TY - JOUR
T1 - Design, Synthesis, and Biological Evaluations of Hydroxypyridonecarboxylic Acids as Inhibitors of HIV Reverse Transcriptase Associated RNase H
AU - Kankanala, Jayakanth
AU - Kirby, Karen A.
AU - Liu, Feng
AU - Miller, Lena
AU - Nagy, Eva
AU - Wilson, Daniel J.
AU - Parniak, Michael A.
AU - Sarafianos, Stefan G.
AU - Wang, Zhengqiang
N1 - Publisher Copyright:
© 2016 American Chemical Society.
PY - 2016/5/26
Y1 - 2016/5/26
N2 - 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 μ). 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.
AB - 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 μ). 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.
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U2 - 10.1021/acs.jmedchem.6b00465
DO - 10.1021/acs.jmedchem.6b00465
M3 - Article
C2 - 27094954
AN - SCOPUS:84971671274
SN - 0022-2623
VL - 59
SP - 5051
EP - 5062
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 10
ER -