I2-Catalyzed Cascade Annulation/Cross-Dehydrogenative Coupling: Excellent Platform to Access 3-Sulfenyl Pyrazolo[1,5-a]pyrimidines with Potent Antibacterial Activity against Pseudomonas aeruginosa and Staphylococcus aureus.

Abstract

The increasing resistance of bacteria to antibiotics has become a serious threat to existing options for treating bacterial infections. We have developed a synthetic methodology for 3-sulfenyl pyrazolo[1,5-a]pyrimidines with potent antibacterial activity. This iodine-catalyzed strategy has been developed by employing amino pyrazoles, enaminones/chalcones, and thiophenols through intermolecular cyclization and subsequent cross-dehydrogenative sulfenylation. This highly regioselective and practicable protocol has been utilized to synthesize structurally diverse 3-sulfenyl pyrazolo[1,5-a]pyrimidines with wide functionalities. This strategy is also extendable toward the synthesis of bis(pyrazolo[1,5-a]pyrimidin-3-yl)sulfanes from amino pyrazole, enaminones/chalcone, and KSCN and the synthesis of 3-sulfenyl pyrazolo[1,5-a]pyrimidine from direct acetophenone. Mechanistic investigation disclosed a radical pathway for C-H sulfenylation and the involvement of 3-iodo pyrazolo[1,5-a]pyrimidine as the active intermediate. The biological investigation disclosed the potent antibacterial activity of sulfenyl pyrazolo[1,5-a]pyrimidines against Pseudomonas aeruginosa and Staphylococcus aureus, whereas pyrazolo[1,5-a]pyrimidine and sulfinyl pyrazolo[1,5-a]pyrimidine have no such antibacterial activity. Sulfenyl pyrazolo[1,5-a]pyrimidines mechanistically inhibited bacterial growth by the accumulation of ROS as well as induction in lipid peroxidation. Subsequently, such circumstances changed the membrane potential and facilitated the interaction with membrane-associated proteins, leading to a loss in membrane integrity and damage to bacterial cell membranes. Moreover, these derivatives potentiated the antibacterial efficacy of the commercial antibiotic ciprofloxacin against the selected bacterial strains and can be considered an alternative therapy against these bacterial infections.