Discovery of a novel 5-carbonyl-1H-imidazole-4-carboxamide class of inhibitors of the HIV-1 integrase–LEDGF/p75 interaction
2013
Serrao, Erik | Xu, Zhong-Liang | Debnath, Bikash | Christ, Frauke | Debyser, Zeger | Long, Ya-Qiu | Neamati, Nouri
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.
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