American Chemical Society
jm9b00010_si_001.pdf (4.85 MB)

Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis. Part II

Download (4.85 MB)
journal contribution
posted on 2019-03-15, 00:00 authored by Wei Zhang, Shichun Lun, Ling-Ling Liu, Shiqi Xiao, Guanfu Duan, Hendra Gunosewoyo, Fan Yang, Jie Tang, William R. Bishai, Li-Fang Yu
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.