Identification and Optimization of Novel Inhibitors of the Polyketide Synthase 13 Thioesterase Domain with Antitubercular Activity

TY - JOUR

T1 - Identification and Optimization of Novel Inhibitors of the Polyketide Synthase 13 Thioesterase Domain with Antitubercular Activity

AU - Green, Simon R.

AU - Wilson, Caroline

AU - Eadsforth, Thomas C.

AU - Punekar, Avinash S.

AU - Tamaki, Fabio K.

AU - Wood, Gavin

AU - Caldwell, Nicola

AU - Forte, Barbara

AU - Norcross, Neil R.

AU - Kiczun, Michael

AU - Post, John M.

AU - Lopez-Román, Eva Maria

AU - Engelhart, Curtis A

AU - Lukac, Iva

AU - Zuccotto, Fabio

AU - Epemolu, Ola

AU - Boshoff, Helena I. M.

AU - Schnappinger, Dirk

AU - Walpole, Chris

AU - Gilbert, Ian H.

AU - Read, Kevin D.

AU - Wyatt, Paul G.

AU - Baragaña, Beatriz

N1 - Copyright: © 2023 The Authors. Published by American Chemical Society.

PY - 2023/11/23

Y1 - 2023/11/23

N2 - There is an urgent need for new tuberculosis (TB) treatments, with novel modes of action, to reduce the incidence/mortality of TB and to combat resistance to current treatments. Through both chemical and genetic methodologies, polyketide synthase 13 (Pks13) has been validated as essential for mycobacterial survival and as an attractive target for Mycobacterium tuberculosis growth inhibitors. A benzofuran series of inhibitors that targeted the Pks13 thioesterase domain, failed to progress to preclinical development due to concerns over cardiotoxicity. Herein, we report the identification of a novel oxadiazole series of Pks13 inhibitors, derived from a high-throughput screening hit and structure-guided optimization. This new series binds in the Pks13 thioesterase domain, with a distinct binding mode compared to the benzofuran series. Through iterative rounds of design, assisted by structural information, lead compounds were identified with improved antitubercular potencies (MIC < 1 μM) and in vitro ADMET profiles.

AB - There is an urgent need for new tuberculosis (TB) treatments, with novel modes of action, to reduce the incidence/mortality of TB and to combat resistance to current treatments. Through both chemical and genetic methodologies, polyketide synthase 13 (Pks13) has been validated as essential for mycobacterial survival and as an attractive target for Mycobacterium tuberculosis growth inhibitors. A benzofuran series of inhibitors that targeted the Pks13 thioesterase domain, failed to progress to preclinical development due to concerns over cardiotoxicity. Herein, we report the identification of a novel oxadiazole series of Pks13 inhibitors, derived from a high-throughput screening hit and structure-guided optimization. This new series binds in the Pks13 thioesterase domain, with a distinct binding mode compared to the benzofuran series. Through iterative rounds of design, assisted by structural information, lead compounds were identified with improved antitubercular potencies (MIC < 1 μM) and in vitro ADMET profiles.

UR - https://www.scopus.com/pages/publications/85178322134

U2 - 10.1021/acs.jmedchem.3c01514

DO - 10.1021/acs.jmedchem.3c01514

M3 - Article

C2 - 37948640

SN - 0022-2623

VL - 66

SP - 15380

EP - 15408

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 22

ER -