untitled European Journal of Chemistry 8 (4) (2017) 422‐429 European Journal of Chemistry ISSN 2153‐2249 (Print) / ISSN 2153‐2257 (Online)  2017 Atlanta Publishing House LLC ‐ All rights reserved ‐ Printed in the USA http://dx.doi.org/10.5155/eurjchem.8.4.422-429.1651 European Journal of Chemistry Journal webpage: www.eurjchem.com Synthesis, single crystal X‐ray diffraction, Hirshfeld surface and biological activity of quinolone derivatives Huma Bano 1, Sarah Shafi 1, Hina Siddiqui 1, Muhammad Iqbal Choudhary 1,2 and Sammer Yousuf 1,* 1 H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi‐75270, Pakistan 2 Department of Biochemistry, Faculty of Science, King Abdulaziz Universisty, Jeddah‐21412, Kingdom of Saudi Arabia * Corresponding author at: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi‐75270, Pakistan. Tel.: +92.21.34824924‐5. Fax: +92.21.4819018‐9. E‐mail address: dr.sammer.yousuf@gmail.com (S. Yousuf). ARTICLE INFORMATION ABSTRACT DOI: 10.5155/eurjchem.8.4.422-429.1651 Received: 10 September 2017 Received in revised form: 19 September 2017 Accepted: 20 September 2017 Published online: 31 December 2017 Printed: 31 December 2017   Two new quinolone derivatives, 5‐nitroquinolin‐8‐yl‐3‐bromobenzoate (1) and 5‐ nitroquinolin‐8‐yl‐3‐chlorobenzoate (2), were synthesized and their structures were elucidated using X‐ray diffraction techniques. Both compounds crystallized in P21/n (monoclinic) space group having four independent molecules in asymmetric unit. The dihedral angle between benzene and planner quinoline rings in compounds 1 and 2 were found to be 117.7(2) and 117.4(2)ᵒ, respectively. No intermolecular hydrogen bonding was observed in compound 1. However, C‐H···O intermolecular interaction was found to connect the molecules in crystal lattice of compound 2. Hirshfeld surfaces analysis was performed to evaluate the directions, and strength of interactions of molecules of compounds and 1 and 2 with neighbouring molecules, and the major contribution in the crystal packing was due to O‐H (1, 24.6% and 2, 25.1%) interactions. The synthesized quinoline derivatives were found as potent anti‐bacterial agents against E. coli reference (ATCC25922 and ATCC 35218) and multi‐drug resistant strains (M2 and M3) with 91.42 to 94.72% inhibition. Both compounds 1 and 2 showed weak antileishmanial activity against L. Major promastigotes in vitro with IC50 values 73.2±3.1 and 72.2±2.3 g/mL, respectively, and also found as cytotoxic in nature against 3T3 fibroblast cell line. KEYWORDS Multi‐drug resistance Quinoline derivatives Anti‐bacterial activity X‐ray crystallography Antileishmanial activity Hirshfeld surface analysis Cite this: Eur. J. Chem. 2017, 8(4), 422‐429 1. Introduction Quinoline, also known as benzopyridine, 1‐benzazine, benzo[b]pyridine, or benzazine, is an aromatic heterocyclic compound having fused phenyl and pyridine moieties. Deriva‐ tives of quinolone have attracted attention of medicinal chemists due to their wide range of biological applications [1]. Among medicinally important heterocyclic compounds, quinolines are the most privileged class of compounds, as they are widely used as ‘‘parental’’ molecules to synthesize a broad range of biologically active molecules as anti‐malarial [2], anti‐ cancer [3], anti‐hypertensive [4], anti‐TB [5], anti‐inflamma‐ tory [6], and anti‐HIV [7,8] agents. The wide range of biological activities prompted structural chemists to explore the substitution pattern of quinoline derivatives, which allows the large libraries of structurally diverse derivatives with interes‐ ting biological activities. Further to our interest in the syn‐ thesis of diverse biologically active derivatives of quinoline, we have synthesized 5‐nitroquinolin‐8‐yl‐3‐bromobenzoate (1), and 5‐nitroquinolin‐8‐yl‐3‐chlorobenzoate (2). Their struc‐ tures were studied by using single crystal X‐ray diffraction techniques, followed by detailed Hirshfeld quantitative analysis of contributions of various non‐covalent interactions towards the crystal stability in compounds 1 and 2. Both quinoline derivatives were also evaluated for their anti‐ leishmanial and anti‐bacterial activity in vitro and interesting results were obtained. Both compounds were also check for their cytotoxicity against 3T3 fibroblast cell line and found to be toxic in nature. 2. Experimental 2.1. Materials, physical measurements and softwares Analytical grade chemicals were purchased from Sigma‐ Aldrich. Single crystal X‐ray diffraction data was collected by using MoKα radiation (λ = 0.71073 Å) on a Bruker SMART APEX‐II diffractometer fitted with CCD detector at a tempera‐ ture of 273(2) K. SAINT program was used to integrate the reflection intensities whereas, multi‐scan method was used for absorption correction (SADABS) [9]. Finally the structures were constructed by using SHELXTL program [10,11]. PLATON calculations were used to find the significant non‐ covalent interactions in the molecule [12]. Quantitative analysis of intermolecular interactions was determined by using CIF file input in software package CrystalExplorer [13]. Bano et al. / European Journal of Chemistry 8 (4) (2017) 422‐429 423 Scheme 1 (1) (2) Figure 1. The molecular structure of compounds 1 and 2. Two‐dimensional fingerprint plots were used to represent these interactions quantitatively using dnorm values by placing de versus di, in which cyan dots represent the area of the interaction towards the total Hirshfeld surface. MDR Escherichia coli strains (ATCC 35218 and ATCC 25922) were purchased from the American Type Cultures Center (ATCC). The duly characterized Pakistani multi‐drug resistant clinical isolates of E. coli (M2 and M3, Source: Human urine) were obtained from the Diagnostic Laboratory of Liaquat National Hospital (LNH), Karachi, Pakistan. All the compounds were dissolved in DMSO with the ratio of 1:1 to prepare the stock solution. 2.2. X‐ray structure determination The constructed was solved and refined by direct and least‐square methods, respectively [10,14]. All non‐hydrogen atoms were refined on the basis of anisotropic thermal displacement parameters while hydrogen atoms were allowed to ride on calculated positions at parent atoms on the basis of isotropic thermal parameters. 2.3. Preparation of quinoline derivatives Quinoline derivatives 1 and 2 were prepared by using the method as described by Moreno‐Fuquen, and co‐workers with slight modification [15]. 8‐Hydroxy‐5‐nitroquionoline (1.0 mmol, 0.19 g) was dissolved in 10 mL acetonitrile. Triethyl amine (0.7 mmol, 0.1 mL) was added and mixture was refluxed for 15 minutes, followed by addition of acid halides (1.0 mmol, 0.21 g (1), 1.0 mmol (2) 0.17 g) and refluxed for 4 to 6 hours. Progress of the reaction was monitored through thin layer chromatography, after complete consumption of starting material, solvent was evaporated under reduced pressure. The crude product was washed with mixture of hexanes: ethyl acetate (v:v, 8:2), dried, and recrystallized from methanol (Scheme 1). 2.4. Evaluation of biological activities Antileishmanial activity was performed by using method described by Choudhary and co‐workers [16]. Anti‐bacterial activity was performed by using methods previously described by Siddiqui and co‐workers [17]. Whereas the cytotoxic acti‐ vity was evaluated by using the MTT assay as explained by Oladimeji et al. [18]. 3. Results and discussion The molecular structures (Figure 1) and ORTEP diagrams of quinoline derivatives 1 and 2 are shown in Figures 2 and 3, respectively. Crystallographic data, selected bond lengths and angles, atomic displacement parameters, and hydrogen bond geometry are presented in Tables 1‐6. Figure 2. ORTEP view of single crystal structure of compound 1. Figure 3. ORTEP view of single crystal structure of compound 2. 3.1. Structural features and crystal packing The structures of compounds 1 and 2 were found to be composed of planner nitro‐substituted quinoline ring system (C1/C7/N2/C9/C10) and planner bromo‐ and chloro‐substi‐ 424 Bano et al. / European Journal of Chemistry 8 (4) (2017) 422‐429 Table 1. Crystallographic data of compounds 1 and 2. Compound 1 2 Empirical formula C16H9BrN2O4 C16H9ClN2O4 Formula weight 373.16 328.70 Temperature (K) 100 (2) 273 (2) Crystal system P21/n P21/n Space group Monoclinic Monoclinic Hall symbol ‐P 2yn ‐P 2yn a (Å) 6.5360 (4) 604835 (6) b (Å) 16.2361 (11) 16.3002 (15) c (Å) 13.6968 (8) 13.5332 (12) β (ᵒ) 96.251(1) 95.264(2) Volume (Å3) 1444.85 (16) 1424.2 (2) Z 4 4 ρcalc (g/cm3) 1.715 1.533 F(000) 744 672 Crystal size (mm3) 0.51×0.39×0.28 0.32×0.23×0.13 Radiation 0.71073 0.71073 2θ range for data collection (ᵒ) 1.95 to 28.34 1.96 to 25.50 Index ranges ‐8 ≤ h ≤ 8, ‐14 ≤ k ≤ 21, ‐18 ≤ l ≤ 15 ‐6 ≤ h ≤ 7, ‐16 ≤ k ≤ 19, ‐16 ≤ l ≤ 16 Radiation collected 10403 8330 Absorption correction 2.863 0.291 Tmin, Tmax 0.221, 0.570 0.912, 0.964 F(000) 744 672 Independent reflections 3606 [Rint= 0.0279] 2647 [Rint= 0.0372] Data/ restrains/parameters 3606 / 0 / 208 2647/0/208 Goodness of fit on F2 1.060 0.840 Final R indices [I>2σ(I)] R1 = 0.0449, wR2 = 0.1140 R1 = 0.0435, wR2 = 0.1022 R indices (all data) R1 = 0.0622, wR2 = 0.1237 R1 = 0.0761, wR2 = 0.1272 Largest diff. peak / hole (eÅ‐3) 0.420 and ‐1.131 0.299 and ‐0.222 Table 2. Selected bond lengths and angles of compound 1. Atom‐Atom Bond lengths [Å] Atom‐Atom Bond lengths [Å] Br(1)‐C(14) 1.885 (2) C(3)‐C(4) 1.426(3) O(3)‐C(11) 1.365 (3) C(4)‐C(5) 1.412(3) O(3)‐C(10) 1.392(2) C(4)‐C(9) 1.426(3) O(4)‐C(11) 1.193(3) C(9)‐C(10) 1.415(3) O(1)‐N(1) 1.206(3) C(13)‐C(14) 1.378(3) N(2)‐C(7) 1.314(3) C(10)‐C(1) 1.350(3) N(2)‐C(9) 1.360(3) C(16)‐C(15) 1.370(4) N(1)‐O(2) 1.220(3) C(16)‐C(17) 1.388(3) N(1)‐C(3) 1.471(3) C(5)‐C(6) 1.357(4) C(12)‐C(13) 1.386(3) C(14)‐C(15) 1.385(4) C(12)‐C(17) 1.387(3) C(2)‐C(1) 1.401(3) C(12)‐C(11) 1.486(3) C(7)‐C(6) 1.400(4) C(3)‐C(2) 1.351(3) Atom‐Atom‐Atom Bond angles [ᵒ] Atom‐Atom‐Atom Bond angles [ᵒ] C(11)‐O(3)‐C(10) 117.66(17) O(4)‐C(11)‐C(12) 125.6(2) C(7)‐N(2)‐C(9) 117.4(2) O(3)‐C(11)‐C(12) 110.90(17) O(1)‐N(1)‐O(2) 122.6(2) C(14)‐C(13)‐C(12) 119.0(2) O(1)‐N(1)‐C(3) 118.8(2) C(1)‐C(10)‐O(3) 118.4(2) O(2)‐N(1)‐C(3) 118.5(2) C(1)‐C(10)‐C(9) 122.6(2) C(13)‐C(12)‐C(17) 120.1(2) O(3)‐C(10)‐C(9) 118.8(2) C(13)‐C(12)‐C(11) 121.23(19) C(15)‐C(16)‐C(17) 120.9(2) C(17)‐C(12)‐C(11) 118.61(19) C(12)‐C(17)‐C(16) 119.6(2) C(2)‐C(3)‐C(4) 122.7(2) C(6)‐C(5)‐C(4) 119.7(2) C(2)‐C(3)‐N(1) 116.0(2) C(13)‐C(14)‐C(15) 121.5(2) C(4)‐C(3)‐N(1) 121.2(2) C(13)‐C(14)‐Br(1) 118.71(18) C(5)‐C(4)‐C(9) 116.2(2) C(15)‐C(14)‐Br(1) 119.77(17) C(5)‐C(4)‐C(3) 127.5(2) C(3)‐C(2)‐C(1) 120.5(2) C(9)‐C(4)‐C(3) 116.30(19) C(16)‐C(15)‐C(14) 118.9(2) N(2)‐C(9)‐C(10) 117.81(19) C(10)‐C(1)‐C(2) 119.0(2) N(2)‐C(9)‐C(4) 123.4(2) N(2)‐C(7)‐C(6) 123.6(2) C(10)‐C(9)‐C(4) 118.83(19) C(5)‐C(6)‐C(7) 119.6(2) O(4)‐C(11)‐O(3) 123.49(19) tuted benzene rings (C11‐C16) linked to each other by carboxylate bridges (C10/O3/O4), represented in Figure 2 and 3. The dihedral angles between the planner quinoline and benzene rings were found to be 117.7(2) and 117.4 (2)ᵒ for compounds 1 and 2, respectively. In compound 1, no inter‐ and intra‐molecular hydrogen bondings were observed, and molecules were found to be arranged in three dimensions (Figure 4). Similarly in compound 2 no classical hydrogen bonding was observed. However, two neighboring molecules were found to be linked through C14‐H14A···O1 intermolecular hydrogen bond with donor acceptor distance 3.4813 Å and angle of 16°, respectively. Molecules found to be arranged along c‐axis (Figure 5). 3.2. Hirshfeld surface and fingerprint plot analysis The quantitative Hirshfeld surface calculations to predict the directions and strength of interactions with neighboring molecules was carried both for compounds 1 and 2. The circular red regions generated Hirshfeld indicated the strong O···H hydrogen‐bonds that can be easily observed in compound 2 as compared to compound 1 (Figure 6 and 7). The two‐dimensional fingerprint plot (Figure 8 and 9) of Hirshfeld of compounds 1 and 2 represent the percent contacts contributed towards crystal packing as depicted in Figures 8 and 10 for compound 1 and Figures 9 and 11 for compound 2. Bano et al. / European Journal of Chemistry 8 (4) (2017) 422‐429 425 Table 3. Selected bond lengths and angles of compound 2. Atom‐Atom Bond lengths [Å] Atom‐Atom Bond lengths [Å] O(3)‐C(11) 1.365(3) C(12)‐C(13) 1.381(3) O(3)‐C(10) 1.394(3) C(12)‐C(17) 1.383(3) C(4)‐C(5) 1.415(3) C(12)‐C(11) 1.485(3) C(4)‐C(9) 1.420(3) C(3)‐C(2) 1.351(4) C(4)‐C(3) 1.425(3) N(2)‐C(7) 1.309(3) O(4)‐C(11) 1.188(3) C(13)‐C(14) 1.381(3) C(10)‐C(1) 1.348(4) C(5)‐C(6) 1.352(4) C(10)‐C(9) 1.409(3) C(7)‐C(6) 1.397(4) C(9)‐N(2) 1.366(3) C(1)‐C(2) 1.393(4) N(1)‐O(1) 1.218(3) C(17)‐C(16) 1.378(4) N(1)‐O(2) 1.219(3) C(14)‐C(15) 1.379(4) N(1)‐C(3) 1.477(3) C(16)‐C(15) 1.369(4) Atom‐Atom‐Atom Bond angles [ᵒ] Atom‐Atom‐Atom Bond angles [ᵒ] C(11)‐O(3)‐C(10) 117.45(19) C(2)‐C(3)‐N(1) 116.4(2) C(5)‐C(4)‐C(9) 116.4(2) O(4)‐C(11)‐O(3) 123.7(2) C(5)‐C(4)‐C(3) 127.6(2) O(4)‐C(11)‐C(12) 125.7(2) C(9)‐C(4)‐C(3) 115.9(2) O(3)‐C(11)‐C(12) 110.6(2) C(1)‐C(10)‐O(3) 118.3(2) C(7)‐N(2)‐C(9) 117.5(2) C(1)‐C(10)‐C(9) 122.3(2) C(14)‐C(13)‐C(12) 119.2(2) O(3)‐C(10)‐C(9) 119.2(2) C(6)‐C(5)‐C(4) 119.3(2) N(2)‐C(9)‐C(10) 117.7(2) N(2)‐C(7)‐C(6) 123.6(3) N(2)‐C(9)‐C(4) 123.0(2) C(10)‐C(1)‐C(2) 119.2(2) C(10)‐C(9)‐C(4) 119.3(2) C(16)‐C(17)‐C(12) 120.0(3) O(1)‐N(1)‐O(2) 123.1(2) C(3)‐C(2)‐C(1) 120.3(2) O(1)‐N(1)‐C(3) 118.7(2) C(15)‐C(14)‐C(13) 121.3(3) O(2)‐N(1)‐C(3) 118.1(3) C(15)‐C(14)‐Cl(1) 119.8(2) C(13)‐C(12)‐C(17) 119.8(2) C(13)‐C(14)‐Cl(1) 118.9(2) C(13)‐C(12)‐C(11) 121.3(2) C(5)‐C(6)‐C(7) 120.0(3) C(17)‐C(12)‐C(11) 118.9(2) C(15)‐C(16)‐C(17) 120.9(3) C(2)‐C(3)‐C(4) 122.8(2) C(16)‐C(15)‐C(14) 118.9(2) Table 4. Anisotropic displacement parameters [Å2] for compound 1. Atom U11 U22 U33 U23 U13 U12 Br(1) 87 (1) 101 (1) 36 (1) 17 (1) 6 (1) ‐28 (1) O(3) 49 (1) 56 (1) 24 (1) 2 (1) ‐3 (1) ‐13 (1) O(4) 52 (1) 58 (1) 38 (1) 11 (1) 2 (1) ‐9 (1) O(1) 58 (1) 75 (1) 74 (1) 12 (1) ‐25 (1) 13 (1) N(2) 43 (1) 39 (1) 41 (1) 2 (1) ‐7 (1) 5 (1) N(1) 41 (1) 59 (1) 43 (1) 9 (1) ‐11 (1) ‐3 (1) C (12) 41 (1) 32 (1) 29 (1) ‐4 (1) 1 (1) ‐1 (1) C (3) 36 (1) 42 (1) 33 (1) 4 (1) ‐5 (1) ‐4 (1) C (4) 36 (1) 33 (1) 29 (1) 3 (1) ‐1 (1) ‐5 (1) O (2) 82 (2) 120 (2) 50 (1) ‐23 (1) ‐27 (1) 21 (2) C (9) 36 (1) 30 (1) 29 (1) 2 (1) ‐2 (1) ‐3 (1) C (11) 40 (1) 38 (1) 29 (1) ‐1 (1) 4 (1) 0 (1) C (13) 44 (1) 40 (1) 30 (1) 0 (1) ‐1 (1) ‐4 (1) C (10) 41 (1) 43 (1) 26 (1) 2 (1) ‐1 (1) ‐7 (1) C (16) 46 (1) 63 (2) 43 (1) ‐10 (1) ‐5 (1) ‐12 (1) C (17) 44 (1) 50 (1) 37 (1) ‐6 (1) 5 (1) ‐9 (1) C (5) 49 (1) 47 (1) 32 (1) ‐6 (1) 1 (1) ‐2 (1) C (14) 57 (1) 41 (1) 31 (1) 2 (1) 1 (1) ‐5 (1) C (2) 34 (1) 56 (1) 48 (1) 2 (1) 2 (1) 7 (1) C (15) 55 (1) 54 (1) 31 (1) ‐3 (1) ‐9 (1) ‐2 (1) C (1) 45 (1) 58 (2) 39 (1) ‐5 (1) 8 (1) 2 (1) C (7) 44 (1) 45 (1) 60 (2) ‐5 (1) ‐1 (1) 11 (1) C (6) 55 (2) 52 (2) 48 (1) ‐13 (1) 10 (1) 3 (1) Table 5. Anisotropic displacement parameters [Å2] for the compound 2. Atom U11 U22 U33 U23 U13 U12 Cl(1) 110(1) 118 (1) 45 (1) 21 (1) 6 (1) ‐32 (1) O(3) 51(1) 65 (1) 31 (1) 5 (1) ‐4 (1) ‐14 (1) C(4) 38(1) 40 (2) 36 (1) 3 (1) ‐1 (1) ‐8 (1) O(4) 54(1) 65 (1) 43 (1) 11 (1) 3 (1) ‐11 (1) C(10) 41(1) 52 (2) 32 (1) 2 (1) ‐2 (1) ‐8 (1) C(9) 37(1) 40 (1) 38 (1) 4 (1) ‐1 (1) ‐5 (1) N(1) 45(1) 68 (2) 48 (1) 10 (1) ‐10 (1) ‐6 (1) C(12) 43(1) 40 (1) 33 (1) ‐4 (1) 1 (1) 1 (1) C(3) 37(1) 49 (2) 39 (1) 7 (1) ‐4 (1) ‐6 (1) C(11) 38 (1) 47 (2) 38 (1) ‐1 (1) 4 (1) 1 (1) N (2) 43 (1) 48 (1) 52 (1) 1 (1) ‐8 (1) 3 (1) O (2) 56 (1) 81 (2) 84 (2) 16 (1) ‐24 (1) 10 (1) C (13) 50 (2) 50 (2) 38 (1) ‐2 (1) ‐2 (1) ‐6 (1) C (5) 55 (2) 54 (2) 37 (1) ‐4 (1) 2 (1) ‐7 (1) C (7) 47 (2) 49 (2) 70 (2) ‐7 (2) 4 (1) 6 (1) C (1) 48 (2) 66 (2) 41 (1) ‐6 (1) 9 (1) 3 (1) C (17) 49 (2) 59 (2) 43 (1) ‐6 (1) 3 (1) ‐8 (1) C (2) 37 (1) 64 (2) 52 (2) 2 (1) 3 (1) 6 (1) C (14) 69 (2) 54 (2) 38 (1) 4 (1) 2 (1) ‐4 (1) C (6) 55 (2) 59 (2) 58 (2) ‐14 (1) 12 (1) 1 (1) C (16) 50 (2) 78 (2) 50 (2) ‐12 (2) ‐8 (1) ‐8 (2) O (1) 80 (2) 115 (2) 53 (1) ‐16 (1) ‐23 (1) 11 (1) C (15) 69 (2) 67 (2) 38 (1) ‐6 (1) ‐13 (1) 2 (2) 426 Bano et al. / European Journal of Chemistry 8 (4) (2017) 422‐429 Table 6. Hydrogen‐bond geometry (Å, °) of compound 2. D—H···A D—H H···A D···A D—H···A C14—H14···O1i 0.93 2.58 3.482 (4) 164 Symmetry code: (i) 1+x, y, 1+z. Figure 4. Crystal packing of compound 1. Hydrogen atoms are omitted for clarity. Figure 5. Crystal packing of compound 2. Hydrogen atoms, except those which involved in hydrogen bonding, are omitted for clarity. Figure 6. The dnorm mapped on Hirshfeld surface for visualizing the intermolecular contacts of the compound 1. Figure 7. The dnorm mapped on Hirshfeld surface for visualizing the intermolecular contacts of the compound 2. Bano et al. / European Journal of Chemistry 8 (4) (2017) 422‐429 427 Figure 8. Two‐dimensional fingerprint plots of compound 1 shows the 99.6% contacts involved in the crystal packing. Figure 9. Two‐dimensional fingerprint plots of compound 2 shows the 100% contacts involved in the crystal packing. O...H 24.6% (Å) di de 0.6 0.6 0.8 0.8 1.0 1.0 1.2 1.2 1.4 1.4 1.6 1.6 1.8 1.8 2.0 2.0 2.2 2.2 2.4 2.4 H...H 18.5% (Å) di de 0.6 0.6 0.8 0.8 1.0 1.0 1.2 1.2 1.4 1.4 1.6 1.6 1.8 1.8 2.0 2.0 2.2 2.2 2.4 2.4 C...H 18.1% (Å) di de 0.6 0.6 0.8 0.8 1.0 1.0 1.2 1.2 1.4 1.4 1.6 1.6 1.8 1.8 2.0 2.0 2.2 2.2 2.4 2.4 Br...H 12.4% (Å) di de 0.6 0.6 0.8 0.8 1.0 1.0 1.2 1.2 1.4 1.4 1.6 1.6 1.8 1.8 2.0 2.0 2.2 2.2 2.4 2.4 O...C 6.9% (Å) di de 0.6 0.6 0.8 0.8 1.0 1.0 1.2 1.2 1.4 1.4 1.6 1.6 1.8 1.8 2.0 2.0 2.2 2.2 2.4 2.4 N...H 4.5% (Å) di de 0.6 0.6 0.8 0.8 1.0 1.0 1.2 1.2 1.4 1.4 1.6 1.6 1.8 1.8 2.0 2.0 2.2 2.2 2.4 2.4 N...C 3.4% (Å) di de 0.6 0.6 0.8 0.8 1.0 1.0 1.2 1.2 1.4 1.4 1.6 1.6 1.8 1.8 2.0 2.0 2.2 2.2 2.4 2.4 Br...O 1.9% (Å) di de 0.6 0.6 0.8 0.8 1.0 1.0 1.2 1.2 1.4 1.4 1.6 1.6 1.8 1.8 2.0 2.0 2.2 2.2 2.4 2.4 Figure 10. Two‐dimensional fingerprint plots indicate the major contributions of intermolecular interactions in compound 1. The fingerprint plot reveals that the contribution of O···H interaction is 24.6%, to the crystal packing (Figure 12) in compound 1 and 25.1% in compound 2 (Figure 13). Other important interactions for compound 1 are H···H (18.5 %), C···H (18.1%), Br···H (12.4%), followed by weak O···C (6.9%), N···C (3.4%), and N···H (4.5%), and for compound 2 are H···H (18.6 %), C···H (18.0%), followed by weak O···C (7%), C···C (5.9%), and N···H (4.5%), interactions (Figure 13). 3.3. In vitro antileishmanial activity Compounds 1 and 2 were evaluated for their for their in vitro antileishmanial activity against Leishmania Major promastigotes (Table 7) and found as weak antileishmanial agents with IC50 values 73.2±3.1 and 72.2±2.3 g/mL, respect‐ tively against the standard antileishmanial drugs, pentamidine (IC50 = 5.09±0.04 g/mL) and amphotericin B (IC50 = 0.29±0.05 g/mL). 428 Bano et al. / European Journal of Chemistry 8 (4) (2017) 422‐429 Table 7. Antileishmanial activity of compounds 1 and 2 against L. Major promastigotes. Compounds IC50 (µM±SEM) * 1 73.2±3.1 2 72.2±2.3 Pentamidine 5.09±0.09 Amphotericin B 0.29±0.05 * SEM = Standard error of mean. Table 8. Cytotoxic activity of compounds 1 and 2 against 3T3 fibroblast cell line. Compounds Cytotoxicity IC50 [μM±SD] * 1 8.3±0.4 2 9.4±1.06 Doxorubicin (standard) 0.56±0.15 * SD = Standard deviation. O...H 25.1% (Å) di de 0.6 0.6 0.8 0.8 1.0 1.0 1.2 1.2 1.4 1.4 1.6 1.6 1.8 1.8 2.0 2.0 2.2 2.2 2.4 2.4 H...H 18.6% (Å) di de 0.6 0.6 0.8 0.8 1.0 1.0 1.2 1.2 1.4 1.4 1.6 1.6 1.8 1.8 2.0 2.0 2.2 2.2 2.4 2.4 C...H 18.0% (Å) di de 0.6 0.6 0.8 0.8 1.0 1.0 1.2 1.2 1.4 1.4 1.6 1.6 1.8 1.8 2.0 2.0 2.2 2.2 2.4 2.4 Cl...H 12.5% (Å) di de 0.6 0.6 0.8 0.8 1.0 1.0 1.2 1.2 1.4 1.4 1.6 1.6 1.8 1.8 2.0 2.0 2.2 2.2 2.4 2.4 O...C 7.0% (Å) di de 0.6 0.6 0.8 0.8 1.0 1.0 1.2 1.2 1.4 1.4 1.6 1.6 1.8 1.8 2.0 2.0 2.2 2.2 2.4 2.4 C...C 5.9% (Å) di de 0.6 0.6 0.8 0.8 1.0 1.0 1.2 1.2 1.4 1.4 1.6 1.6 1.8 1.8 2.0 2.0 2.2 2.2 2.4 2.4 N...H 4.5% (Å) di de 0.6 0.6 0.8 0.8 1.0 1.0 1.2 1.2 1.4 1.4 1.6 1.6 1.8 1.8 2.0 2.0 2.2 2.2 2.4 2.4 C�N 3.5% (Å) di de 0.6 0.6 0.8 0.8 1.0 1.0 1.2 1.2 1.4 1.4 1.6 1.6 1.8 1.8 2.0 2.0 2.2 2.2 2.4 2.4 Figure 11. Two‐dimensional fingerprint plots indicate the major contributions of intermolecular interactions in compound 2. Figure 12. The relative contributions to the 99.6% of Hirshfeld surface area for the various intermolecular contacts in compound 1. Figure 13. The relative contributions to the 100% of Hirshfeld surface area for the various intermolecular contacts in compound 2. 3.4. In vitro cytotoxic activity Compounds 1 and 2 were also evaluated for their cytotoxic effect against T3T fibroblast cell lines. Both compounds 1 and 2 were found to be cytotoxic in nature with IC50 values 8.3±0.4 and 9.4±1.06 g/mL, respectively. Doxorubicine (IC50 = 0.56±0.15 g/mL) was used as a standard drug to compare the activity against 3T3 cell line (Table 8). 3.5. In vitro anti‐bacterial activity The in vitro antibacterial activity of compounds 1 and 2 against E. coli reference (ATCC25922 and ATCC 35218) and multi‐drug resistant (M2 and M3) strains was also inves‐ tigated. Compounds 1 and 2 exhibited potent anti‐bacterial activity against E. coli reference cell cultures ATCC 35218 (1, 91.42%, 2, 92.95% inhibition) and ATCC 25922 (1, 93.18%, and 2, 94.5, % inhibition). Bano et al. / European Journal of Chemistry 8 (4) (2017) 422‐429 429 Table 9. Anti‐bacterial activity of compounds 1 and 2 against reference and multi‐drug resistant clinical isolates of E. coli. Compounds % Inhibition ATCC 25922 ATCC 35218 M2 M3 1 91.42 93.18 93.59 93.11 2 92.95 94.5 94.30 94.72 Standards Ofloxacin = 96.75, Gentamycin = 96.63 Ofloxacin = 0.0, Gentamycin = 97.2 Ofloxacin = 0.0, Gentamycin = 92.07 The activity was found to be comparable to the tested standard drugs, ofloxacin and gentamycin which showed 96.75 and 96.63% inhibition against ATCC 35218 and ATCC 25922 cell cultures, respectively. Similarly both compounds were also appeared as potent anti‐bacterial agent against E. coli multi‐ drug resistant clinical isolates M2 (1, 93.59 % inhibition, 2, 94.30 % inhibition) and M3 (1, 93.11 % inhibition, 2, 94.72 % inhibition). The activity was found to be comparable to the tested standard drugs gentamycin which showed 97.20 and 92.07 % inhibition against E. coli multi‐drug resistant clinical isolates M2 and M3, respectively while ofloxacin was found to be inactive against both M2 and M3 strains. Results are summarized in Table 9. 4. Conclusion Two new quinoline derivatives 1 and 2 were synthesized, and their three‐dimensional structures were deduced by single crystal X‐ray diffraction analysis. In the crystal packing of quinoline derivative 2, two neighboring molecules are inter‐ connected via C‐H···O interactions, and the repeating motif of connected molecules arranged along c axis. We also calculated the individual molecular interactions in terms of histogram by using Hirshfeld surface analysis and fingerprint plots for compounds 1 and 2 and found that the contribution of O···H intermolecular interactions is more than other (C···H, N···H, etc.) interactions towards crystal stability. The synthesized compounds were found as potent anti‐bacterial agents against E. coli reference (ATCC25922 and ATCC 35218) and multi‐ drug resistant strains (M2 and M3) and showed weak anti‐ leishmanial activity against L. Major promastigotes in vitro. The synthesized quinoline derivatives were also appeared as cytotoxic in nature against 3T3 fibrobalst cell line. Acknowledgments Dr. Sammer Yousuf is thankful to the Higher Education Commission of Pakistan for the financial support through research fundings 20‐2830/R&D/HEC and 20‐2216/R&D/ HEC. 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