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

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 <i>in vitro</i> 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 <i>E. coli</i>; 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 <i>S. aureus</i>. Finally, SAR was discussed, revealing the essential role of the <i>N</i>-aryl and/or heteroaryl moiety in directing the biological activity of each compound towards a specific target. An <i>in silico</i> 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 <i>via</i> modulation of the IL6/JAK2/STAT3 signaling pathway and representing promising building blocks as STAT3 inhibitors and antimicrobial leads for future modifications.