Synthesis of New Nitroimidazooxazine Derivatives Designed as Antitubercular Agents

Abstract

Mycobacterium tuberculosis (MTB), the main agent that causes tuberculosis (TB), is responsible for the annual death of 1.5 million people worldwide. Currently, one of the biggest global concerns is the increasing number of cases of multidrug-resistant (MDR-TB) and extensively drug resistant (XDR-TB) strains due to the high mortality rate, difficulty in treatment and the high costs involved. Bedaquiline is the only therapeutic resource approved by the US Food and Drug Administration (FDA) for the treatment of MDR-TB and XDR-TB after a gap of more 50 years. However, resistant strains of this drug have already been characterized, justifying the need to discover new drugs. We have identified in our research group (applicant's doctoral project) a series of compounds with potent antituberculosis activity. The most active compounds presented MIC90 values ranging from 0.2 - 3.5 µM against M. tuberculosis H37Rv. In addition, these compounds showed promising results in preliminary studies against resistant isolate strains. Therefore, in order to expand the current series and the structure-activity relationship studies, we designed a new series of compounds, in which, a nitroimidazooxazine ring replaced the benzofuroxan moiety. The nitroimidazooxazine is the pharmacophore presented in several antituberculosis compounds, including two drug candidates that are currently in clinical phase-3, pretomanid and delamanid. The research group of Professor William Alexander Denny from the University of Auckland has extensive experience with the synthesis of this heterocycle and has published dozens of scientific articles in high-impact journals. In addition, the research group has research projects supported by the Global Alliance for TB Drug Development, which seeks the development of second-generation analogues of pretomanid (nitroimidazooxazine). These novel compound series will be further evaluated against M. tuberculosis H37Rv and MDR clinical isolates at the Laboratory of Mycobacteria, School of Pharmaceutical Sciences, São Paulo State University, Araraquara, Brazil, under the supervision of Professor Fernando Rogério Pavan.