According to World Health Organization, the Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), caused 9.6 million of new cases and 2 million deaths worldwide in 2015. The current treatment for drug-sensitive TB recommends a combination of isoniazid (INH), rifampicin (RMP), ethambutol, and pyrazinamide for 6 months; however, this same treatment is not effective against multidrug-resistant TB (MDR-TB) and extensively drug resistant (XDR-TB). Therefore, the search for safe and effective new drugs against resistant strains is urgent. Here, the synthesis and evaluation of 1,2,5-oxadiazole 2-N-oxide using drug-sensitive Mtb and MDR-TB strains were characterized. The compounds exhibited MIC90 values ranging from 0.40 - 0.43 μM against Mtb H37Rv strain in active state. Three compounds have shown activity against latency state with MIC90 values ranging from 2.0 -7.7 μM. The cytotoxicity assay against MRC-5 cell line have shown IC50 values ranging from 854 - 1281 μM and selective index from 2033 – 3204, respectively. All these 3 compounds also demonstrated activity against Mtb monoresistant strains for the main drugs available in the therapy. The most active compound (4c), exhibited bactericidal activity in time−kill experiments performed for up to 15 days. Specifically, this compound reduced the initial inoculum (6,73 ± 0.18 Log10UFC.mL-1) sharply until the seventh day and maintained 1 Log10UFC.mL-1 by the fifteenth day, being more active that the first line drugs INH and RMP. Bioavailability studies using Balb/c mice have shown that plasma containing compound 4c administered at 300 mg/Kg/body inhibited Mtb H37Rv strains in active state. In the time 2h, it was observed a inhibition of 46% of Mtb load, while for RMP that value was found as being 76%. Animals infected with Mtb were treated during 20 days orally with compound 4c (200 mg / Kg/ body weight) by once-daily dosing. It was observed absence of Mtb in the lung of all animals treated with 4c. This effect was not observed for RMP. Preliminar toxicological analysis reveals that compound 4c is not mutagenic and genotoxic. In addition, biochemical parameters did not suggest liver and kidney toxicity for animals treated with this compound. All these data suggested that the N-oxide compound (4c) is a new compound active against MDR-TB and could be a new therapeutic alternative against resistant strains.

Synthesis and antimycobacterial activity of new N-oxide compounds active against multi-resistant tuberculosis

256th National Meeting (2018)

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