Synthesis of new phenothiazine-pyrazolo[1,5- <i>a</i> ]pyrimidine hybrids with promising antibacterial activity

Pharmacophores from bioactive compounds are joined by molecular hybridization to provide hybrids with improved bacterial inhibitory potency. In this work, some new phenothiazine-based 2,7-diarylpyrazolo[1,5-a]pyrimidines 1 connected to various aryl groups were prepared efficiently. The new hybrids were obtained, in 80-94% yields, by reacting the proper 3-aryl-1H-pyrazol-5-amines with phenothiazine-based enones in refluxing ethanol for 6–8 h. The reaction was catalyzed by choline hydroxide (46 wt% in H2O). A wide spectrum of bacterial inhibitory efficacy was observed by screening the new hybrids against various bacteria. In general, the presence of para-substituted aryl units connected to electron-withdrawing groups resulted in improved antibacterial efficacy. Hybrid 1c, attached to 4-chlorophenyl and 4-nitrophenyl units at pyrazolopyrimidine-C2 and C7, respectively, demonstrated good efficacy against S. aureus and E. coli with an MIC/MBC of 2.38/4.75 µM. Also, it showed promising anti-MRSA efficacy with an MIC/MBC of 4.75/19.0 µM.