title: Synthesis and biological activity of furoxan derivatives against Mycobacterium tuberculosis.
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 (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.
authors: School of Pharmaceutical Sciences, UNESP - Univ Estadual Paulista, Araraquara, 14800903, Brazil.
authors: Guilherme Felipe Dos Santos
authors: GFDS
authors: Fernandes
authors: School of Pharmaceutical Sciences, UNESP - Univ Estadual Paulista, Araraquara, 14800903, Brazil.
authors: Paula Carolina
authors: PC
authors: de Souza
authors: School of Pharmaceutical Sciences, UNESP - Univ Estadual Paulista, Araraquara, 14800903, Brazil.
authors: Leonardo Biancolino
authors: LB
authors: Marino
authors: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Turin, 10124, Italy.
authors: Konstantin
authors: K
authors: Chegaev
authors: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Turin, 10124, Italy.
authors: Stefano
authors: S
authors: Guglielmo
authors: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Turin, 10124, Italy.
authors: Loretta
authors: L
authors: Lazzarato
authors: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Turin, 10124, Italy.
authors: Roberta
authors: R
authors: Fruttero
authors: School of Pharmaceutical Sciences, UNESP - Univ Estadual Paulista, Araraquara, 14800903, Brazil.
authors: Man Chin
authors: MC
authors: Chung
authors: School of Pharmaceutical Sciences, UNESP - Univ Estadual Paulista, Araraquara, 14800903, Brazil.
authors: Fernando Rogério
authors: FR
authors: Pavan
authors: School of Pharmaceutical Sciences, UNESP - Univ Estadual Paulista, Araraquara, 14800903, Brazil. Electronic address: santosjl@fcfar.unesp.br.
authors: Jean Leandro
authors: JL
authors: Dos Santos
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D006801:Humans; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000995:Antitubercular Agents; D010069:Oxadiazoles; C010166:furoxans
keywords: Antituberculosis agents; Furoxan; Mycobacterium tuberculosis; Phenotypic screening; Tuberculosis