Synthesis and biological activity of furoxan derivatives against Mycobacterium tuberculosis

Autor(es)

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

• Tipo de documento: Artigo Científico
• Fonte: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY; v. 123, p. 523-531, NOV 10 2016.
• Citações Web of Science: 22

Resumo

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)

• Processo FAPESP: 14/11586-9 - Estudos in vitro e in vivo de compostos furoxânicos com potencial aplicação para o tratamento da tuberculose
• Beneficiário: Paula Carolina de Souza
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 14/24811-0 - Planejamento e síntese de novos derivados quinoxalinas 1,4-di-N-óxido como compostos para tratamento de tuberculose multiresistente (MDR) e latente
• Beneficiário: Guilherme Felipe dos Santos Fernandes
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Mestrado
• Processo FAPESP: 14/02240-1 - Planejamento, Síntese e Avaliação Anti Mycobacterium tuberculosis de Novos Derivados N-óxidos
• Beneficiário: Guilherme Felipe dos Santos Fernandes
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 13/14957-5 - Investigação do potencial contra tuberculose de uma nova classe de compostos furoxânicos e compostos nanoestruturados de rutênio(II) e cobre(II)
• Beneficiário: Fernando Rogério Pavan
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores