Design, synthesis, antimicrobial evaluations and in silico studies of novel pyrazol-5(4H)-one and 1H-pyrazol-5-ol derivatives

Abstract

A new series of 1,4-disubstituted 3-methylpyrazol-5(4 H )-one derivatives were synthesized by reacting various substituted aromatic aldehydes with 3-methylpyrazol-5(4 H )-one derivatives through Knoevenagel condensation by conventional as well as by exposure to microwave irradiations. After that newly synthesized compounds of 1,4-disubstituted 3-methyl-1 H -pyrazol-5-ol were prepared from these derivatives by reduction reaction of sodium borohydride at 0–5 °C. Sixty-four heterocyclic compounds containing a pyrazole moiety were synthesized with good to excellent yields (51 to 91%). Compounds ( 3d , 3m , 4a , 4b , 4d , and 4g ) showed potent antibacterial activity against MSSA (Methicillin-susceptible strains of Staphylococcus aureus ) and MRSA (Methicillin-resistant strains of Staphylococcus aureus ) with MIC (the minimum inhibitory concentration) ranging between 4 and 16 µg/mL as compared to ciprofloxacin (MIC = 8–16 µg/mL). Compounds ( 4a , 4h , 4i , and 4l ) showed potent antifungal activity against Aspergillus niger with MIC ranging between 16 and 32 µg/mL as compared to fluconazole (MIC = 128 µg/mL). In particular, compound 4a exhibited the strongest activity among the synthesized compounds in both bacterial and fungal strains with MIC ranging between 4 and 16 µg/mL. Furthermore, the nine most active compounds showed a good ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile in comparison to ciprofloxacin and fluconazole as reference drugs. Molecular docking predicted that DHFR (dihydrofolate reductase) protein from Staphylococcus aureus and NMT ( N -myristoyl transferase) protein from Candida albicans are the most suitable targets for the antimicrobial activities of these potent compounds.