One-pot green synthesis of pyrazole-clubbed 2-amino-4H-pyrano[3,2-h]quinoline-3-carbonitrile derivatives as potent antimicrobial agents: in silico ADME and SAR studies

The escalating challenge of antimicrobial resistance (AMR) necessitates the development of novel therapeutic agents. In this study, we present an efficient, eco-friendly, and metal-free multicomponent synthesis of a new series of pyrazole-fused 2-amino-4H-pyrano[3,2-h]quinoline-3-carbonitrile derivatives (7a–j) via a piperidine-catalyzed, solvent-free liquid-assisted grinding (LAG) method. This green synthetic approach yields the target compounds in excellent yields without the need for purification or toxic reagents. The synthesized compounds were evaluated in vitro for antimicrobial activity against gram-positive (Bacillus cereus, Staphylococcus aureus), gram-negative (Escherichia coli, Pseudomonas aeruginosa) bacteria, and pathogenic fungi (Candida albicans, Candida tropicalis). Notably, derivatives 7b, d, e, and j exhibited significant activity, with minimum inhibitory concentration (MIC) values comparable to or exceeding those of standard drugs. Structure–activity relationship (SAR) analysis and in silico ADME profiling of the active compounds (7b, d, e and j) revealed favorable pharmacokinetic and safety profiles, highlighting their potential as promising antimicrobial candidates. This work underscores the value of green synthetic methodologies in drug discovery and provides a foundation for the further development of pyrano[3,2-h] quinoline-based antimicrobial agents.

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