Discovery and Optimization of Tambjamines As a Novel Class of Antileishmanial Agents.

Authors

Papireddy Kancharla, Portland State University
Diana Ortiz, Portland State University
Corinne M. Fargo, Oregon Health & Science University
Xiaowei Zhang, Department of Veterans Affairs Medical Center
Yuexin Li, Department of Veterans Affairs Medical Center
Marco Sanchez, Oregon Health & Science University
Amrendra Kumar, Portland State University
Monish Yeluguri, Portland State University
Rozalia A. Dodean, Portland State UniversityFollow
Diana Caridha, Walter Reed Army Institute of Research
Michael S. Madejczyk, Walter Reed Army Institute of Research
Monica Martin, Walter Reed Army Institute of Research
Xiannu Jin, Walter Reed Army Institute of Research
Cameron Blount, Walter Reed Army Institute of Research
Ravi Chetree, Walter Reed Army Institute of Research
Kristina Pannone, Walter Reed Army Institute of Research
Hieu T. Dinh, Walter Reed Army Institute of Research
Jesse DeLuca, Walter Reed Army Institute of Research
Martin Evans, Walter Reed Army Institute of Research
Robert Nadeau, Walter Reed Army Institute of Research
Chau Vuong, Walter Reed Army Institute of Research
Susan Leed, Walter Reed Army Institute of Research
William E. Dennis, Walter Reed Army Institute of Research
Norma Roncal, Walter Reed Army Institute of Research
Brandon S. Pybus, Walter Reed Army Institute of Research
Patricia J. Lee, Walter Reed Army Institute of Research
Alison Roth, Walter Reed Army Institute of Research
Kevin A. Reynolds, Portland State University
Jane X. Kelly, Portland State University
Scott M. Landfear, Oregon Health & Science University

Published In

Journal of Medicinal Chemistry

Document Type

Citation

Publication Date

5-9-2024

Abstract

Leishmaniasis is a neglected tropical disease that is estimated to afflict over 12 million people. Current drugs for leishmaniasis suffer from serious deficiencies, including toxicity, high cost, modest efficacy, primarily parenteral delivery, and emergence of widespread resistance. We have discovered and developed a natural product-inspired tambjamine chemotype, known to be effective against spp, as a novel class of antileishmanial agents. Herein, we report in vitro and in vivo antileishmanial activities, detailed structure-activity relationships, and metabolic/pharmacokinetic profiles of a large library of tambjamines. A number of tambjamines exhibited excellent potency against both and parasites with good safety and metabolic profiles. Notably, tambjamine offered excellent potency and provided partial protection to leishmania-infected mice at 40 and/or 60 mg/kg/10 days of oral treatment. This study presents the first account of antileishmanial activity in the tambjamine family and paves the way for the generation of new oral antileishmanial drugs.

Rights

© 2024 American Chemical Society

Locate the Document

https://doi.org/10.1021/acs.jmedchem.4c00517

DOI

10.1021/acs.jmedchem.4c00517

Persistent Identifier

https://archives.pdx.edu/ds/psu/41822

Citation Details

Kancharla, P., Ortiz, D., Fargo, C. M., Zhang, X., Li, Y., Sanchez, M., Kumar, A., Yeluguri, M., Dodean, R. A., Caridha, D., Madejczyk, M. S., Martin, M., Jin, X., Blount, C., Chetree, R., Pannone, K., Dinh, H. T., DeLuca, J., Evans, M., … Landfear, S. M. (2024). Discovery and Optimization of Tambjamines as a Novel Class of Antileishmanial Agents. Journal of Medicinal Chemistry.