Lessons from seven decades of antituberculosis drug discovery

Abstract

Despite massive global efforts tuberculosis rates continue to climb and drug-resistance rates are rising to alarming levels. Discovering new agents for treating this bacterial pathogen poses unique challenges, but these challenges have been faced throughout the entire modern history of research into anti-infectives. This review looks back at every decade since the 1940s and summarizes the most important drugs developed during each decade highlighting the lessons learned during these successful medicinal chemistry programs. Looking forward we must accelerate the integration of these past lessons with the impressive advances that have been made in the basic understanding of the biology of this disease.

Fig. (1).

Streptomycin (1) discovered in 1943 and the aminoglyco-sides discovered subsequently such as kanamycin (2) in 1957 and amikacin (3), a semisynthetic derivative of kanamycin made in 1972 to circumvent the emerging problem of resistance arising from inactivation through modification of the amine, are still used in TB therapy particularly for treating MDR infections.

Fig. (2).

Isoniazid: progenitors and progeny. Thiacetazone (4), an example of the thiosemicarbazides synthesized originally by Domagk in the 1940s and 50s gave rise to isoniazid (5), an intermediate in the synthesis that was discovered to be more active than the products. Many derivatives of isoniazid were tested in the clinic, including iproniazid (6) that ultimately proved to be less effective than isoniazid despite radical changes in the moods of many sanatoria patients. Ultimately iproniazid was found to inhibit monoamine oxidase (MAO) and gave rise to a whole family of MAO inhibitors such as isocarboxazid (7), tranylcypromine (8), and phenelzine (9) that were used for decades as antidepressants.

Fig. (3).

The long road from the isolation of rifamycins to an orally available agent. Rifamycin B (10) was the only stable molecule that could be isolated from the fermentation broth of the microbe that produced a potent antimycobacterial agent. The poor activity of rifamycin B could be improved by “activation” to rifamycin O (11) followed by deglycoylation to form rifamycin S (12) which could be reduced under mild conditions to form rifamycin SV (13) which was used parentally to treat TB. The key observation (highlighted) that allowed the production of rifampicin (15) was a Mannich reaction allowing the production of 3-formylrifamycin SV (14).

Fig. (4).

Antitubercular oxazolidinones. Early hits in the series such as 15, 16, 17 and 18 showed promising antibacterial activity but toxicity issues showed up almost immediately. The key insight that saved the series was the nearly equivalent PK and activity of compounds 16 and 17 demonstrating that STR and SAR were distinct Linezolid (19) ultimately resulted as an important broad — spectrum agent and newer agents such as PNU—100480 (20) are currently being examined again for antitubercular activity.

Fig. (5).

Antitubercular nitroimidazoles. Inspired by the natural product azomycin (21), nitroimidazole-containing antibiotics such as metronidazole (22) were developed and are widely used antibac-terials with anaerobic activity. Building on earlier programs at Ciba-Geigy Hindustan that first explored bicyclic nitroimidazoles for their aerobic activity against TB, PathoGenesis produced PA-824 (23) that is currently in Phase II clinical trials while Otsuka Pharmaceuticals produced OPC-67683 (24) that is like-wise in the clinic. These candidates were primarily driven by opti mization of whole cell activity, combined with activity in murine models of TB.

Fig. (6).

Diarylquinolines and benzothiazinones. The newest generation of TB agents, both molecules were selected in whole cell screens and resulted in important new targets for future programs. TMC207 (25) targets the ATP synthase of TB and kills even non-replicating bacteria, BTZ043 (26) targets an enzyme involved in cell wall arabinan biosynthesis.