Benzoheterocyclic Oxime Carbamates Active against Mycobacterium tuberculosis: Synthesis, Structure–Activity Relationship, Metabolism, and Biology Triaging
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 iden...
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| Veröffentlicht in: | Journal of medicinal chemistry 2021-07, Vol.64 (13), p.9444-9457 |
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| container_title | Journal of medicinal chemistry |
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| creator | van der Westhuyzen, Renier Mabhula, Amanda Njaria, Paul M Müller, Rudolf Ngumbu Muhunga, Denis Taylor, Dale Lawrence, Nina Njoroge, Mathew Brunschwig, Christel Moosa, Atica Singh, Vinayak Rao, Srinivasa P.S Manjunatha, Ujjini H Smith, Paul W Warner, Digby F Street, Leslie J Chibale, Kelly |
| description | 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. |
| doi_str_mv | 10.1021/acs.jmedchem.1c00707 |
| format | Article |
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| subjects | Chemistry, Medicinal Life Sciences & Biomedicine Pharmacology & Pharmacy Science & Technology |
| title | Benzoheterocyclic Oxime Carbamates Active against Mycobacterium tuberculosis: Synthesis, Structure–Activity Relationship, Metabolism, and Biology Triaging |
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