Design, synthesis, antimicrobial evaluation, molecular docking studies, and in silico prediction of ADME properties for novel pyrazolo[1,5-a]pyrimidine and its fused derivatives

Abstract

Dienamine 2 was synthesized by reacting 5-aminopyrazole 1 with two moles of (DMF DMA). Enamine 2 underwent subsequent reactions with various reagents in different reaction media, leading to the formation of distinct compounds. In an acidic environment, enamine 2 reacted with acetyl acetone, benzoyl acetone, dimedone, and ethyl acetoacetate, resulting in the synthesis of compounds 9a, 9b, 13, and 17, respectively. Conversely, in a basic medium, dienamine 2 combined with malononitrile, ethyl cyanoacetate, and malononitrile dimer, yielding compounds 21a, 21b, and 25. Moreover, by reacting with ammonium acetate in acetic acid, dienamine 2 produced compounds 28. The synthesized compounds underwent in vitro testing against various bacterial and fungal strains, revealing significant antibacterial activity against hazardous bacterial strains. To identify potential bacterial targets, an in-silico study was initiated. Molecular docking investigations indicated that compound 25 exhibited the highest binding affinity toward dihydrofolate reductase and penicillin-binding proteins. Furthermore, compound 25 demonstrated robust physiochemical properties, bioavailability, and drug-like characteristics. These results collectively suggest the potential of compound 25 as a promising antibacterial agent with favorable drug properties.