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Indole-based allosteric inhibitors of HIV-1 integrase.

ABSTRACT: Employing a scaffold hopping approach, a series of allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) have been synthesized based on an indole scaffold. These compounds incorporate the key elements utilized in quinoline-based ALLINIs for binding to the IN dimer interface at the principal LEDGF/p75 binding pocket. The most potent of these compounds displayed good activity in the LEDGF/p75 dependent integration assay (IC50=4.5?M) and, as predicted based on the geometry of the five- versus six-membered ring, retained activity against the A128T IN mutant that confers resistance to many quinoline-based ALLINIs.

SUBMITTER: Patel PA

PROVIDER: S-EPMC5018460 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Indole-based allosteric inhibitors of HIV-1 integrase.

Patel Pratiq A PA Kvaratskhelia Nina N Mansour Yara Y Antwi Janet J Feng Lei L Koneru Pratibha P Kobe Mathew J MJ Jena Nivedita N Shi Guqin G Mohamed Mosaad S MS Li Chenglong C Kessl Jacques J JJ Fuchs James R JR

Bioorganic & medicinal chemistry letters 20160813 19

Employing a scaffold hopping approach, a series of allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) have been synthesized based on an indole scaffold. These compounds incorporate the key elements utilized in quinoline-based ALLINIs for binding to the IN dimer interface at the principal LEDGF/p75 binding pocket. The most potent of these compounds displayed good activity in the LEDGF/p75 dependent integration assay (IC50=4.5μM) and, as predicted based on the geometry of the five- versus six-me ...[more]

PMID: 27568085

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