Identification of inhibitors targeting polyketide synthase 13 of Mycobacterium tuberculosis as antituberculosis drug leads

Wang, Xiao; Zhao, Wenting; Wang, Bin; Ding, Wei; Guo, Hao; Zhao, Hongshan; Meng, Jianzhou; Liu, Sihan; Lu, Yu; Liu, Yishuang; Zhang, Dongfeng

doi:10.1016/j.bioorg.2021.105110

Cited by 18 publications

(13 citation statements)

References 19 publications

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“…Unfortunately, within this benzofuran series there is a clear association of the lipophilic amine for both direct target binding and off-target cardiovascular toxicity associated with hERG channel inhibition. This is important to highlight to the field as the original TAM16 molecule was considered an exciting early lead being referenced in TB development pipelines () and in new agent literature. , Furthermore, other groups have recently reported two related series as promising early start points, that are also dependent on a similar basic group interaction between molecule and Pks13 and thus have the same potential liability. , To fully exploit the Pks13 TE domain as a promising target, it will require: more extensive evaluation of changes to the piperidine in P 3 to reduce further the lipophilicity/basicity; a more significantly in-depth exploration, replacing the piperidine/benzofuran core with an alternative core, which was beyond the scope of this lead optimization project; or the initiation of a screening campaign to identify alternative chemical start points.…”

Section: Discussionmentioning

confidence: 99%

“…27,28 Furthermore, other groups have recently reported two related series as promising early start points, that are also dependent on a similar basic group interaction between molecule and Pks13 and thus have the same potential liability. 29,30 To fully exploit the Pks13 TE domain as a promising target, it will require: more extensive evaluation of changes to the piperidine in P 3 to reduce further the lipophilicity/basicity; a more significantly in-depth exploration, replacing the piperidine/benzofuran core with an alternative core, which was beyond the scope of this lead optimization project; or the initiation of a screening campaign to identify alternative chemical start points.…”

Section: ■ Conclusionmentioning

confidence: 99%

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Optimization of TAM16, a Benzofuran That Inhibits the Thioesterase Activity of Pks13; Evaluation toward a Preclinical Candidate for a Novel Antituberculosis Clinical Target

et al. 2021

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With increasing drug resistance in tuberculosis (TB) patient populations, there is an urgent need for new drugs. Ideally, new agents should work through novel targets so that they are unencumbered by preexisting clinical resistance to current treatments. Benzofuran 1 was identified as a potential lead for TB inhibiting a novel target, the thioesterase domain of Pks13. Although, having promising activity against Mycobacterium tuberculosis, its main liability was inhibition of the hERG cardiac ion channel. This article describes the optimization of the series toward a preclinical candidate. Despite improvements in the hERG liability in vitro, when new compounds were assessed in ex vivo cardiotoxicity models, they still induced cardiac irregularities. Further series development was stopped because of concerns around an insufficient safety window. However, the demonstration of in vivo activity for multiple series members further validates Pks13 as an attractive novel target for antitubercular drugs and supports development of alternative chemotypes.

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Section: Discussionmentioning

confidence: 99%

Section: ■ Conclusionmentioning

confidence: 99%

Optimization of TAM16, a Benzofuran That Inhibits the Thioesterase Activity of Pks13; Evaluation toward a Preclinical Candidate for a Novel Antituberculosis Clinical Target

et al. 2021

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“…The chromen-4-one derivative 76 (Figure ) was also recently confirmed as a Pks13 inhibitor, having been designed by structure-guided scaffold morphing of benzofuran 73 . , In vitro studies on 76 revealed an MIC 90 value of 1.4 μM against Mtb H37Rv, low cytotoxicity against Vero cells (CC 50 164 μM), and superb stability toward mouse liver microsomes (96% parent after 30 min) . The PK profile of 76 in BALB/c mice was also considered acceptable (a half-life of 1.4 h and an oral bioavailability of 21% at 100 mg/kg).…”

Section: Preclinical Promisesmentioning

confidence: 99%

Tuberculosis Drug Discovery: Challenges and New Horizons

et al. 2022

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Over the past 2000 years, tuberculosis (TB) has claimed more lives than any other infectious disease. In 2020 alone, TB was responsible for 1.5 million deaths worldwide, comparable to the 1.8 million deaths caused by COVID-19. The World Health Organization has stated that new TB drugs must be developed to end this pandemic. After decades of neglect in this field, a renaissance era of TB drug discovery has arrived, in which many novel candidates have entered clinical trials. However, while hundreds of molecules are reported annually as promising anti-TB agents, very few successfully progress to clinical development. In this Perspective, we critically review those anti-TB compounds published in the last 6 years that demonstrate good in vivo efficacy against Mycobacterium tuberculosis. Additionally, we highlight the main challenges and strategies for developing new TB drugs and the current global pipeline of drug candidates in clinical studies to foment fresh research perspectives.

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“…Further, they revealed the crucial need of the substituents at positions 2, 5, and 6 of the 4H-chromen-4-one for optimization of MIC of these compounds. [73] Compound 46, with 2-hydroxyphenyl at second position of 4H-chromen-4-one, has been revealed with the highest activity (MIC of 0.45 μg/ mL), being comparable to their previously identified 4H-chromen-4-one derivative. [74] Further, identified hit 46 with IC 50 of 14.30 μM inhibited the enzymatic reaction of Pks13 by binding to TE domain (PDB ID: 5 V3Y).…”

Section: Othersmentioning

confidence: 83%

Comprehensive Coverage on Anti‐mycobacterial Endeavour Reported in 2021

et al. 2022

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Tuberculosis (TB) has been the highly contagious airborne disease caused by Mycobacterium tuberculosis and the major leading infectious disease with the higher upsurge of morbidity and mortality. Owing to problems in the current regimen for TB and emergence of drug resistance strains, there is a strong necessity for development of new anti-TB drugs with better efficacy, reduced duration of action, along with improved patient compliance. Towards this, the scaffolds reported in 2021 with anti-tubercular activity such as benzofuran, benzothiazinone, benzimidazoles, indole, piperidine, piperazine, pyrazole, pyridine, pyrimidine, pyrrolidine, quinoxaline, triazole, etc. have been critically reviewed along with their structureactivity relationships, mode of actions with anticipations of intuitions to design the newer anti-mycobacterial scaffolds.The present work provide the organized coverage of diversified scaffolds with anti-tubercular profile reported in 2021 along with the insightful discussion on their merits and demerits. The mode of anti-tubercular action against Mycobacterium tuberculosis strains have been presented keeping in mind the novel drug candidates against drug resistant strains [a] Dr.

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Identification of inhibitors targeting polyketide synthase 13 of Mycobacterium tuberculosis as antituberculosis drug leads

Cited by 18 publications

References 19 publications

Optimization of TAM16, a Benzofuran That Inhibits the Thioesterase Activity of Pks13; Evaluation toward a Preclinical Candidate for a Novel Antituberculosis Clinical Target

Optimization of TAM16, a Benzofuran That Inhibits the Thioesterase Activity of Pks13; Evaluation toward a Preclinical Candidate for a Novel Antituberculosis Clinical Target

Tuberculosis Drug Discovery: Challenges and New Horizons

Comprehensive Coverage on Anti‐mycobacterial Endeavour Reported in 2021

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