Exploration of Pyrazole-Sulfonamide Hybrids: Synthesis, Molecular Modeling, Potential Antimicrobial, DHFR Inhibitor,...

New pyrazolyl sulfonamide conjugates 5, 6, and 7 were synthesized by reacting N-(4-(hydrazinecarbonyl) aryl) benzenesulfonamide with acetyl acetone, ethyl acetoacetate, and/or 2-(ethoxymethylene)malononitrile. The DFT computations of the constructed derivatives exhibited comparable bent shapes. The conjugates 5a-b and 6a-b displayed parallel HOMO-LUMO structures, whereas the nitro-derivatives 5c and 6c exhibited alternative configurations of their FMOs. Furthermore, the antimicrobial activity was assessed against different bacterial and fungal pathogens. Pyrazole derivatives 5c, 6b, 7a, and 7c exhibited high activity against S. aureus (MIC = 3.125-6.25 μg/mL) and E. coli (MIC = 3.125 μg/mL), exceeding the activity of standard antibiotics, with 6b demonstrating the broadest spectrum of activity against both bacteria and fungi. The in vitro DHFR inhibitory effects of the investigated sulfonamides were examined and compared with those of methotrexate. Among the screened derivatives, hybrids 7a-c displayed more potent inhibitory activities, thereby determining the effect of substitution patterns on activity. Additionally, the molecular docking of the manufactured analogs against the dihydrofolate reductase enzyme (PDB: 3TZF) was investigated, where hybrid 6a exhibited the highest activity with a binding score (S = -6.5129 kcal/mol), which was greater than that of methotrexate (S = -6.4743 kcal/mol). Moreover, pharmacokinetic characteristics were simulated using SwissADME to evaluate drug-likeness and potential oral bioavailability. All hybrids exhibited beneficial physicochemical properties within acceptable drug-likeness limits, confirming the pyrazole-sulfonamide scaffold as an optimization target for future orally active drug candidates with good pharmacokinetic potential.