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

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.