Antiproliferative and in Silico Admet Study of New 4-(Piperidin-1-Ylmethyl)-2- (Thiophen-2-Yl) Quinoline Analogues

Abstract

Objective: Synthesis and antiproliferative study of novel 4-(piperidin-1-ylmethyl)-2-(thiophen-2-yl) quinoline 7(a-j) derivatives.Methods: 4-(piperidin-1-ylmethyl)-2-(thiophen-2-yl) quinolines were synthesized by the addition of 4-(chloromethyl)-2-(thiophen-2-yl) quinoline (0.01 mol), piperidine (0.01 mol) in DMF (10 v) and K 2 CO 3 ( 0.02 mol). The anticancer activity of the title compounds performed against T-47D, HeLa, HepG2, and MCF-7 human cancer cell lines growth was investigated by MTT assay. Results:The compounds 7b and 7g exhibited 90% of the growth inhibitory effect on T-47D, HeLa, and MCF-7 and also 80% growth inhibition in HepG2 when compared with standard drug paclitaxel. Conclusion:The synthesized compounds 4-(piperidin-1-ylmethyl)-2-(thiophen-2-yl) quinoline 7(a-j) exhibited a considerable degree of growth inhibition of human cancer cell lines. The synthesized molecules 7(a-j) are in acceptable range and are less toxic and can be considered as possible hits for drug discovery.In continuation of search on new compounds for antiproliferation treatment from our laboratory [28][29][30][31][32], we discovered that 2-(1-benzofuron-2-yl) quinoline-4-carboxylic acid and its esters [28] and 2-(benzofuran-2-yl)-4-(5-phenyl-4H-1,2,4-triazol-3-yl) quinoline and its derivatives [29] have possessed appreciable cytotoxic properties. Hence, the present work deals with the synthesis and antiproliferative potential of 4-(piperidin-1-ylmethyl)-2-(thiophen-2-yl) quinoline and its derivatives, along with detailed in silico pharmacokinetic and druglikeness properties Scheme 1. METHODS MaterialsCommercially available chemicals are used in the synthesis of compounds 7(a-j). The compounds were purified by column chromatography using silica gel 100-200 mesh with occasional monitoring by pre-coated aluminum thin layer chromatography (TLC) plates procured from Merck. Melting points were recorded by the open capillary method and are uncorrected by Raga Melting Point Apparatus. The 1 H-nuclear magnetic resonance (NMR) and 13 C-NMR spectra were recorded on a 400 MHz and 100 MHz, Bruker spectrometer using CDCl 3 as solvent and TMS as an internal standard. Mass spectra were recorded on the liquid chromatography-mass spectrometry Agilent mass spectrometer. Method 2-(1-thiophene-2-yl)quinoline-4-carboxylic acid 3(a-b)Isatin 1(a-b) (0.01 mol) and ethanol (10 v) were taken in a round bottom flask, to this 33% aq. KOH was added dropwise at 0-5°C followed by addition of 2-acetylthiophene 2 (0.01 mol). The reaction was refluxed at 75°C for 8 h. After completion, the reaction mixture was neutralized with dilute HCl. The precipitate, thus, formed was filtered, washed with ethyl acetate to remove impurities and dried to get compound 3(a-b). Methyl 2-(1-thiophene-2-yl) quinolone-4-carboxylates 4(a-b)2-(1-thiophene-2-yl) quinoline-4-carboxylic acid 3(a-b) (0.01 mol) was taken in methanol (10 v) in a round bottom flask, to this two drops of Conc. H 2 SO 4 was added. The reaction was refluxed at 75°C for 8 h. After completion, the reaction mixt...