A new series of thiazole
central scaffold-based small molecules
of hLDHA inhibitors were designed using an in silico approach. Molecular docking analysis of designed
molecules with hLDHA (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 NO2 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 hLDHA inhibitory activities and in vitro anticancer activity in six cancer cell lines. Biochemical enzyme
inhibition assays showed the highest hLDHA inhibitory
activity observed with compounds 8b, 8c,
and 8l. Compounds 8b, 8c, 8j, 8l, and 8m depicted significant
anticancer activities, exhibiting IC50 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 IC50 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). Insilico 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.