TY - JOUR
T1 - Synthesis and evaluation of novel oxanthrene scaffold-derived oxazolidinone antibiotics with potent antitubercular activity and low cellular toxicity
AU - Latterell, Kelsey R.
AU - Keil, Evan
AU - Kraemer, Benjamin R.
AU - Huisken, Joe B.
AU - Thomas, Ben A.
AU - Daniels, Noah
AU - Kaushik, Amit
AU - Olson, Maria Lillian
AU - Noriega, Pamela Meléndez
AU - Daniels, Maria Alejandra Pizarro
AU - Janzen, Daron E.
AU - Lamichhane, Gyanu
AU - Campo, Monica
AU - Ippoliti, J. Thomas
N1 - Publisher Copyright:
© 2025 Elsevier Ltd
PY - 2026/3
Y1 - 2026/3
N2 - 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.
AB - 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.
KW - Antibacterial activity
KW - Antibiotic
KW - Mycobacterium tuberculosis
KW - Oxanthrene
KW - Oxazolidinone
KW - Tuberculosis
UR - https://www.scopus.com/pages/publications/105025132636
UR - https://www.scopus.com/pages/publications/105025132636#tab=citedBy
U2 - 10.1016/j.bmcl.2025.130505
DO - 10.1016/j.bmcl.2025.130505
M3 - Article
C2 - 41397658
AN - SCOPUS:105025132636
SN - 0960-894X
VL - 132
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
M1 - 130505
ER -