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 LDHA inhibitors were designed using an approach. Molecular docking analysis of designed molecules with 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 , , and showed good binding affinity (-8.1 to -8.8 kcal/mol), whereas an additional interaction of NO at the ortho position in compounds with Gln 99 through hydrogen bonding enhanced the affinity to -9.8 kcal/mol. Selected high-scored compounds were synthesized and screened for LDHA inhibitory activities and anticancer activity in six cancer cell lines. Biochemical enzyme inhibition assays showed the highest LDHA inhibitory activity observed with compounds , , and . Compounds , , , , and depicted significant anticancer activities, exhibiting IC values in the range of 1.65-8.60 μM in HeLa and SiHa cervical cancer cell lines. Compounds and exhibited notable anticancer activity with IC values of 7.90 and 5.15 μM, respectively, in liver cancer cells (HepG2). Interestingly, compounds and did not induce noticeable toxicity in the human embryonic kidney cells (HEK293). 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.