Open AccessOptimization of TAM16, a Benzofuran That Inhibits the Thioesterase Activity of Pks13; Evaluation toward a Preclinical Candidate for a Novel Antituberculosis Clinical Target
Author(s) -
Caroline Wilson,
Peter C. Ray,
Fabio Zuccotto,
Jorge Hernández,
Anup Aggarwal,
Claire J. Mackenzie,
Nicola Caldwell,
Malcolm Taylor,
Margaret Huggett,
Michael Mathieson,
Dinakaran Murugesan,
Alasdair Smith,
Susan H. Davis,
Mattia Cocco,
Maloy Kumar Parai,
Ankit Acharya,
Fábio K. Tamaki,
Paul Scullion,
Ola Epemolu,
Jennifer Riley,
Laste Stojanovski,
Eva María López-Román,
Pedro Alfonso Torres-Gómez,
Ana Maria Toledo,
Laura Guijarro-López,
Isabel Camino,
Curtis A. Engelhart,
Dirk Schnappinger,
Lisa M. Massoudi,
Anne J. Lenaerts,
Gregory T. Robertson,
Chris Walpole,
David J. Matthews,
David M. Floyd,
James C. Sacchettini,
Kevin D. Read,
Lourdes Encinas,
Robert H. Bates,
Simon R. Green,
Paul G. Wyatt
Publication year - 2021
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.1c01586
Subject(s) - herg , benzofuran , pharmacology , mycobacterium tuberculosis , chemistry , cardiotoxicity , in vivo , tuberculosis , drug discovery , computational biology , medicine , biochemistry , potassium channel , microbiology and biotechnology , biology , toxicity , stereochemistry , organic chemistry , pathology
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.