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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.
J Org Chem 2019; 84(22):14476-14486JO

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.

Authors+Show Affiliations

Sharjah Institute for Medical Research , University of Sharjah , P.O. Box 27272, Sharjah , UAE.Department of Chemistry , University of Jordan , 11942 Amman , Jordan.Sharjah Institute for Medical Research , University of Sharjah , P.O. Box 27272, Sharjah , UAE. College of Pharmacy , University of Sharjah , P.O. Box 27272, Sharjah , UAE.Sharjah Institute for Medical Research , University of Sharjah , P.O. Box 27272, Sharjah , UAE. College of Pharmacy , University of Sharjah , P.O. Box 27272, Sharjah , UAE.Temple University , Department of Chemistry , 201 Beury Hall , Philadelphia , Pennsylvania 19122 , United States.Sharjah Institute for Medical Research , University of Sharjah , P.O. Box 27272, Sharjah , UAE.Sharjah Institute for Medical Research , University of Sharjah , P.O. Box 27272, Sharjah , UAE.Sharjah Institute for Medical Research , University of Sharjah , P.O. Box 27272, Sharjah , UAE.Sharjah Institute for Medical Research , University of Sharjah , P.O. Box 27272, Sharjah , UAE.Sharjah Institute for Medical Research , University of Sharjah , P.O. Box 27272, Sharjah , UAE. College of Pharmacy , University of Sharjah , P.O. Box 27272, Sharjah , UAE.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31633919

Citation

Srinivasulu, Vunnam, et al. "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 Journal of Organic Chemistry, vol. 84, no. 22, 2019, pp. 14476-14486.
Srinivasulu V, Khanfar M, Omar HA, et al. 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. J Org Chem. 2019;84(22):14476-14486.
Srinivasulu, V., Khanfar, M., Omar, H. A., ElAwady, R., Sieburth, S. M., Sebastian, A., ... Al-Tel, T. H. (2019). 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 Journal of Organic Chemistry, 84(22), pp. 14476-14486. doi:10.1021/acs.joc.9b01919.
Srinivasulu V, et al. 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. J Org Chem. 2019 Nov 15;84(22):14476-14486. PubMed PMID: 31633919.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Srinivasulu,Vunnam, AU - Khanfar,Monther, AU - Omar,Hany A, AU - ElAwady,Raafat, AU - Sieburth,Scott McN, AU - Sebastian,Anusha, AU - Zaher,Dana M, AU - Al-Marzooq,Farah, AU - Hersi,Fatema, AU - Al-Tel,Taleb H, Y1 - 2019/10/31/ PY - 2019/10/22/pubmed PY - 2019/10/22/medline PY - 2019/10/22/entrez SP - 14476 EP - 14486 JF - The Journal of organic chemistry JO - J. Org. Chem. VL - 84 IS - 22 N2 - 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. SN - 1520-6904 UR - https://www.unboundmedicine.com/medline/citation/31633919/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 DB - PRIME DP - Unbound Medicine ER -