Benzoheterocyclic Oxime Carbamates Active against Mycobacterium tuberculosis: Synthesis, Structure-Activity Relationship, Metabolism, and Biology Triaging

被引：13

作者：

van der Westhuyzen, Renier ^{[1
]}

Mabhula, Amanda ^{[2
]}

Njaria, Paul M. ^{[2
]}

Mueller, Rudolf ^{[1
]}

Muhunga, Denis Ngumbu ^{[1
]}

Taylor, Dale ^{[3
]}

Lawrence, Nina ^{[3
]}

Njoroge, Mathew ^{[3
]}

Brunschwig, Christel ^{[3
]}

Moosa, Atica ^{[4
]}

Singh, Vinayak ^{[1
,2
]}

Rao, Srinivasa P. S. ^{[5
,6
]}

Manjunatha, Ujjini H. ^{[5
,6
]}

Smith, Paul W. ^{[5
]}

Warner, Digby F. ^{[4
,7
]}

Street, Leslie J. ^{[1
]}

Chibale, Kelly ^{[7
,8
]}

机构：

[1] Univ Cape Town, Drug Discovery & Dev Ctr H3D, Dept Chem, ZA-7701 Cape Town, South Africa

[2] Univ Cape Town, South African Med Res Council, Dept Chem, Drug Discovery & Dev Res Unit, ZA-7701 Cape Town, South Africa

[3] Univ Cape Town, Drug Discovery & Dev Ctr H3D, Div Clin Pharmacol, ZA-7701 Cape Town, South Africa

[4] Univ Cape Town, Dept Pathol, SAMRC NHLS UCT Mol Mycobacteriol Res Unit, ZA-7701 Cape Town, South Africa

[5] Novartis Inst Trop Dis NITD, Singapore 138670, Singapore

[6] Novartis Inst Trop Dis NITD, 5959 Horton St, Emeryville, CA 94608 USA

[7] Univ Cape Town, Inst Infect Dis & Mol Med, ZA-7701 Cape Town, South Africa

[8] Univ Cape Town, Drug Discovery & Dev Ctr H3D, Dept Chem, South African Med Res Council,Drug Discovery & De, ZA-7701 Cape Town, South Africa

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2021年 / 64卷 / 13期

基金：

英国医学研究理事会;

关键词：

PYRAZINAMIDE; RESISTANCE; DISCOVERY; MECHANISM;

D O I：

10.1021/acs.jmedchem.1c00707

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Screening of a library of small polar molecules against Mycobacterium tuberculosis (Mtb) led to the identification of a potent benzoheterocyclic oxime carbamate hit series. This series was subjected to medicinal chemistry progression underpinned by structure-activity relationship studies toward identifying a compound for proof-of-concept studies and defining a lead optimization strategy. Carbamate and free oxime frontrunner compounds with good stability in liver microsomes and no hERG channel inhibition liability were identified and evaluated in vivo for pharmacokinetic properties. Mtb-mediated permeation and metabolism studies revealed that the carbamates were acting as prodrugs. Toward mechanism of action elucidation, selected compounds were tested in biology triage assays to assess their activity against known promiscuous targets. Taken together, these data suggest a novel yet unknown mode of action for these antitubercular hits.

引用

页码：9444 / 9457

页数：14

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