Design and Synthesis of Thiazole Scaffold-Based Small Molecules as Anticancer Agents Targeting the Human Lactate Dehydrogenase A Enzyme.

A new series of thiazole central scaffold-based small molecules of h LDHA inhibitors were designed using an in silico approach. Molecular docking analysis of designed molecules with h LDHA (PDB ID: 1I10) demonstrates that Ala 29, Val 30, Arg 98, Gln 99, Gly 96, and Thr 94 possessed strong interaction with the compounds. Compounds 8a , 8b , and 8d showed good binding affinity (-8.1 to -8.8 kcal/mol), whereas an additional interaction of NO 2 at the ortho position in compounds 8c with Gln 99 through hydrogen bonding enhanced the affinity to -9.8 kcal/mol. Selected high-scored compounds were synthesized and screened for h LDHA inhibitory activities and in vitro anticancer activity in six cancer cell lines. Biochemical enzyme inhibition assays showed the highest h LDHA inhibitory activity observed with compounds 8b , 8c , and 8l . Compounds 8b , 8c , 8j , 8l , and 8m depicted significant anticancer activities, exhibiting IC 50 values in the range of 1.65-8.60 μM in HeLa and SiHa cervical cancer cell lines. Compounds 8j and 8m exhibited notable anticancer activity with IC 50 values of 7.90 and 5.15 μM, respectively, in liver cancer cells (HepG2). Interestingly, compounds 8j and 8m did not induce noticeable toxicity in the human embryonic kidney cells (HEK293). In silico absorption, distribution, metabolism, and excretion profiling demonstrates that the compounds possess drug-likeness, and results may pave the way for the development of novel thiazole-based biologically active small molecules for therapeutics.