학술논문
Discovery and Optimization of Tambjamines as a Novel Class of Antileishmanial Agents.
Document Type
Academic Journal
Author
Kancharla P; Department of Chemistry, Portland State University, Portland, Oregon 97201, United States.; Ortiz D; Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, Oregon 97239, United States.; Fargo CM; Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, Oregon 97239, United States.; Zhang X; Department of Veterans Affairs Medical Center, Portland, Oregon 97239, United States.; Li Y; Department of Veterans Affairs Medical Center, Portland, Oregon 97239, United States.; Sanchez M; Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, Oregon 97239, United States.; Kumar A; Department of Chemistry, Portland State University, Portland, Oregon 97201, United States.; Yeluguri M; Department of Chemistry, Portland State University, Portland, Oregon 97201, United States.; Dodean RA; Department of Chemistry, Portland State University, Portland, Oregon 97201, United States.; Caridha D; Experimental Therapeutics Branch, CIDR, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, United States.; Madejczyk MS; Experimental Therapeutics Branch, CIDR, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, United States.; Martin M; Experimental Therapeutics Branch, CIDR, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, United States.; Jin X; Experimental Therapeutics Branch, CIDR, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, United States.; Blount C; Experimental Therapeutics Branch, CIDR, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, United States.; Chetree R; Experimental Therapeutics Branch, CIDR, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, United States.; Pannone K; Experimental Therapeutics Branch, CIDR, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, United States.; Dinh HT; Experimental Therapeutics Branch, CIDR, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, United States.; DeLuca J; Experimental Therapeutics Branch, CIDR, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, United States.; Evans M; Experimental Therapeutics Branch, CIDR, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, United States.; Nadeau R; Experimental Therapeutics Branch, CIDR, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, United States.; Vuong C; Experimental Therapeutics Branch, CIDR, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, United States.; Leed S; Experimental Therapeutics Branch, CIDR, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, United States.; Dennis WE; Experimental Therapeutics Branch, CIDR, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, United States.; Roncal N; Experimental Therapeutics Branch, CIDR, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, United States.; Pybus BS; Experimental Therapeutics Branch, CIDR, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, United States.; Lee PJ; Experimental Therapeutics Branch, CIDR, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, United States.; Roth A; Experimental Therapeutics Branch, CIDR, Walter Reed Army Institute of Research, Silver Spring, Maryland 20910, United States.; Reynolds KA; Department of Chemistry, Portland State University, Portland, Oregon 97201, United States.; Kelly JX; Department of Chemistry, Portland State University, Portland, Oregon 97201, United States.; Department of Veterans Affairs Medical Center, Portland, Oregon 97239, United States.; Landfear SM; Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, Oregon 97239, United States.
Source
Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE
Subject
Language
English
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.