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

Journal Article · · Journal of Medicinal Chemistry
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  1. Univ. of Dundee (United Kingdom)
  2. Texas A & M Univ., College Station, TX (United States)
  3. GlaxoSmithKline, Madrid (Spain)
  4. Cornell Univ., Ithaca, NY (United States). Weill Medical College
  5. Colorado State Univ., Fort Collins, CO (United States)
  6. McGill Univ. Health Centre, Montreal, QC (Canada)
+ Show Author Affiliations

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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1844689
Journal Information:
Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 1 Vol. 65; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH

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