Recent Progress in the Discovery and Development of 2-Nitroimidazooxazines and 6-Nitroimidazooxazoles to Treat Tuberculosis and Neglected Tropical Diseases

Abstract

Nitroimidazole drugs have a long history as therapeutic agents to treat bacterial and parasitic diseases. The discovery in 1989 of a bicyclic nitroimidazole lead, displaying in vitro and in vivo antitubercular activity, spurred intensive exploration of this and related scaffolds, which led to the regulatory approval of pretomanid and delamanid as a new class of tuberculosis drugs. Much of the discovery work related to this took place over a 20-year period ending in 2010, which is covered in a number of cited reviews. This review highlights subsequent research published over the 2011–August 2020 timeframe, and captures detailed structure–activity relationship studies and synthetic strategies directed towards uncovering newer generation drugs for both tuberculosis and selected neglected tropical diseases. Additionally, this review presents in silico calculations relating to the drug-like properties of lead compounds and clinical agents, as well as chemical development and manufacturing processes toward providing bulk drug supplies.

Synthesis of Optically Active Bicyclic Derivatives of Nitroimidazoles

“…Scheme 1. The synthesis of chiral bicyclic nitroimidazole derivatives (7)(8)(9)(10)(11)(12)(13)(14).…”

“…The benzene ring protons in the aniline system provided the multiplet signals which were observed in the range of 7.0-7.4 ppm. The peak was located at about 5.4 ppm (7,8,9,10) or 5.2 ppm (11,12,13,14) and was assigned to the -OH group. The proton from the carbon atom bound to the hydroxyl group was visible in the form of a multiplet in the area of 4.7-4.8 ppm (7,8,9,10), and in the case of compounds substituted with an aliphatic amine (11,12,13,14), these signals were shifted towards the higher magnetic field strength and were in the range of 4.4-4.5 ppm.…”

“…The peak was located at about 5.4 ppm (7,8,9,10) or 5.2 ppm (11,12,13,14) and was assigned to the -OH group. The proton from the carbon atom bound to the hydroxyl group was visible in the form of a multiplet in the area of 4.7-4.8 ppm (7,8,9,10), and in the case of compounds substituted with an aliphatic amine (11,12,13,14), these signals were shifted towards the higher magnetic field strength and were in the range of 4.4-4.5 ppm. The remaining protons from the tetrahydropyrimidine ring were observed in the ranges of 4.3-4.4 ppm and 3.9-4.1 ppm.…”

“…The spectra of compounds with a methyl group in the C-2 position of the imidazole ring showed the presence of a singlet at 2.13 ppm (13,14) or at 2.26 ppm (9,10) derived from three H atoms of the methyl group. The remaining multiplets, occurring in the range of 0.8-4.0 ppm in the spectra of the compounds (11,12,13,14), were derived from hydrogen atoms of aliphatic chains, constituting the rest of the butylamine.…”

“…Systems containing the imidazo[2,1-b] [1,3]oxazine ring have been found to be active against tuberculosis as well. The most promising compound of this series, PA-824 (Pretomanid), has an MIC of 0.06 µg/mL against M. bovis BCG and high activity against Mtb H37Rv [10][11][12]. It is used mainly for the treatment of pulmonary extensively drug resistant (XDR) and nonresponsive multidrug resistant tuberculosis.…”