Isatin/thiosemicarbohydrazone hybrids: facile synthesis, and their evaluation as anti-proliferative agents and metabolic enzyme inhibitors

We are reporting a novel series of thiosemicarbazone derivatives derived from isatin (1-6), structural determination, and investigation of the inhibitory properties against proliferative, carbonic anhydrase, and cholinesterase enzymes. The anti-proliferative effects of the compounds were measured by XTT assay against MCF-7 and MDA-MB-231 cancerous cell lines. Compound 3 showed significant cytotoxic effects on both MCF-7 and MDA-MB-231 cell lines, with IC50 values of 8.19 & mu;M and 23.41 & mu;M, respectively. In addition, the compounds (1-6) inhibited the hCA I and II, their Ki values 2.01 & PLUSMN; 0.35 - 21.55 & PLUSMN; 2.56 and 1.24 & PLUSMN; 0.33 - 25.03 & PLUSMN; 5.48 & mu;M, respectively. AChE was also successfully inhibited by these compounds (1-6), with Ki values ranging from 40.37 & PLUSMN; 8.23 to 125.43 & PLUSMN; 24.93 & mu;M. The best Ki values for 3, 6, and 4 for & alpha;-glycosidase were 564.35 & PLUSMN; 72.06, 594.38 & PLUSMN; 52.04, and 683.437 & PLUSMN; 66.58 & mu;M, respectively. Binding affinities were determined to be-6.697 kcal/mol,-8.251 kcal/mol,-9.932 kcal/mol, and-4.946 kcal/mol for hCA I, hCA II, AChE, and & alpha;-glucosidase enzymes, respectively. These findings reveal that the formed compounds containing isatin moieties were crucial in the enzyme inhibition.