Synthesis and biological activity of furoxan derivatives against Mycobacterium tuberculosis.

Autor: Fernandes GFDS; School of Pharmaceutical Sciences, UNESP - Univ Estadual Paulista, Araraquara, 14800903, Brazil., de Souza PC; School of Pharmaceutical Sciences, UNESP - Univ Estadual Paulista, Araraquara, 14800903, Brazil., Marino LB; School of Pharmaceutical Sciences, UNESP - Univ Estadual Paulista, Araraquara, 14800903, Brazil., Chegaev K; Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Turin, 10124, Italy., Guglielmo S; Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Turin, 10124, Italy., Lazzarato L; Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Turin, 10124, Italy., Fruttero R; Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Turin, 10124, Italy., Chung MC; School of Pharmaceutical Sciences, UNESP - Univ Estadual Paulista, Araraquara, 14800903, Brazil., Pavan FR; School of Pharmaceutical Sciences, UNESP - Univ Estadual Paulista, Araraquara, 14800903, Brazil., Dos Santos JL; School of Pharmaceutical Sciences, UNESP - Univ Estadual Paulista, Araraquara, 14800903, Brazil. Electronic address: santosjl@fcfar.unesp.br.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2016 Nov 10; Vol. 123, pp. 523-531. Date of Electronic Publication: 2016 Jul 21.
DOI: 10.1016/j.ejmech.2016.07.039
Abstrakt: 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 (MTB) H37Rv (ATCC 27294) and a clinical isolate MDR-TB strain. The furoxan derivatives have exhibited MIC90 values ranging from 1.03 to 62 μM (H37Rv) and 7.0-50.0 μM (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 logPo/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.
(Copyright © 2016 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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