Accelerated Synthesis of Novel Indole-3-Sulfonamides Leveraging High-Throughput Experimentation

Abstract Non-nucleoside reverse transcriptase inhibitors are key compounds of current antiretroviral therapy for people living with human immunodeficiency virus (HIV). Indole-3-sulfonamides have demonstrated good biological profile against HIV. Here we describe a high-throughput experimentation (HTE)-compatible route to access indole-3-sulfonamides through a selective activation of the S–N bond of a primary indole-3-sulfonamide. This selective activation strategy enables efficient installation of diverse amine substituents with broad functional-group tolerance. Cheminformatic tools were integrated into the workflow to analyze accessible chemical space, prioritize amine nucleophiles, and guide building-block selection to maximize structural diversity. The protocol rapidly delivered a set of novel indole-3-sulfonamide analogs, demonstrating practical applicability and efficiency for medicinal chemistry campaigns.