3-Hydroxypyrimidine-2,4-dione-5-N-benzylcarboxamides Potently Inhibit HIV-1 Integrase and RNase H

Bulan Wu, Jing Tang, Daniel J. Wilson, Andrew D. Huber, Mary C. Casey, Juan Ji, Jayakanth Kankanala, Jiashu Xie, Stefan G. Sarafianos, Zhengqiang Wang

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43 Scopus citations


Resistance selection by human immunodeficiency virus (HIV) toward known drug regimens necessitates the discovery of structurally novel antivirals with a distinct resistance profile. On the basis of our previously reported 3-hydroxypyrimidine-2,4-dione (HPD) core, we have designed and synthesized a new integrase strand transfer (INST) inhibitor type featuring a 5-N-benzylcarboxamide moiety. Significantly, the 6-alkylamino variant of this new chemotype consistently conferred low nanomolar inhibitory activity against HIV-1. Extended antiviral testing against a few raltegravir-resistant HIV-1 clones revealed a resistance profile similar to that of the second generation INST inhibitor (INSTI) dolutegravir. Although biochemical testing and molecular modeling also strongly corroborate the inhibition of INST as the antiviral mechanism of action, selected antiviral analogues also potently inhibited reverse transcriptase (RT) associated RNase H, implying potential dual target inhibition. In vitro ADME assays demonstrated that this novel chemotype possesses largely favorable physicochemical properties suitable for further development.

Original languageEnglish (US)
Pages (from-to)6136-6148
Number of pages13
JournalJournal of medicinal chemistry
Issue number13
StatePublished - Jul 14 2016

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© 2016 American Chemical Society.


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