2. Academic Validation
  3. Synthesis and evaluation of novel oxanthrene scaffold-derived oxazolidinone antibiotics with potent antitubercular activity and low cellular toxicity

Synthesis and evaluation of novel oxanthrene scaffold-derived oxazolidinone antibiotics with potent antitubercular activity and low cellular toxicity

  • Bioorg Med Chem Lett. 2026 Mar:132:130505. doi: 10.1016/j.bmcl.2025.130505.
Kelsey R Latterell 1,  Evan Keil 1,  Benjamin R Kraemer 1,  Joe B Huisken 1,  Ben A Thomas 1,  Noah Daniels 1,  Amit Kaushik 2,  Maria Lillian Olson 3,  Pamela Meléndez Noriega 4,  Maria Alejandra Pizarro Daniels 3,  Daron E Janzen 5,  Gyanu Lamichhane 6,  Monica Campo 7,  J Thomas Ippoliti 8
Affiliations

Affiliations

  • 1 Department of Chemistry, University of St. Thomas, 2115 Summit Ave, St. Paul, MN 55105, United States.
  • 2 Taskforce for Resistance Emergence & Antimicrobial Technology and Center for Non-tuberculous Mycobacteria and Bronchiectasis, Department of Medicine, Johns Hopkins University, 1550 Orleans St, Baltimore, MD 21287, United States.
  • 3 Department of Medicine, University of Minnesota, 2101 6th Street SE, WMBB 2-112, Minneapolis, MN 55455, United States.
  • 4 School of Medicine, Ponce Health Sciences University, Sala Ponce, 388 Calle Luis F, Ponce, PR 00716.
  • 5 Department of Chemistry and Biochemistry, St. Catherine University, 2004 Randolph Ave, St. Paul, MN 55105, United States.
  • 6 Taskforce for Resistance Emergence & Antimicrobial Technology and Center for Non-tuberculous Mycobacteria and Bronchiectasis, Department of Medicine, Johns Hopkins University, 1550 Orleans St, Baltimore, MD 21287, United States. Electronic address: lamichhane@jhu.edu.
  • 7 Department of Medicine, University of Minnesota, 2101 6th Street SE, WMBB 2-112, Minneapolis, MN 55455, United States. Electronic address: mcampo@umn.edu.
  • 8 Department of Chemistry, University of St. Thomas, 2115 Summit Ave, St. Paul, MN 55105, United States. Electronic address: jtippoliti@stthomas.edu.
PMID: 41397658 DOI: 10.1016/j.bmcl.2025.130505
Abstract

Oxazolidinones are a class of Antibiotics used to treat Bacterial infections in humans and are a component of the treatment regimen for multidrug-resistant tuberculosis. However, current clinically used examples of the class display poor safety profiles, and improved, next-generation drugs are urgently needed. Here we report the synthesis of two novel oxazolidinones: T504 and its regioisomer T542. Alongside the previously reported compound T145, we evaluate their inhibitory activity against the causative agent of tuberculosis, Mycobacterium tuberculosis. We also explore their antimycobacterial activity in a human monocyte-derived macrophage model of Infection. Both T145 and T504 demonstrate potent activity and low cellular toxicity in human macrophages. The investigation reveals vast discrepancies in activities between the two regioisomers (T504 and T542), offering insights into the structure-activity relationship of substitutions on the oxanthrene scaffold.

Keywords

Antibacterial activity; Antibiotic; Mycobacterium tuberculosis; Oxanthrene; Oxazolidinone; Tuberculosis.

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