Segretti Natanael Dante, Simões Cristina Kortstee, Corrêa Michelle Fidelis, Felli Veni Maria Andres, Miyata Marcelo, Cho Sang Hyun, Franzblau Scott Gary, Fernandes João Paulo Dos Santos
Departamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, Av. Prof. Lineu Prestes 580, 05508-000 Butantã, São Paulo, SP, Brazil.
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.
Tuberculosis (Edinb). 2016 Jul;99:11-16. doi: 10.1016/j.tube.2016.04.002. Epub 2016 Apr 9.
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.
结核病（TB）是由结核分枝杆菌（Mtb）引起的一种重要传染病，每年导致数千人死亡。尽管治疗中有抗分枝杆菌药物，但只有少数新化学实体进入临床试验，事实上，自利福平问世以来，只有两种重要药物进入市场。吡嗪酰胺的活性剂吡嗪酸（POA）已通过前药方法进行研究，以获得具有抗结核分枝杆菌活性的新分子，然而，直到现在，这些分子对非复制型结核分枝杆菌的活性尚未得到评估。此外，必须对药代动力学进行初步评估，以避免临床试验期间出现未来问题。在本文中，我们展示了六种作为前药的POA酯，以评估它们在复制型和非复制型结核分枝杆菌中的抗结核分枝杆菌活性，结果表明这些活性受培养基组成（尤其是白蛋白）的影响很大。亲脂性似乎在活性中起主要作用，这可能是由于它控制了膜的通透性。还描述了POA的新型重复前药，它们具有有趣的活性。我们还评估了这些前药组合的细胞毒性，结果表明它们没有重要的细胞毒性特征。
