JOURNAL OF THE CZECH PHARMACEUTICAL SOCIETY AND THE SLOVAK PHARMACEUTICAL SOCIETY

Čes. slov. farm. 2021, 70(5):164-171 | DOI: 10.5817/CSF2021-5-164

Telacebec (Q203): Is there a novel effective and safe anti-tuberculosis drug on the horizon?

Ivan Malík1,2,*, Jozef Čižmárik1, Gustáv Kováč2, Mária Pecháčová1, Lucia Hudecová2
1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University in Bratislava, Slovak Republic
2 Institute of Chemistry, Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Slovak Medical University in Bratislava, Slovak Republic

High prevalence and stronger emergency of various forms of drug-resistant tuberculosis (DR-TB), including the multidrug-resistant (MDR-TB) as well as extensively drug-resistant (XDR-TB) ones, caused by variously resistant Mycobacterium tuberculosis pathogens, make first-line anti-tuberculosis (anti-TB) agents therapeutically more and more ineffective. Therefore, there is an imperative to develop novel highly efficient (synthetic) agents against both drug-sensitive-TB and DR-TB. The exploration of various heterocycles as prospective core scaffolds for the discovery, development and optimization of anti-TB drugs remains an intriguing scientific endeavour.

Telacebec (Q203; TCB), a molecule containing an imidazo[1,2-a]pyridine-3-carboxamide (IPA) structural motif, is considered a novel very promising anti-TB agent showing a unique mechanism of action. The compound blocks oxidative phosphorylation by inhibiting a mycobacterial respiratory chain due to interference with a specific cytochrome b subunit (QcrB) of transmembrane bc1 menaquinol-cytochrome c oxidoreductase as an essential component for transporting electrons across the membrane from menaquinol to other specific subunit, cytochrome c (QcrC). Thus, the ability of mycobacteria to synthesize adenosine-5'-triphosphate is limited and energy generating machinery is disabled. The

TCB molecule effectively fights drug-susceptible, MDR as well as XDR M. tuberculosis strains. The article briefly explains a mechanism of an anti-TB action related to the compounds containing a variously substituted IPA scaffold and is focused on their fundamental structure-anti-TB activity relationships as well. Special consideration is paid to

TCB indicating the importance of particular structural fragments for maintaining (or even improving) favourable pharmacodynamic, pharmacokinetic and/or toxicological properties. High lipophilicity of

TCB might be regarded as one of the key physicochemical properties with positive impact on anti-TB effect of the drug. In January 2021, the

TCB molecule was also involved in phase-II clinical trials focused on the treatment of Coronavirus Disease-19 caused by Severe Acute Respiratory Syndrome Coronavirus 2.

Keywords: Mycobacterium tuberculosis; drug-resistant tuberculosis; imidazo[1,2-a]pyridine-3-carboxamides; telacebec (Q203); respiratory chain

Received: March 14, 2021; Accepted: September 13, 2021; Published: May 1, 2021  Show citation

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Malík I, Čižmárik J, Kováč G, Pecháčová M, Hudecová L. Telacebec (Q203): Is there a novel effective and safe anti-tuberculosis drug on the horizon? Čes. slov. farm. 2021;70(5):164-171. doi: 10.5817/CSF2021-5-164.
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