A PASE synthesis of tetrazoloquinolines and its applications in the syntheses of bioactive compounds

Abstract

Tetrazoloquinolines, formed by the fusion of quinoline and tetrazole moieties, can engage multiple biological targets, often resulting in improved potency and selectivity. As synthetic methods continue to advance, the exploration of these derivatives could significantly contribute to the discovery of new drug candidates with enhanced efficacy and reduced side effects. This study presents a novel pot, atom, step and economical (PASE) double-annulation strategy for the rapid synthesis of tetrazoloquinoline derivatives. Utilizing a cascade reaction process, we investigated the reactivity of readily available 2-azidobenzaldehydes to achieve the diverse synthesis of tetrazoloquinoline scaffolds with the structural tolerance of substrate types. This novel approach not only enhances the synthetic diversity and efficiency of tetrazoloquinolines with the step-economic process, validated by the successful cases such as HCV, CK2, and IRAK4 inhibitors, but also highlights the versatility of cascade reactions in heterocycles development, paving the way for further exploration of tetrazoloquinoline candidates in drug discovery. Additionally, a comprehensive green chemistry metrics analysis shows significant improvements in both process-efficiency and environmental impact over previously reported synthetic methods.