Discovery of a novel 5-carbonyl-1H-imidazole-4-carboxamide class of inhibitors of the HIV-1 integrase–LEDGF/p75 interaction

• Published in: Bioorganic & medicinal chemistry 2013-10, Vol.21 (19), p.5963-5972
• Main Authors: Serrao, Erik, Xu, Zhong-Liang, Debnath, Bikash, Christ, Frauke, Debyser, Zeger, Long, Ya-Qiu, Neamati, Nouri
• Format: Article
• Language: English
• Subjects: 2B4J; 5-carbonyl-1H-Imidazole-4-carboxamide; Aminoimidazole Carboxamide - analogs & derivatives; Aminoimidazole Carboxamide - chemical synthesis; Aminoimidazole Carboxamide - chemistry; Aminoimidazole Carboxamide - pharmacology; antiretroviral agents; Antiviral; Binding Sites; catalytic activity; Cells, Cultured; Drug Discovery; drugs; Enzyme Activation - drug effects; HIV Integrase Inhibitors - chemical synthesis; HIV Integrase Inhibitors - chemistry; HIV Integrase Inhibitors - pharmacology; HIV-1; Human immunodeficiency virus 1; Humans; Inhibitory Concentration 50; Integrase; Intercellular Signaling Peptides and Proteins - chemistry; LEDGF/p75; Models, Molecular; Molecular Structure; mutation; Protein Binding; Protein–protein interaction; screening; Structure-Activity Relationship; structure-activity relationships
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2013.07.047

Though much progress has been made in the inhibition of HIV-1 integrase catalysis, clinical resistance mutations have limited the promise of long-term drug prescription. Consequently, allosteric inhibition of integrase activity has emerged as a promising approach to antiretroviral discovery and development. Specifically, inhibitors of the interaction between HIV-1 integrase and cellular cofactor LEDGF/p75 have been validated to diminish proviral integration in cells and deliver a potent reduction in viral replicative capacity. Here, we have contributed to the development of novel allosteric integrase inhibitors with a high-throughput AlphaScreen-based random screening approach, with which we have identified novel 5-carbonyl-1H-imidazole-4-carboxamides capable of inhibiting the HIV-1 integrase–LEDGF/p75 interaction in vitro. Following a structure–activity relationship analysis of the initial 1H-imidazole-4,5-dicarbonyl core, we optimized the compound’s structure through an industrial database search, and we went further to synthesize a selective and non-cytotoxic panel of inhibitors with enhanced potency.