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.
Clicks: 269
ID: 63573
2019
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 multidrug resistant bacteria and a panel of cancer cell lines identified potential antibacterial and anticancer lead drug candidates. Further investigation of the anticancer leads, indicated their activity as tubulin-polymerization inhibitors, representing a promising approach for cancer therapy.
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| Authors | Srinivasulu, Vunnam;Khanfar, Monther A A;Omar, Hany A;ElAwady, Raafat;Sieburth, Scott McN;Sebastian, Anusha;Zaher, Dana M;Al Marzooq, Farah;Hersi, Fatema;Al-Tel, Taleb H; |
| Journal | The Journal of organic chemistry |
| Year | 2019 |
| DOI | 10.1021/acs.joc.9b01919 |
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