Synthesis and evaluation of new nitroimidazooxazine derivatives designed to act against drug-resistant Mycobacterium tuberculosis

Abstract

Although the treatment of tuberculosis (TB) has been made advances in recent years, it can be noted huge challenges such as the emergence of resistant strains become difficult the goals to achieve the eliminating the disease soon. According to the World Health Organization (WHO), in 2018 about 10 million new cases were diagnosed and around 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 difficult and challenging. In this context, intense efforts made by our research group have enabled, over the past 11 years, 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 the synthetized compounds, the benzofuroxan derivative, known as BZ8, protein synthesis inhibitor, reduced the colony-forming units in the animals' lungs infected with the bacillus, an unprecedented effect, not observed for any antitubercular drug currently available. Since then, structure-activity-relationship studies have granted the identification of structural patterns important 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. In addition, all designed compounds will be synthesized and characterized by analytical methods and through phenotypic screening, nitroimidazooxazine derivatives will be evaluated against MTB H37Rv strains and MDR-TB and XDR-TB clinical isolates characterized phenotypically and genotypically. 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. Lastly, 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.