2-Quinolone-1,2,3-triazole-benzofuran-N-acylhydrazone hybrids as antiviral and antimicrobial agents: synthesis, in vitro screening and molecular modeling.

To address the growing threat of coinfections and microbial resistance, this study reports the synthesis of a novel multi-pharmacophore scaffold combining 2-quinolone, 1,2,3-triazole, benzofuran and N-acylhydrazone moieties. These hybrids were characterized spectroscopically and assessed for their antiviral, antibacterial and antifungal activities. Most of the tested compounds exhibited interesting efficacy against multiple microbial species. Compound 6a exhibited potent broad-spectrum antimicrobial activity; it completely inhibited E. coli and P. aeruginosa at 0.15 µmol/mL and showed even greater potency against S. aureus (0.08 µmol/mL), outperforming ampicillin and rifampicin. It also inhibited C. glabrata at 0.15 µmol/mL, being 22-fold more potent than fluconazole. Compound 6j displayed dual efficacy against HSV-2 (EC50 = 54.69 µM) and S. aureus (MBC = 0.13 µmol/mL), alongside activity against the fungal strains C. albicans, C. glabrata and C. tropicalis (all with MFCs of 0.25 µmol/mL). Compound 6 m was 4-fold more active than ampicillin against S. aureus (MIC = MBC = 0.07 µmol/mL) and was highly effective against all tested Candida strains (0.14-0.29 µmol/mL). Compound 6p demonstrated pronounced efficacy toward S. aureus and C. albicans at MICs of 0.07 µmol/mL. These active leads (6a, 6j, 6 m and 6p) presented low-to-moderate cytotoxicity on human embryonic lung (HEL) cells, showing morphological changes at MCC values ranging from 20 to 100 µM. Molecular docking revealed high microbial target affinities (binding energies from - 7.1 to - 11.0 kcal/mol), while dynamics simulations confirmed stable 6j binding to S. aureus DNA gyrase and HSV-2 protease. Coupled with favorable ADMET profiles, these hybrids represent promising multitarget antimicrobial candidates.