title: Antimycobacterial activity of pyrazinoate prodrugs in replicating and non-replicating Mycobacterium tuberculosis.
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.
authors.affiliation: Departamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, Av. Prof. Lineu Prestes 580, 05508-000 Butantã, São Paulo, SP, Brazil.
authors.forename: Natanael Dante
authors.initials: ND
authors.lastname: Segretti
authors.affiliation: Departamento de Ciências Exatas e da Terra, Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, Rua São Nicolau 210, 09913-030 Centro, Diadema, SP, Brazil.
authors.forename: Cristina Kortstee
authors.initials: CK
authors.lastname: Simões
authors.affiliation: Departamento de Ciências Exatas e da Terra, Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, Rua São Nicolau 210, 09913-030 Centro, Diadema, SP, Brazil.
authors.forename: Michelle Fidelis
authors.initials: MF
authors.lastname: Corrêa
authors.affiliation: Departamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, Av. Prof. Lineu Prestes 580, 05508-000 Butantã, São Paulo, SP, Brazil.
authors.forename: Veni Maria Andres
authors.initials: VMA
authors.lastname: Felli
authors.affiliation: Departamento de Ciências Biológicas, Faculdade de Ciências Farmacêuticas, Universidade Estadual Paulista "Júlio de Mesquita Filho", Rodovia Araraquara-Jaú km 1, 14801-902, Araraquara, SP, Brazil.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Miyata
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood St., 60612-7231 Chicago, IL, USA.
authors.forename: Sang Hyun
authors.initials: SH
authors.lastname: Cho
authors.affiliation: Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood St., 60612-7231 Chicago, IL, USA.
authors.forename: Scott Gary
authors.initials: SG
authors.lastname: Franzblau
authors.affiliation: Departamento de Ciências Exatas e da Terra, Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, Rua São Nicolau 210, 09913-030 Centro, Diadema, SP, Brazil. Electronic address: joao.fernandes@unifesp.br.
authors.forename: João Paulo Dos Santos
authors.initials: JPDS
authors.lastname: Fernandes
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D004952:Esters / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D011355:Prodrugs / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D011718:Pyrazinamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D013329:Structure-Activity Relationship; D014709:Vero Cells
chemical_list: D000995:Antitubercular Agents; D004952:Esters; D011355:Prodrugs; D011718:Pyrazinamide; C005296:pyrazinoic acid
keywords: Antimycobacterial prodrug; Duplicated prodrug; LORA assay; Pyrazinoate ester