Sequencing [4 + 1]-Cycloaddition and Aza-Michael Addition Reactions: A Diastereoselective Cascade for the Rapid Access of Pyrido[2′,1′:2,3]/Thiazolo[2′,3′:2,3]imidazo[1,5‑a]quinolone Scaffolds as Potential Antibacterial and Anticancer Motifs

The design and synthesis of a quality compound library containing a small number of skeletally diverse scaffolds, whose members rapidly deliver new chemical probes active against multiple phenotypes, is paramount in drug discovery. In this context, an efficient one-pot strategy for the synthesis of a mini library of sp3-enriched hexa­hydropyrido­[2′,1′:2,3]­imidazo­[1,5-a]­quinolinium and hexa­hydrothiazolo­[2′,3′:2,3]­imidazo­[1,5-a]­quinolinium architectures, is described. This new one-pot method features a combination of Sc­(OTf)3-catalyzed [4 + 1]-cycloaddition with aza-Michael addition reactions. The cascade results in a rapid and diastereoselective formation of these scaffolds via desymmetrization of the oxidative dearomatization products of phenols. Phenotypic screening of the mini library against multiple drug-resistant bacteria and a panel of cancer cell lines identified potential antibacterial and anticancer lead drug candidates. Further investigation of the anticancer leads, indicated by their activity as tubulin-polymerization inhibitors, represents a promising approach for cancer therapy.