NDLI: Tetrahydropyrazolo[1,5-a]Pyrimidine-3-Carboxamide and N-Benzyl-6′,7′-Dihydrospiro[Piperidine-4,4′-Thieno[3,2-c]Pyran] Analogues with Bactericidal Efficacy against Mycobacterium tuberculosis Targeting MmpL3

Content Provider	PubMed Central
Author	Remuiñán, Modesto J. Esther, Pérez-herrán Joaquín, Rullás Alemparte, Carlos María, Martínez-hoyos Dow, David J. Afari, Johnson Mehta, Nalini Esquivias, Jorge Jiménez, Elena Ortega-muro, Fátima Teresa, Fraile-gabaldón María Spivey, Vickey L. Loman, Nicholas J. Pallen, Mark J. Constantinidou, Chrystala Minick, Douglas J. Cacho, Mónica José, Rebollo-lópez María González, Carolina Sousa, Verónica Iñigo, Angulo-barturen Alfonso, Mendoza-losana Barros, David Besra, Gurdyal S. Ballell, Lluís Cammack, Nicholas
Editor	Tyagi, Anil Kumar
Copyright Year	2013
Abstract	Mycobacterium tuberculosis is a major human pathogen and the causative agent for the pulmonary disease, tuberculosis (TB). Current treatment programs to combat TB are under threat due to the emergence of multi-drug and extensively-drug resistant TB. As part of our efforts towards the discovery of new anti-tubercular leads, a number of potent tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (THPP) and N-benzyl-6′,7′-dihydrospiro[piperidine-4,4′-thieno[3,2-c]pyran] (Spiro) analogues were recently identified against Mycobacterium tuberculosis and Mycobacterium bovis BCG through a high-throughput whole-cell screening campaign. Herein, we describe the attractive in vitro and in vivo anti-tubercular profiles of both lead series. The generation of M. tuberculosis spontaneous mutants and subsequent whole genome sequencing of several resistant mutants identified single mutations in the essential mmpL3 gene. This ‘genetic phenotype’ was further confirmed by a ‘chemical phenotype’, whereby M. bovis BCG treated with both the THPP and Spiro series resulted in the accumulation of trehalose monomycolate. In vivo efficacy evaluation of two optimized THPP and Spiro leads showed how the compounds were able to reduce >2 logs bacterial cfu counts in the lungs of infected mice.
Related Links	http://dx.doi.org/10.1371/journal.pone.0060933
Starting Page	60933
File Format	PDF
ISSN	19326203
e-ISSN	19326203
Journal	PLoS ONE
Issue Number	4
Volume Number	8
Language	English
Publisher	Public Library of Science
Publisher Date	2013-04-01
Access Restriction	Open
Rights Holder	Public Library of Science
Subject Keyword	Biochemistry, Genetics and Molecular Biology(all) Agricultural and Biological Sciences(all) Medicine(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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Synthesis of 2,3-disubstituted derivatives of pyrano-, thiopyrano-, and benzoannelated pyrido[2,3-b]thieno[3,2-d]pyrimidines

Tetrahydropyrazolo[1,5-a]Pyrimidine-3-Carboxamide and N-Benzyl-6′,7′-Dihydrospiro[Piperidine-4,4′-Thieno[3,2-c]Pyran] Analogues with Bactericidal Efficacy against Mycobacterium tuberculosis Targeting MmpL3

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