Chemical Classes Presenting Novel Antituberculosis Agents Currently in Different Phases of Drug Development: A 2010-2020 Review

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a curable airborne disease currently treated using a drug regimen consisting of four drugs. Global TB control has been a persistent challenge for many decades due to the emergence of drug-resistant Mtb strains. The duration and complexity of TB treatment are the main issues leading to treatment failures. Other challenges faced by currently deployed TB regimens include drug-drug interactions, miss-matched pharmacokinetics parameters of drugs in a regimen, and lack of activity against slow replicating sub-population. These challenges underpin the continuous search for novel TB drugs and treatment regimens. This review summarizes new TB drugs/drug candidates under development with emphasis on their chemical classes, biological targets, mode of resistance generation, and pharmacokinetic properties. As effective TB treatment requires a combination of drugs, the issue of drug-drug interaction is, therefore, of great concern; herein, we have compiled drug-drug interaction reports, as well as efficacy reports for drug combinations studies involving antitubercular agents in clinical development.

Keywords: diarylquinolines; drug development; fluoroquinolones; nitroimidazoles; pharmacokinetics; tuberculosis.

Scheme 1

TB drugs and drug candidates and their associated targets.

Figure 1

The chemical structures of potential anti-TB fluoroquinolones.

Figure 2

The chemical structures of diarylquinoline analogs in TB clinical studies.

Figure 3

The chemical structure of nitroimidazoles undergoing clinical development as TB drugs.

Figure 4

The chemical structures of oxazolidinones currently in TB clinical trials.

Figure 5

The chemical structure of SQ-109.

Figure 6

The structures of Q203 and its analogs (TB47 and ND-11543) that show potential as novel TB agents.

Figure 7

The chemical structures of novel DprE1 inhibitors under clinical development for Mtb treatment.

Figure 8

The chemical structure of CPZEN-45, a potential drug candidate for TB therapy.

Figure 9

The chemical structures of riminophenazines: CFZ and TBI-166 with potential anti-TB properties.

Figure 10

The chemical structures of pyrrole drug candidates being investigated for TB treatment.

Figure 11

The chemical structures of GSK-693 and NITD-916; novel direct Mtb InhA inhibitors.

Figure 12

The chemical structures of faropenem and ertapenem.

Figure 13

The chemical structure of GSK-070, an oxoborate drug in TB clinical trials.