Hit to lead optimization of a series of N-[4-(1,3-benzothiazol-2-yl)phenyl]acetamides as monoacylglycerol lipase inhibitors with potential anticancer activity

摘要

A total of thirty five new N-[4-(1,3-benzothiazol-2-yl)phenyl]acetamide derivatives were synthesized and structures of all the compounds were confirmed on the basis of elemental analysis and collective use of IR, H-1 NMR, C-13 NMR and mass spectral data. Compounds were tested for their ability to inhibit human monoacylglycerol lipase (hMAGL) enzyme. Eight compounds 4, 19-21, 24-26, and 34 reduced the hMAGL activity less than 50% at 100 nM concentrations. The halogen substituted aniline derivatives 20, 21 and 24-26 were found to be most active among all the synthesized compounds having IC50 value in the range of 6.5-9 nM. Twenty five compounds were selected by NCI, USA for one dose anticancer screening. Compound 21 (NSC: 780167) and 24 (NSC: 780168) fulfilled prearranged doorstep growth inhibition criteria and further selected for NCI full panel five dose assay at 10-fold dilutions of five different concentrations (0.01, 0.1, 1, 10 and 100 mu M). Both the compounds 21 and 24 were found to be most active against MCF7 and MDA-MB-468 breast cancer cell lines. The GI(50) value of 32.5 nM (MCF7) and 23.8 nM (MDA-MB-468) was observed for compound 21. Compound 24 showed GI(50) values of 37.1 nM against MCF7 breast cancer cell line and 25.1 nM against MDA-MB-468 breast cancer cell line. (C) 2016 Elsevier Masson SAS. All rights reserved.