Discovery and Optimization of Tambjamines as a Novel Class of Antileishmanial Agents.
J Med Chem
; 67(10): 8323-8345, 2024 May 23.
Article
em En
| MEDLINE
| ID: mdl-38722757
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Leishmania donovani
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Leishmania mexicana
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Antiprotozoários
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article