Microwave accelerated green access to functionalized pyrazolo[5,1-b]quinazoline-3-carboxylate scaffold and their pharmacological screening

Abstract

Herein, we explored an environmentally benign synthesis of pyrazolo[5,1-b]quinazoline-3-carboxylate derivatives 4(a-u) as potential antimicrobial, antitubercular as well as antimalarial agents. Our approach employed microwave-assisted PEG-400 as a biodegradable reaction medium to expedite the one-pot fusion of 1,3-dicarbonyl compounds 1(a-c), substituted aldehydes 2(a-g), and ethyl-3-aminopyrazole-4-carboxylate (3a). The current protocol offers the advantages of a low E-factor, high atom economy, mild reaction condition, reusability of PEG-400 and produce water as a byproduct with a favorable yield (up to 96% yield) in a short reaction time. Compared to the MIC values of standard antibiotics against their respective strains, compounds 4g exhibited superior activity against Bacillus subtilis while compound 4r demonstrated a more favorable MIC against Pseudomonas aeruginosa. Against Candida albicans, compounds 4c, 4f, 4i, 4o, 4r, and 4u showed excellent antifungal activity as compared standard medications griseofulvin and fluconazole. Compounds 4d and 4p showed significant antitubercular activity against Mycobacterium tuberculosis H37Rv whereas compounds 4d, 4e, 4p and 4q showed good antimalarial activity against Plasmodium falciparum in contrast to standard drug ciprofloxacin and quinine respectively. In vitro cytotoxicity assay against S. pombe cells indicated that the majority of tested compounds exhibit more than 80% cell viability, suggesting their non-toxic nature. A molecular docking study was conducted to elucidate the potential interactions between compound 4u and the active site of DNA gyrase. Based on the noteworthy findings from the investigation of drug-like properties and ADMET predictions, these derivatives depict an efficient multifunctional action and offer prospective access for future discoveries of antimicrobial, antitubercular, as well as antimalarial studies.