Synthesis and anti-Mycobacterium tuberculosis evaluation of new nitroimidazooxazine derivatives useful for the treatment of multidrug-resistant tuberculosis

Abstract

Although advances have been made in recent years for the treatment of tuberculosis (TB), huge challenges such as the emergence of resistant strains become distant the goals to achieve the eliminating the disease in the near future. According to the World Health Organization (WHO), in 2018 about 10 million new cases were diagnosed and 1.2 million deaths occurred. Among the new cases, 484,000 patients had exhibited multidrug-resistant TB (MDR-TB) or extensively drug-resistant TB (XDR-TB), making treatment even more time-consuming and challenging. Over the past 11 years, intense efforts made by our research group have enabled, through a national and international research network, the discovery of new prototypes with potent anti-Mycobacterium tuberculosis (MTB) activity, including against MDR-TB and XDR-TB strains . Of these, the benzofuroxan derivative, known as BZ8 - protein synthesis inhibitor, reduced the colony-forming units in the animals' lungs to zero during the treatment of animals infected with the bacillus, an noteworthy effect not observed for any antitubercular drug currently available. Since then, structure-activity-relationship studies have allowed the identification of structural patterns necessary to maintain anti-MTB activity. In this project, we propose to obtain novel nitroimidazooxazine derivatives, designed through molecular modification approaches, as lead compounds active against MDR-TB and XDR-TB. All designed compounds will be synthesized and characterized by analytical methods. In addition, through phenotypic screening, nitroimidazooxazine derivatives will be evaluated against MTB H37Rv strains and MDR-TB and XDR-TB clinical isolates characterized phenotypically and genotypically. The intramacrophagic activity of MTB H37Rv in J774A.1 murine macrophages will also be investigated. Studies of spontaneous mutant isolation and resistance frequency will be conducted. In addition, to assess the mutagenicity and genotoxicity, it will be carried out in vitro and in vivo assays. It is expected in this study to identify new lead compounds that could be an alternative to the treatment of multidrug-resistant tuberculosis and / or that can improve the current treatment. (AU)