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

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
PMCID: PMC12758384 (available on 2026-12-13)
DOI: 10.1016/j.bmcl.2025.130505

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

Kelsey R Latterell et al. Bioorg Med Chem Lett. 2026 Mar.

. 2026 Mar:132:130505.

doi: 10.1016/j.bmcl.2025.130505. Epub 2025 Dec 13.

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
PMCID: PMC12758384 (available on 2026-12-13)
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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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Authors J. Thomas Ippoliti and Gyanu Lamichhane are listed as inventors on U.S. patents 10,870,646 and 11,896,584, which protect the chemical compounds described in this manuscript and their derivatives. Both patents are assigned to Johns Hopkins University and the University of St. Thomas. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References

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

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

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