ABSTRACT
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. A key feature of this series is the presence of a boron atom in the heterocyclic core structure, which is essential to the observed trypanocidal activity. We also report the in vivo pharmacokinetic properties of lead compounds from the series and selection of SCYX-7158 as a preclinical candidate.
Subject(s)
Antiprotozoal Agents/chemistry , Benzoxazoles/chemistry , Trypanosomiasis, African/drug therapy , Administration, Oral , Animals , Antiprotozoal Agents/pharmacokinetics , Antiprotozoal Agents/therapeutic use , Benzamides/chemistry , Benzamides/pharmacokinetics , Benzamides/therapeutic use , Benzoxazoles/pharmacokinetics , Benzoxazoles/therapeutic use , Boron Compounds/chemistry , Boron Compounds/pharmacokinetics , Boron Compounds/therapeutic use , Brain/metabolism , Disease Models, Animal , Drug Evaluation, Preclinical , Humans , Male , Mice , Structure-Activity Relationship , Trypanosoma brucei brucei/isolation & purificationABSTRACT
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.
Subject(s)
Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Trypanocidal Agents/pharmacology , Trypanosoma brucei brucei/drug effects , Amines/chemistry , Animals , Blood-Brain Barrier , Inhibitory Concentration 50 , Mice , Molecular Structure , Permeability , Pyrimidines/chemistry , Quantitative Structure-Activity Relationship , Trypanocidal Agents/chemical synthesis , Trypanocidal Agents/chemistryABSTRACT
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. The syn-beta-silyl alkoxide eliminated stereospecifically at -78 degrees C to give an E olefin, whereas the anti-beta-silyl alkoxide was unreactive. The reaction mixture was then acidified and heated to induce stereospecific elimination of the anti isomer to give the same E olefin via a complementary cationic pathway. This route was used to complete the first synthesis of the meroterpene (+/-)-3-hydroxybakuchiol. In addition, we synthesized another meroterpene corresponding to the natural product corylifolin and offer evidence that the structure of corylifolin was misassigned.
ABSTRACT
[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. The enedione moiety was found to be unreactive toward simple thiols unless the quaternary center was removed. Using the powerful Moore reaction, we have synthesized (+/-)-madindoline A and B in 11 steps.
