Development of thiazole-5-carboxylate derivatives as selective inhibition of monoacylglycerol lipase as a target in Cancer.

The signalling function of 2-arachidonoylglycerol (2-AG) in endocannabinoid system is delineated by Monoacylglycerol lipase (MAGL). MAGL readdresses the lipid stores in the direction of pro-tumorigenic signalling lipids in cancer cells. Selective as well as potent MAGL inhibitors are limited in number hence their continuous development may lead to a breakthrough invention in the field of MAGL inhibitors. In succession of the above, we have synthesised 2-amino-4-methylthiazole-5-carboxylate derivatives and characterized them by collective use of IR, 1H-NMR, 13C-NMR, Mass spectral data and elemental analysis. Thirteen compounds (3c-g, 4c, 4e, 4f and 6b-f) inhibited MAGL with IC50 value 0.037-9.60 µM. Two compounds (3g and 4c) were found most potent with IC50 value 0.037 and 0.063µM respectively. Thirty synthesised compounds were sent to NCI for anticancer screening, out of which nine compounds were selected for one dose anticancer assay. Compounds 3g(NSC:788170) and 4c(NSC:788176)were found to be most potent during one dose anticancer screening and fulfilled the specified threshold for growth inhibition criteria of NCI and were further selected for full panel five dose assay at 10-fold dilutions of five different concentrations. The compound 3g displayed GI50 value 0.865 µM against EKVX (Non-Small Cell Lung Cancer cell line), and 1.20 µM against MDA-MB-468(Breast Cancer cell Line), while (4c) showed GI50 value 0.34 and 0.96 µM against HOP-92 and EKVX (Non-Small Cell Lung Cancer cell line) and 1.08 µM against MDA-MB-231/ATCC (Breast Cancer cell Line). In addition, molecular docking studies of the said MAGL inhibitors have also been presented in this article.