Assessment of the Physicochemical Properties and Stability for Pharmacokinetic Prediction of Pyrazinoic Acid Derivatives

Author(s)

Franchin, Taisa Busaranho ^[1] ; Ulian Silva, Bruna Cristina ^[1] ; DeGrandis, Rone Aparecido ^[2] ; Correa, Michelle Fidelis ^[3] ; Simoes de Queiroz Aranha, Cecilia Maria ^[3] ; Fernandes, Joao Paulo S. ^[3] ; Campos, Michel Leandro ^[4] ; Peccinini, Rosangela Goncalves ^[1]

Affiliation

^[1] Sao Paulo State Univ UNESP, Dept Nat Act Principles & Toxicol, Araraquara, SP - Brazil

^[2] Sao Paulo State Univ, Dept Biol Sci, Araraquara, SP - Brazil

^[3] Univ Fed Sao Paulo, Dept Pharmaceut Sci, Diadema, SP - Brazil

^[4] Univ Fed Mato Grosso, Hlth Res & Educ Ctr NUPADS, 1200 Alexandre Ferronato Ave, BR-78550728 Sinop, MT - Brazil

• Document type: Journal article
• Source: CURRENT DRUG METABOLISM; v. 21, n. 9, p. 714-721, 2020.
• Web of Science Citations: 0

Abstract

Background: Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis, which still has high prevalence worldwide. in addition, cases of drug resistance are frequently observed. In the search for new anti-TB drugs, compounds with antimycobacterial activity have been developed, such as derivatives of pyrazinoic acid, which is the main pyrazinamide metabolite. In a previous study, the compounds were evaluated and showed moderate antimycobacterial activity and no important cytotoxic profile; however, information about their pharmacokinetic profile is lacking. Objective: The aim of this work was to perform physicochemical, permeability, and metabolic properties of four pyrazinoic acid esters. Method: The compounds were analyzed for their chemical stability, n-octanol:water partition coefficient (logP) and apparent permeability (P-app) in monolayer of Caco-2 cells. The stability of the compounds in rat and human microsomes and in rat plasma was also evaluated. Results: The compounds I. II and IV were found to be hydrophilic, while compound Ill was the most lipophilic (logP 1.59) compound. All compounds showed stability at the three evaluated pHs (1.2, 7.4 and 8.8). The apparent permeability measured suggests good intestinal absorption of the compounds. Additionally, the compounds showed metabolic stability under action of human and rat microsomal enzymes and stability in rat plasma for at least 6 hours. Conclusion: The results bring favorable perspectives for the future development of the evaluated compounds and other pyrazinoic acid derivatives. (AU)

• FAPESP's process: 16/23139-2 - Synthesis and biological evaluation of the LINS01 series as procognitive agents: a multitarget approach
• Grantee: Michelle Fidelis Corrêa
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 16/25028-3 - Antihistamines H3R/H4R as procognitive agents: a multitarget approach
• Grantee: João Paulo dos Santos Fernandes
• Support Opportunities: Regular Research Grants
• FAPESP's process: 16/23229-1 - ADME study of drug candidates for the treatment of tuberculosis
• Grantee: Taísa Busaranho Franchin
• Support Opportunities: Scholarships in Brazil - Master