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

Vunnam Srinivasulu, Monther Khanfar, Hany A. Omar, Raafat Elawady, Scott Mc N. Sieburth, Anusha Sebastian, Dana M. Zaher, Farah Al-Marzooq, Fatema Hersi, Taleb H. Al-Tel

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)14476-14486
Number of pages11
JournalJournal of Organic Chemistry
Volume84
Issue number22
DOIs
Publication statusPublished - Nov 15 2019
Externally publishedYes

ASJC Scopus subject areas

  • Organic Chemistry

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