Studies on Cycloheptathiophene-3-carboxamide Derivatives as Allosteric HIV-1 RibonucleaseH Inhibitors

Despite the significant progress achieved with combination antiretroviral therapy in the fight against human immunodeficiency virus (HIV) infection, the difficulty to eradicate the virus together with the rapid emergence of multidrug-resistant strains clearly underline a pressing need for innovative agents, possibly endowed with novel mechanisms of action. In this context, owing to its essential role in HIV genome replication, the reverse transcriptase associated ribonucleaseH (RNaseH) has proven to be an appealing target. To identify new RNaseH inhibitors, an in-house cycloheptathiophene-3-carboxamide library was screened; this led to compounds endowed with inhibitory activity, the structural optimization of which led to the catechol derivative 2-(3,4-dihydroxybenzamido)-N-(pyridin-2-yl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide (compound 33) with an IC50 value on the RNaseH activity in the nanomolar range. Mechanistic studies suggested selective inhibition of the RNaseH through binding to an innovative allosteric site, which could be further exploited to enrich this class of inhibitors.