2. Academic Validation
  3. Novel isoxazole thiophene-containing compounds active against Mycobacterium tuberculosis

Novel isoxazole thiophene-containing compounds active against Mycobacterium tuberculosis

  • Bioorg Med Chem Lett. 2025 Apr 15:119:130108. doi: 10.1016/j.bmcl.2025.130108.
Gabrielle Martinez 1,  Kirsten Tolentino 1,  Paridhi Sukheja 1,  Jasmine Webb 1,  Case W McNamara 1,  Arnab K Chatterjee 1,  Baiyuan Yang 2
Affiliations

Affiliations

  • 1 Calibr-Skaggs Institute for Innovative Medicines, a division of Scripps Research, La Jolla, CA 92037, United States.
  • 2 Calibr-Skaggs Institute for Innovative Medicines, a division of Scripps Research, La Jolla, CA 92037, United States. Electronic address: byang@scripps.edu.
PMID: 39863083 DOI: 10.1016/j.bmcl.2025.130108
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.

Keywords

Cholesterol; Cytotoxicity; Formal hit profiling; Hit to lead; Mycobacterium tuberculosis; Pharmacokinetic; Rv1625c/Cya; Structure–activity relationship.

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