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- W4254684562 abstract "Our group recently reported the identification of novel coumestan derivatives as Mycobacterium tuberculosis ( Mtb) Pks13-thioesterase (TE) domain inhibitors, with mutations observed (D1644G and N1640K) in the generated coumestan-resistant Mtb colonies. Herein, we report a further structure-activity relationships exploration exploiting the available Pks13-TE X-ray co-crystal structure that resulted in the discovery of extremely potent coumestan analogues 48 and 50. These molecules possess excellent anti-tuberculosis activity against both the drug-susceptible (MIC = 0.0039 μg/mL) and drug-resistant Mtb strains (MIC = 0.0078 μg/mL). Moreover, the excellent in vitro activity is translated to the in vivo mouse serum inhibitory titration assay, with administration of coumestan 48 at 100 mg/kg showing an 8-fold higher activity than that of isoniazid or TAM16 given at 10 or 100 mg/kg, respectively. Preliminary ADME-Tox data for the coumestans were promising and, coupled with the practicality of synthesis, warrant further in vivo efficacy assessments of the coumestan derivatives." @default.
- W4254684562 created "2022-05-12" @default.
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- W4254684562 date "2019-03-15" @default.
- W4254684562 modified "2023-10-17" @default.
- W4254684562 title "Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against <i>Mycobacterium tuberculosis</i>. Part II" @default.
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- W4254684562 doi "https://doi.org/10.1021/acs.jmedchem.9b00010" @default.
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