Design, synthesis and SAR of novel naphthalene–sulfonamide hybrids: anticancer assessment, gene expression analysis of IL6/JAK2/STAT3 signaling in MCF7 cells and antimicrobial evaluation

Abstract

A multi-target and molecular hybridization drug design approach was used in the design and synthesis of novel 6-acetylnaphthalene-2-sulfonamide derivatives (5a–5j) for anticancer and antimicrobial evaluation. The compounds 5a, 5b, 5e, and 5i revealed the most cytotoxic activity against the human breast cancer cell line (MCF7) with a good safety profile against the normal Madin–Darby canine kidney cell line (MDCK). Compounds 5b and 5i exhibited significant antiproliferative activity in MCF7 cells by downregulating IL6, JAK2, STAT3, BCL2, Cyclin D1, and c-MYC, while upregulatiing BAX expression levels, relative to control values, as confirmed by qRT-PCR analysis. Moreover, the antibacterial and anti-mycotic activities for 5a–5j were assessed, and the minimum inhibitory concentration (MIC) was evaluated for the promising compounds. In in vitro enzymatic assays, compounds 5e and 5b potently inhibited STAT3 phosphorylation with IC₅₀ = 3.01 μM and 3.59 μM, respectively, compared with cryptotanshinone (IC₅₀ = 3.52 μM); compound 5b potently inhibited topoisomerase IV (IC₅₀ = 5.3 μg mL⁻¹, norfloxacin IC₅₀ = 8.24 μg mL⁻¹) and moderately inhibited DNA gyrase in E. coli; and compound 5e effectively inhibited topoisomerase IV (IC₅₀ = 7.65 μg mL⁻¹, norfloxacin IC₅₀ = 7.07 μg mL⁻¹) and moderately inhibited DNA gyrase in S. aureus. Finally, SAR was discussed, revealing the essential role of the N-aryl and/or heteroaryl moiety in directing the biological activity of each compound towards a specific target. An in silico study was performed to predict ADME and docking for the promising hybrids. Collectively, the 6-acetylnaphthalene-2-sulfonamide hybrids suppressed MCF7 cell proliferation and induced apoptosis via modulation of the IL6/JAK2/STAT3 signaling pathway and representing promising building blocks as STAT3 inhibitors and antimicrobial leads for future modifications.