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

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

J. Med. Chem. 2022, 65, 1, 409–423


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.