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

Q1 · MEDICINE

Article

Author: Read, Kevin D. ; Lopez-Román, Eva Maria ; Wilson, Caroline ; Huggett, Margaret ; Caldwell, Nicola ; Guijarro-Lopez, Laura ; Aggarwal, Anup ; Engelhart, Curtis A. ; Schnappinger, Dirk ; Robertson, Gregory T. ; Bates, Robert H. ; Mathieson, Michael ; Matthews, David ; Acharya, Arjun ; Hernandez, Jorge ; Taylor, Malcolm ; Sacchettini, James C. ; Smith, Alasdair ; Scullion, Paul ; Cocco, Mattia ; Walpole, Chris ; Davis, Susan ; Floyd, David ; Stojanovski, Laste ; Epemolu, Ola ; Wyatt, Paul G. ; Tamaki, Fabio ; Zuccotto, Fabio ; Lenaerts, Anne ; Toledo, Ana Maria ; Massoudi, Lisa M. ; Parai, Maloy K. ; Camino, Isabel ; Murugesan, Dinakaran ; Mackenzie, Claire ; Riley, Jennifer ; Torres-Gómez, Pedro Alfonso ; Ray, Peter ; Encinas, Lourdes ; Green, Simon R.

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.

01 Mar 2020·European Journal of Medicinal ChemistryQ1 · MEDICINE

Design, synthesis, and biological evaluation of novel 4H-chromen-4-one derivatives as antituberculosis agents against multidrug-resistant tuberculosis

Q1 · MEDICINE

Article

Author: Wang, Bin ; Fu, Lei ; Zhao, Hongyi ; Lu, Yu ; Liu, Yuke ; Sheng, Li ; Zhao, Wenting ; Zhang, Dongfeng

A series of 4H-chromen-4-one derivatives obtained by scaffold morphing of the benzofuran compound, TAM16, were tested for antitubercular activity. Compound 8d was active against drug-sensitive and multidrug-resistant tuberculosis. A preliminary druggability evaluation showed that compound 8d displayed favorable mouse and human microsomal stability, low cytotoxicity, and acceptable oral bioavailability. An in vivo study indicated that compound 8d exhibited modest efficacy in an acute mouse model of TB after 3 weeks of treatment. Thus, 8d is a promising antituberculosis lead compound.

01 Dec 2019·European Journal of Medicinal ChemistryQ1 · MEDICINE

Benzofuran-isatin hybrids and their in vitro anti-mycobacterial activities against multi-drug resistant Mycobacterium tuberculosis

Q1 · MEDICINE

Article

Author: Lei Ye ; Feng Gao ; Jiaqi Xiao ; Shijia Zhao ; Gang Huang ; Yabin Wang ; Fangong Kong

A series of benzofuran-isatin hybrids 6a-n and 7a-g linked by alkyl linkers were designed and synthesized. Among them, hybrids 6a-l and 7a-g were assessed for their in vitro anti-mycobacterial activities against two multi-drug resistant Mycobacterium tuberculosis (MDR-MTB) strains and the cytotoxicity towards CHO cells. The preliminary results indicated that all hybrids (MIC: 0.125-16 μg/mL) showed excellent activity against the tested MDR-MTB strains, and low cytotoxicity (CC₅₀: 64->512 μg/mL) towards CHO cells. Among them, hybrid 7e (MIC: 0.125 and 0.25 μg/mL) was highly active against the tested two MDR-MTB strains, which was 8-16 folds better than ciprofloxacin (MIC: 1 and 4 μg/mL), ≥512 folds more potent than rifampicin (MIC: 64 and > 128 μg/mL) and isoniazid (MIC: >128 μg/mL), but it was less active than TAM16 (MIC: <0.06 μg/mL). Moreover, the hybrid 7e (CC₅₀: 128 μg/mL) also showed low cytotoxicity towards CHO cells, and high selectivity index (1,024). However, the metabolic stability and in vivo pharmacokinetic profiles of hybrid 7e were inferior to TAM16, so it still needs to be modified so as to get the optimized hybrid for potential use in mycobacterial treatment.

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Indication	Highest Phase	Country/Location	Organization	Date
Tuberculosis	Preclinical	US	Texas A&M University	12 Jul 2017

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