Rapid identification of novel indolylarylsulfone derivatives as potent HIV-1 NNRTIs <i>via</i> miniaturized CuAAC click-chemistry-based combinatorial libraries

This article presents the rapid identification of novel indolylarylsulfone (IAS) derivatives as potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) for HIV-1 through a miniaturized click-chemistry-based combinatorial library approach. Utilizing copper(i)-catalyzed azide-alkyne cycloaddition (CuAAC), a reliable and biocompatible click chemistry technique, the researchers synthesized and characterized a series of IAS derivatives. Several compounds selected through the <i>in situ</i> enzyme inhibition assay demonstrated promising activity in subsequent cellular level tests. Notably, compound C1N4 displayed the most potent anti-HIV-1 IIIB activity with an EC₅₀ of 0.024 μM and low cytotoxicity (CC₅₀ > 215.88 μM). Molecular docking studies provided insights into the binding mode of these novel compounds within the NNIBP, aiding in the structure-based design of future NNRTIs. The findings underscore the potential of click chemistry in the discovery of new anti-HIV agents with improved efficacy and safety profiles.