.40 Hz, 1H), 8.62 (s, 1H), 8.58 (s, 1H), 8.37 (dd, J=1.60, 8.80 Hz, 1H), 8.19 (d, J=9.20 Hz, 1H), 7.99-8.00 (m, 2H), 7.90 (t, J=6.00 Hz, 1H), 7.71 (dd, J=2.40, 8.80 Hz, 1H), 7.53-7.54 (m, 1H), 7.25 (s, 1H), 4.57 (q, J=6.80 Hz, 2H), 1.53 (t, J=7.20 Hz, 3H) ppm. 13C NMR (100 MHz, DMSOd6) =14.06 (CH3), 61.98 (CH2), 123.73 (C), 124.14 (CH), 125.96 (CH), 126.82 (CH), 127.89 (CH), 128.13 (CH), 130.49 (CH), 130.68 (CH), 131.76 (CH), 132.69 (CH), 132.81 (C), 133.72 (C), 132.45 (C), 135.84 (C), 146.98 (C), 157.31 (C), 165.27 (C=O) ppm. MS. m/z =362.12 (M+1). Ethyl-6-chloro-2-(3-hydroxynaphthalen-2-yl)quinoline-4carboxylate (2i) Elution from silica using 10% ethyl acetate in hexane afforded the title compound (2i) as a yellow solid, Yield= 90%. MP=175-180oC. 1H NMR (400 MHz, DMSO-d6): =10.05 (s, 1H), 8.80 (d, J=2.40 Hz, 1H), 8.15 (t, J=17.20 Hz, 2H), 7.87-7.88 (m, 3H), 7.43 (dd, J=3.20, 6.60 Hz, 1H), 7.30-7.31 (m, 3H), 4.45 (q, J=7.20 Hz, 2H), 1.35 (t, J=6.80 Hz, 3H) ppm. 13C NMR (100 MHz, DMSO-d6): =13.91 (CH3), 61.90 (CH2), 110.01 (CH), 123.68 (CH), 124.09 (CH), 124.65 (C), 126.79 (CH), 127.83 (CH), 128.04 (CH), 128.83 (C), 130.42 (C), 131.71 (CH), 132.64 (CH), 133.66 (C), 134.2 (C), 135.93 (C), 145.74 (C), 152.80 (C), 157.26 (C), 165.22 (C=O) ppm. MS. m/z =377.98 (M+). Ethyl-2-(anthracen-9-yl)-6-chloroquinoline-4-carboxylate (2j) Elution from silica using 10% ethyl acetate in hexane afforded the title compound (2j) as a pale brown solid, Yield= 85%. MP=160-165oC. 13C NMR (100 MHz, DMSO-d6) =14.12 (CH3), 60.90 (CH2), 124.63 (CH), 124.27 (C), 125.23 (CH), 126.33 (CH), 127.67 (CH), 127.39 (CH), 127.34 (CH), 127.61 (CH), 128.35 (CH), 128.94 (CH), 128.95 (C), 130.32 (C), 131.23 (CH), 132.07 (CH), 134.29 (C), 135.18 (C), 139.24 (C), 145.75 (C), 155.46 (C), 166.01 (C=O) ppm. MS. m/z =411.60 (M+). 2.3. ADME-Toxicity Prediction

Ethyl-6-chloro-2-(2,4,5-trimethoxyphenyl)quinoline-4carboxylate (2g) Elution from silica using 10% ethyl acetate in hexane afforded the title compound (2g) as a brown solid, Yield= 90%. MP=145-150oC. IR (KBr):  2935.65(ArH), 1718.55(C=O) cm-1.1H NMR(400 MHz, CDCl3): =8.71 (d, J=8.40 Hz, 1H), 8.52 (s, 1H), 7.76 (d, J=7.60 Hz, 1H), 7.63 (t, J=6.00 Hz, 1H), 7.29 (s, 1H), 6.64 (s, 1H), 4.52 (q, J=6.80

The molecular descriptors of synthesized compounds 2aj are optimized using QSAR properties. The SAR activities of these compounds are significantly helpful to understand pharmacokinetics to derive physicochemical properties and to predict biological activity such as absorption, distribution, metabolism, excretion and toxicity (ADMET) respectively. The AdmetSAR [30] helps to evaluate biologically active molecules and eliminate the biologically poor active lead

Design, Synthesis and Molecular Docking Studies

Letters in Drug Design & Discovery, 2016, Vol. 13, No. 9

3. RESULTS AND DISCUSSION

molecules which contain undesirable functional groups based on Lipinski rule. The statistical calculation for lead molecules includes surface area, geometry and fingerprint properties which help to understand biologically important end points. Aqueous solubility (PlogS), Blood-Brain Barrier penetration (QPlogBB), intestinal absorption (logHIA) [31], Hepatotoxicity, Caco-2 cell permeability (QPPCaco) also helps to understand drug metabolism for top docking lead molecules [32]. Further, the toxicity of all the synthesized ligands (2a-j) was performed by using toxicity predication ACD/ I-Lab 2.0. The toxicity profile includes screening of intraperitonial, oral, intravenous and subcutaneous toxic effects of blood, cardiovascular system, gastrointestinal tract kidney, liver and lungs.

3.1. Chemistry The reaction sequence used for the synthesis of 2aryl/heteroaryl-ethyl-6-chloroquinoline-4-carboxylates (2a-j) is depicted in Scheme 1. The 2-aryl/heteroaryl-6chloroquinoline-4-carboxylic acids (1a-j) were esterified with ethanol in the presence of concentrated sulfuric acid. After, 15-17 hr the crude products were purified by column chromatography using silica gel (60-120 mesh, petroleum ether: ethyl acetate, 9:1 v/v). To our delight furnished analytically pure 2-aryl/heteroaryl-ethyl-6-chloroquinoline-4carboxylates (2a-j). Additionally, the structures were confirmed by spectral analysis like 1H NMR, 13C NMR and LCMS.

2.4. In silico Molecular Docking Studies

Initially, the 6-chloro-2-(furan-2-yl)-quinoline-4carboxylic acid (1a) was esterified with ethanol in the presence of concentrated sulfuric acid to get the expected ethyl6-chloro-2-(furan-2-yl)quinoline-4-carboxylate (2a) with good to excellent yield, thus the optimum reaction condition was set. Finally, by adopting optimized reaction condition the various 2-aryl/heteroaryl-ethyl-6-chloroquinoline-4carboxylates (2a-j) were synthesized, in which the boiling temperature was varied and continued to reflux between 1517 hr depending on the nature of the 2-aryl/heteroaryl-6chloroquinoline-4-carboxylic acids (Table 1). The authenticities of the compounds were confirmed by 1H NMR, 13C NMR and LCMS spectral analysis. Further, the antimalarial property through molecular docking studies with farnesyltransferase protein was assessed for all new ten ligands (2aj).

The three dimensional structure of target protein farnesyltransferase (PDB ID: 3E [33]) was downloaded from PDB structural database. Thus, the PDB file was then opened in SPDB viewer was edited and the heteroatoms were removed while adding C terminal oxygen. The active pockets on target protein molecule were found out using CASTpserver [34]. The ligands were drawn using Chem Draw Ultra 6.0 and assigned with proper 2D orientation (Chem Office package). 3D coordinates were prepared using PRODRG server [35]. Auto dock V3.0 was used to perform Automated Molecular Docking in AMD Athlon (TM) 2x2 215 at 2.70 GHz, with 1.75 GB of RAM. Auto Dock 3.0 was compiled and run under Microsoft Windows XP service pack 3. For docking, grid map is required in Auto Dock, the size of the grid box was set at 72, 106 and 82 Å (R, G, and B), and grid center 25.714, 26.958, 9.32 for x, y, and z-coordinates [36]. All torsions were allowed to rotate during docking. The Lamarckian genetic algorithm and the pseudo-Solis and Wets methods were applied for minimization, using default parameters [37].

The 1H NMR, 13C NMR and LCMS interpretation for compound ethyl-6-chloro-2-(furan-2-yl)quinoline-4-carboxylate (2a) is as follows.

H3C HO

CH2 O

O

Cl

EtOH, H2SO4

O

Cl

reflux 15-17hr N

N

R

R

2a-j

1a-j CH3 O R=

CH3 ,

, a

N

O

Br ,

,

b

c

,

d

Cl

e

f

OCH3 ,

OCH3 ,

H3CO g

h

985

,

HO i

j

Scheme 1. Synthesis of 2-aryl/heteroaryl-ethyl 6-chloroquinoline-4-carboxylates (2a–j).

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Letters in Drug Design & Discovery, 2016, Vol. 13, No. 9 17

H3C

16

CH2 O

15

5

Cl

4

10

6

O 3 11

7 8

9

N

2

O

14

1 12 13

Fig. (3). Ethyl-6-chloro-2-(furan-2-yl)quinoline-4-carboxylate (2a). Table 1.

Physical data of 2-aryl/heteroaryl-ethyl-6-chloroquinoline-4-carboxylates (2a–j)a.

Entry

R

Time (hr)

2a

a

15

2b

b

15

2c

c

17

2d

d

15

2e

e

17

2f

f

15

2g

g

15

2h

h

15

2i

i

15

2j

j

15

The 1H NMR spectrum of compound 2a reveals, a quartet at =4.48 ppm with coupling constant 7.20 Hz corresponds to two methylene protons at C16-H and a triplet at =1.41 ppm with coupling constant 6.80 Hz corresponds to three methyl protons at C17-H respectively. The seven aromatic proton peak appeared in the expected region of =6.75-8.62 ppm. The additional support to elucidate the structure was obtained from 13C NMR spectrum of 2a. The appearance of peak at =13.93 corresponds to C-17 carbon, peak at =62.00 corresponds to C-16 carbon and peak at =164.81 is for C-15 carbon. The aromatic carbons were found to appear at  in between 111.75-151.92. The compound 2a was further confirmed by LCMS analysis which shows a peak at 301.90 which corresponds to molecular ion +1. Thus from all these spectral evidence the structure of compound 2a was confirmed. Similarly, structures of all other derivatives (2bj) were established. 3.2. Pharmacokinetics Properties In order to predict the drug likeliness of the synthesized compounds, Lipinski rule of five was tested (molecular weight