Synthesis and biological activity of furoxan derivatives against Mycobacterium tuberculosis

Author(s)

dos Santos Fernandes, Guilherme Felipe ; de Souza, Paula Carolina ; Marino, Leonardo Biancolino ; Chegaev, Konstantin ; Guglielmo, Stefano ; Lazzarato, Loretta ; Fruttero, Roberta ; Chung, Man Chin ; Pavan, Fernando Rogerio ; dos Santos, Jean Leandro

• Document type: Journal article
• Source: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 123, p. 523-531, NOV 10 2016.
• Web of Science Citations: 22

Abstract

Tuberculosis (TB) remains a serious health problem responsible to cause millions of deaths annually. The scenario becomes alarming when it is evaluated that the number of new drugs does not increase proportionally to the emergence of resistance to the current therapy. Furoxan derivatives, known as nitric oxide (NO) donors, have been described to exhibit antitubercular activity. Herein, a novel series of hybrid furoxan derivatives (1,2,5-oxadiazole 2-N-oxide) (compounds 4a-c, 8a-c and 14a-c) were designed, synthesized and evaluated in vitro against Mycobacterium tuberculosis (MTh) H(37)Rv (ATCC 27294) and a clinical isolate MDR-TB strain. The furoxan derivatives have exhibited MIC90 values ranging from 1.03 to 62 mu M (H(37)Rv) and 7.0-50.0 mu M (MDR-TB). For the most active compounds (8c, 14a, 14b and 14c) the selectivity index ranged from 3.78 to 52.74 (MRC-5 cells) and 1.25-34.78 (J774A.1 cells). In addition, it was characterized for those compounds logP(o/w), values between 2.1 and 2.9. All compounds were able to release NO at levels ranging from 0.16 to 44.23%. Among the series, the phenylsulfonyl furoxan derivatives (compounds 14a-c) were the best NO-donor with the lowest MIC90 values. The most active compound (14c) was also stable at different pHs (5.0 and 7.4). In conclusion, furoxan derivatives were identified as new promising compounds useful to treat tuberculosis. (C) 2016 Elsevier Masson SAS. All rights reserved. (AU)

• FAPESP's process: 13/14957-5 - Research potential against tuberculosis of a new class of furoxan compounds and nanostructured compounds of the ruthenium(II) and copper (II)
• Grantee: Fernando Rogério Pavan
• Support type: Research Grants - Young Investigators Grants
• FAPESP's process: 14/02240-1 - Design, Synthesis and anti Mycobacterium tuberculosis activity of new N-oxides derivatives
• Grantee: Guilherme Felipe dos Santos Fernandes
• Support type: Scholarships in Brazil - Master
• FAPESP's process: 14/24811-0 - Design and synthesis of new 1,4-di-N-oxide quinoxaline as antitubercular compounds to treat multi drug-resistant (MDR) and latent tuberculosis
• Grantee: Guilherme Felipe dos Santos Fernandes
• Support type: Scholarships abroad - Research Internship - Master's degree
• FAPESP's process: 14/11586-9 - Studies in vitro and in vivo of furoxan compounds with potential application for the treatment of tuberculosis
• Grantee: Paula Carolina de Souza
• Support type: Scholarships in Brazil - Doctorate