Antimycobacterial activity of pyrazinoate prodrugs in replicating and non-replicating Mycobacterium tuberculosis

Antimycobacterial activity of pyrazinoate prodrugs in replicating and non-replicating Mycobacterium tuberculosis

Author Segretti, Natanael Dante Google Scholar
Simoes, Cristina Kortstee Autor UNIFESP Google Scholar
Correa, Michelle Fidelis Autor UNIFESP Google Scholar
Andres Felli, Veni Maria Google Scholar
Miyata, Marcelo Google Scholar
Cho, Sang Hyun Google Scholar
Franzblau, Scott Gary Google Scholar
dos Santos Fernandes, Joao Paulo Autor UNIFESP Google Scholar
Abstract Tuberculosis (TB) is an important infectious disease caused by Mycobacterium tuberculosis (Mtb) and responsible for thousands of deaths every year. Although there are antimycobacterial drugs available in therapeutics, just few new chemical entities have reached clinical trials, and in fact, since introduction of rifampin only two important drugs had reached the market. Pyrazinoic acid (POA), the active agent of pyrazinamide, has been explored through prodrug approach to achieve novel molecules with anti-Mtb activity, however, there is no activity evaluation of these molecules against non-replicating Mtb until the present. Additionally, pharmacokinetic must be preliminary evaluated to avoid future problems during clinical trials. In this paper, we have presented six POA esters as prodrugs in order to evaluate their anti-Mtb activity in replicating and non-replicating Mtb, and these showed activity highly influenced by medium composition (especially by albumin). Lipophilicity seems to play the main role in the activity, possibly due to controlling membrane passage. Novel duplicated prodrugs of POA were also described, presenting interesting activity. Cytotoxicity of these prodrugs set was also evaluated, and these showed no important cytotoxic profile. (C) 2016 Elsevier Ltd. All rights reserved.
Keywords Antimycobacterial prodrug
Duplicated prodrug
LORA assay
Pyrazinoate ester
xmlui.dri2xhtml.METS-1.0.item-coverage Edinburgh
Language English
Sponsor Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)
Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)
Grant number FAPESP: 2013/20479-9
Date 2016
Published in Tuberculosis. Edinburgh, v. 99, p. 11-16, 2016.
ISSN 1472-9792 (Sherpa/Romeo, impact factor)
Publisher Churchill Livingstone
Extent 11-16
Access rights Closed access
Type Article
Web of Science ID WOS:000380756100002

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