Design, Synthesis, and Biological Evaluations of Hydroxypyridone­carboxylic Acids as Inhibitors of HIV Reverse Transcriptase Associated RNase H

Targeting the clinically unvalidated
reverse transcriptase (RT) associated ribonuclease H (RNase H) for
human immunodeficiency virus (HIV) drug discovery generally entails
chemotypes capable of chelating two divalent metal ions in the RNase
H active site. The hydroxypyridone­carboxylic acid scaffold has
been implicated in inhibiting homologous HIV integrase (IN) and influenza
endonuclease via metal chelation. We report herein the design, synthesis,
and biological evaluations of a novel variant of the hydroxypyridone­carboxylic
acid scaffold featuring a crucial N-1 benzyl or biarylmethyl
moiety. Biochemical studies show that most analogues consistently
inhibited HIV RT-associated RNase H in the low micromolar range in
the absence of significant inhibition of RT polymerase or IN. One
compound showed reasonable cell-based antiviral activity (EC50 = 10 μM). Docking and crystallographic studies corroborate
favorable binding to the active site of HIV RNase H, providing a basis
for the design of more potent analogues.