Dual-action antibacterial and anticancer agents: Design, synthesis, and mechanistic investigation of novel 4H-pyran-pyrazole hybrids.

Abstract

This study involved the design, synthesis, and comprehensive biological evaluation of a new library of 4H-pyran-pyrazole hybrid molecules. The compounds were synthesized via versatile multicomponent and cyclocondensation reactions and characterized using spectroscopic techniques. Their biological potential was assessed through a multifaceted in vitro approach. Cytotoxicity screening against MDA-MB-415, MCF-7, and HepG2 cancer cell lines and normal cells HFL-1 and WI-38 revealed moderate and weak dose-dependent effects. Notably, derivatives 13a and 13d exhibited superior potency against MCF-7 breast cancer cells (IC₅₀ = 66.70 and 105.91 μM, respectively), outperforming the standard drug Tamoxifen. Antimicrobial evaluation identified compounds 4 and 11 as standout leads. Compound 11 demonstrated broad-spectrum bactericidal activity against Gram-positive pathogens, potent inhibition of S. aureus biofilm formation at sub-MIC concentrations (74.2% reduction at ½ MIC), and favorable killing kinetics. Conversely, the parent scaffold 4 was highly effective against Gram-negative E. coli and was identified as a potent dual inhibitor of bacterial DNA gyrase (IC₅₀ = 67.51 μM) and topoisomerase IV (IC₅₀ = 74 μM). Antifungal activity revealed a divergent structure-activity relationship, with the lipophilic tricyclic derivative 9 emerging as a potent fungicidal agent. Molecular docking studies against P-glycoprotein and the S. aureus choline-binding domain provided rational structural insights into the observed antitumor and antimicrobial activities, highlighting key interactions for target engagement. The results establish a clear structure-activity relationship and identify 11 as a promising multi-action lead compound, combining potent bactericidal and antibiofilm activities, thereby offering a robust foundation for developing new anticancer and antimicrobial agents.