Structure simplification of GNE-140 and discovery of a pyridone based analogue as a potential lead for hLDHA inhibitors

Abstract

Abstract In this paper, taking GNE-140, a structurally complicated hLDHA inhibitor, as a lead compound, 19 simple analogues with a pyrimidone, pyranone or pyridone core were designed and conveniently synthesized. Subsequent biological evaluation indicated that although the pyrimidone core had a weak contribution to hLDHA inhibition, compounds with pyranone or pyridone core exhibited better anti-hLDHA activity. Notably, pyridone-bearing compound 1c showed significant selective inhibition of hLDHA (IC50 = 19.5 ± 2.9 µM) over hLDHB (IC50 = 117.6 ± 13.2 µM). Meanwhile, 1c showed inhibition on the lactate production of lung cancer cell A549. Thus, the result of this study indicated 1c is worthy of further study owing to its convenient synthesis and strong selective hLDHA inhibition.