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

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.