Optimized Synthesis of Novel C2-Substituted Benzo[B]thiophene Derivatives via Suzuki-Miyaura Cross-Coupling and Investigation of Their Biological Activities

Abstract

The paper presents the synthesis of benzo[b]thiophene derivatives with a sulfur-containing heterocyclic skeleton via the Suzuki-Miyaura cross-coupling reaction, process optimization, and investigation of their biological activity. The structures of the synthesized compounds were confirmed by 1H and 13C NMR spectroscopy and matrix-assisted laser desorption/ionization time of flight mass spectrometry. The yield was increased by using the most commonly used types of base, solvent, and catalyst. As a result of the studies, the best yield was observed with the Cs2CO3 base, the THF/H2O solvent mixture, and the Pd(OAc)2 + SPhos catalyst system. The synthesized molecules were evaluated for antibacterial activity against four clinical isolates (S. epidermidis, S. aureus, E. coli, and K. pneumoniae). Compound G1 exhibited potent antibacterial activity against Gram-positive strains, with MIC values of 32 mu g/mL (S. epidermidis) and 64 mu g/mL (S. aureus), superior to ampicillin. In order to predict the binding modes and interaction profiles of the compounds with the selected biological targets, molecular docking analyses were conducted using computational modeling approaches. SAR analysis was performed to assess the impact of structural changes on biological activity. These findings highlight the potential of benzo[b]thiophene scaffolds as privileged structures for diversity-driven synthesis and bioactivity-driven library design.