2. Academic Validation
  3. Discovery and Optimization of Tambjamines as a Novel Class of Antileishmanial Agents

Discovery and Optimization of Tambjamines as a Novel Class of Antileishmanial Agents

  • J Med Chem. 2024 May 23;67(10):8323-8345. doi: 10.1021/acs.jmedchem.4c00517.
Papireddy Kancharla 1,  Diana Ortiz 2,  Corinne M Fargo 2,  Xiaowei Zhang 3,  Yuexin Li 3,  Marco Sanchez 2,  Amrendra Kumar 1,  Monish Yeluguri 1,  Rozalia A Dodean 1,  Diana Caridha 4,  Michael S Madejczyk 4,  Monica Martin 4,  Xiannu Jin 4,  Cameron Blount 4,  Ravi Chetree 4,  Kristina Pannone 4,  Hieu T Dinh 4,  Jesse DeLuca 4,  Martin Evans 4,  Robert Nadeau 4,  Chau Vuong 4,  Susan Leed 4,  William E Dennis 4,  Norma Roncal 4,  Brandon S Pybus 4,  Patricia J Lee 4,  Alison Roth 4,  Kevin A Reynolds 1,  Jane X Kelly 1 3,  Scott M Landfear 2
Affiliations

Affiliations

  • 1 Department of Chemistry, Portland State University, Portland, Oregon 97201, United States.
  • 2 Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, Oregon 97239, United States.
  • 3 Department of Veterans Affairs Medical Center, Portland, Oregon 97239, United States.
  • 4 Experimental Therapeutics Branch, CIDR, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, United States.
PMID: 38722757 DOI: 10.1021/acs.jmedchem.4c00517
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 Plasmodium 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 Leishmania mexicana and Leishmania donovani parasites with good safety and metabolic profiles. Notably, tambjamine 110 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.

Figures
Products