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

Malík, Ivan; Čiẑmárik, J; Kováč, G.; Pecháčová, Mária; Hudecova, Lucia

doi:10.5817/csf2021-5-164

Cited by 6 publications

(4 citation statements)

References 44 publications

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“…Q203, the most advanced anti-TB drug candidate from this class, is in phase II clinical trial. 77,78 The development of Q203 offered a new horizon to anti-TB drug discovery research targeting QcrB. Several synthetic modification strategies of imidazopyridine amides have been acquired around Q203, particularly the long-side chain modification to reduce lipophilicity and induce polarity.…”

Section: Discussionmentioning

confidence: 99%

Recent developments of imidazo[1,2-a]pyridine analogues as antituberculosis agents

et al. 2023

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Section: Discussionmentioning

confidence: 99%

Recent developments of imidazo[1,2-a]pyridine analogues as antituberculosis agents

et al. 2023

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“…Telacebec (Q203; TCB) is a highly bioactive imidazopyridine molecule with a unique imidazo[1,2‐a]pyridine‐3‐carboxamide (IPA) structure that exhibits remarkable anti‐TB activities. Among drug‐resistant and multidrug‐resistant mycobacterium tuberculosis strains, Telacebec molecule exhibits high effectiveness [13b] . The safety, tolerability, early bactericidal activity, and pharmacokinetics of Telacebec are being evaluated in a Phase 2 study [14] .…”

Section: Introductionmentioning

confidence: 99%

Imidazopyridine Hydrazine Conjugates as Potent Anti‐TB Agents with their Docking, SAR, and DFT Studies

Soumyashree,

Reddy,

Sunitha Kumari

et al. 2024

ChemistrySelect

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Novel imidazopyridines hydrazine conjugates were designed and synthesized for their anti‐tubercular (anti‐TB) activity. A cytotoxicity assay was conducted with Vero cells to determine the safety profile of the most effective compounds. It was found that compound (IA3) (MIC=0.78 μM) and (IA8) (MIC=1.12 μM) were nearly 3.7 and 2.5 times more active than pyrazinamide. Based on Density functional theory (DFT), these molecules exhibited better charge transfer between molecular orbital's, which made them suitable for biological applications. Molecular docking on Mycobacterium tuberculosis InhA bound to NITD‐916 (PDB: 4R9S) revealed that compounds possessed greater binding affinity towards proteins. In addition, the most active anti‐TB compounds (IA3) and (IA8) exhibited high levels of interaction with the target protein and exceptional safety profile, suggesting they may prove to be effective leads for new drugs.

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“…In contrast to the well-studied isoniazid and ethionamide, only a few studies have been performed on perchlozone MICs for clinical strains of M. tuberculosis and their molecular mechanisms of action [ 27 ]. In this report, we describe the phenotypic and genetic characteristics of clinical isolates of M. tuberculosis from the Moscow region, with variable susceptibility to perchlozone, ethionamide, and isoniazid.…”

Section: Introductionmentioning

confidence: 99%

Perchlozone Resistance in Clinical Isolates of Mycobacterium tuberculosis

Ushtanit

Mikhailova²,

Krylova³

et al. 2023

Antibiotics

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The emergence of drug-resistant tuberculosis forced the development of new drugs and the screening of more effective or less toxic analogues. Mycolic acid biosynthesis is targeted by several antituberculosis drugs, isoniazid being one of the most important in tuberculosis therapy. Recently, perchlozone, acting on another step in the FAS-II cycle, was officially approved for tuberculosis treatment in the Russian Federation and was included in the Russian national clinical guidelines. Using the serial dilution method on 7H10 agar plates for perchlozone and a Sensititre MYCOTB microdilution plate, we analyzed the phenotypic properties of primary clinical isolates of M. tuberculosis and analyzed the molecular determinants of resistance to isoniazid, ethionamide, and perchlozone. We found a wide variation in the MIC of perchlozone from 2 to 64 mg/L, correlating with the overall resistance profile: the MIC was higher for MDR and pre-XDR isolates. The cross-resistance between ethionamide and perchlozone was driven by mutations in the ethA gene encoding monooxygenase responsible for the activation of both drugs. The presumably susceptible to perchlozone and wild-type strains had MICs ranging from 2 to 4 mg/L, and the breakpoint was estimated to be 4 or 8 mg/L. In conclusion, susceptibility to perchlozone is retained for a part of the MDR strains, as is susceptibility to ethionamide, providing the possibility of therapy for such cases based on phenotypic or molecular analysis.

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

Abstract: 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 pathog

Cited by 6 publications

References 44 publications

Recent developments of imidazo[1,2-a]pyridine analogues as antituberculosis agents

Recent developments of imidazo[1,2-a]pyridine analogues as antituberculosis agents

Imidazopyridine Hydrazine Conjugates as Potent Anti‐TB Agents with their Docking, SAR, and DFT Studies

Perchlozone Resistance in Clinical Isolates of Mycobacterium tuberculosis

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