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

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.

Figure 1.

Biologically active natural PGs (2 and 3), and TAs (4 and 5), and their common biosynthetic precursor MBC (1).

Figure 2.

Key 2,2'-bipyrrole-5-carboxaldehydes 1 and 6–24 for the synthesis of A- and B-ring functionalized TAs.

Figure 3.

In vivo efficacy of 95, 101, and 110 in mice. (A) mice (initially 5 per treatment) infected with L. mexicana were treated with vehicle, 101 and 110 and footpad lesion thickness was measured. p Values were determined by two-tailed paired t-test; (B) Mice infected with RS-LUC-expressing L. mexicana were treated (days 20–29) with vehicle, 95, 101 and 110 and imaged at 6 weeks post-infection. The ratio of Relative Luminescence Units (RLU) for each mouse was calculated by dividing the RLU at day 45 post-infection (pi) by the RLU at day 19, just before treatment was begun. This ratio quantifies the increase in RLU between day 19 and day 45. Statistical significance was determined using ANOVA and Dunnett’s post-test. *** p<0.001, ** p<0.01, * p<0.05.

Scheme 1.

Synthesis of Aryloxy and Aryl Substituted 2,2'-Bipyrrole-5-carboxaldehydes (20–24).

Scheme 2.

Synthesis of Tambjamine Analogues 42–124.