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Novel isoxazole thiophene-containing compounds active against Mycobacterium tuberculosis
Gabrielle Martinez1, Kirsten Tolentino1, Paridhi Sukheja1
1Calibr-Skaggs Institute for Innovative Medicines, a division of Scripps Research, La Jolla, CA 92037, United States.
Abstract:
Screening of the ChemDiv molecular library in cholesterol media against Mycobacterium tuberculosis (Mtb) H37Rv strain identified a novel isoxazole thiophene hit as a putative Rv1625c/Cya activator with a promising in vitro activity and good pharmacokinetic properties. Twenty-nine analogs were synthesized to assess the structure-activity relationships (SAR) to further improve potency. The most notable analog was P15, which showed an intramacrophage EC50 = 1.96 µM and exhibited 58.0 % oral bioavailability when it was dosed orally at 20 mg/kg in a mouse pharmacokinetic (PK) study. The overall medicinal chemistry campaign revealed limited SAR that did not support further investigation into this series.
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