Benzoxaboroles: a new class of potential drugs for human African trypanosomiasis.

Human African trypanosomiasis, caused by the kinetoplastid parasite Trypanosoma brucei, affects thousands of people across sub-Saharan Africa, and is fatal if left untreated. Treatment options for this disease, particularly stage 2 disease, which occurs after parasites have infected brain tissue, are limited due to inadequate efficacy, toxicity and the complexity of treatment regimens. We have discovered and optimized a series of benzoxaborole-6-carboxamides to provide trypanocidal compounds that are orally active in murine models of human African trypanosomiasis.

SAR of 2-amino and 2,4-diamino pyrimidines with in vivo efficacy against Trypanosoma brucei.

A series of 2,4-diaminopyrimidines was investigated and compounds were found to have in vivo efficacy against Trypanosoma brucei in an acute mouse model. However, in vitro permeability data suggested the 2,4-diaminopyrimidenes would have poor permeability through the blood brain barrier. Consequently a series of 4-desamino analogs were synthesized and found to have improved in vitro permeability.

2,4-Diaminopyrimidines as potent inhibitors of Trypanosoma brucei and identification of molecular targets by a chemical proteomics approach.

Background: There is an urgent need to develop new, safe and effective treatments for human African trypanosomiasis (HAT) because current drugs have extremely poor safety profiles and are difficult to administer. Here we report the discovery of 2,4-diaminopyrimidines, exemplified by 4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid phenylamide (SCYX-5070), as potent inhibitors of Trypanosoma brucei and the related trypanosomatid protozoans Leishmania spp.

Methodology/principal Findings: In this work we show that loss of T.

Convergent stereocontrol in peterson olefinations. Application to the synthesis of (+/-)-3-hydroxybakuchiol and corylifolin.

The iron-catalyzed Kirmse reaction was used to generate neopentyl alpha-silyl thioethers that were elaborated to meroterpenes using two complementary routes: one route involved a sila-Pummerer rearrangement, and the other route involved a Peterson olefination. While severe eclipsing interactions undermined the efficiency of the stereospecific sila-Pummerer rearrangement, they made it possible to stereoselectively generate E olefins without isolation or separation of syn- and anti-beta-silyl alkoxides. Addition of a neopentyl alpha-silyl alkyllithium intermediate to an aryl aldehyde generated a mixture of syn- and anti-beta-silyl alkoxides.

Synthesis of (+/-)-madindolines and chemical models. Studies of chemical reactivity.

[reaction: see text] The madindolines are believed to inhibit cytokine signaling through the gp130 receptor. Model compounds of madindolines were synthesized and tested for thiol reactivity. The heterocyclic moiety of madindoline was shown to form thiol adducts via the Savige-Fontana reaction.