ABSTRACT
Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is an increasing threat to global health. Available medicines were introduced over 40 years ago, have undesirable side effects, and give equivocal results of cure in the chronic stage of the disease. We report the development of two compounds, 6 and (S)-7, with PCR-confirmed curative activity in a mouse model of established T. cruzi infection after once daily oral dosing for 20 days at 20 mg/kg 6 and 10 mg/kg (S)-7. Compounds 6 and (S)-7 have potent in vitro activity, are noncytotoxic, show no adverse effects in vivo following repeat dosing, are prepared by a short synthetic route, and have druglike properties suitable for preclinical development.
Subject(s)
Chagas Disease/drug therapy , Pyrimidines/pharmacology , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/drug effects , Animals , Chagas Disease/parasitology , Disease Models, Animal , Dose-Response Relationship, Drug , Male , Mice , Molecular Structure , Parasitic Sensitivity Tests , Pyrimidines/administration & dosage , Pyrimidines/chemistry , Structure-Activity Relationship , Trypanocidal Agents/administration & dosage , Trypanocidal Agents/chemistryABSTRACT
BACKGROUND: Inhibitors of Trypanosoma cruzi with novel mechanisms of action are urgently required to diversify the current clinical and preclinical pipelines. Increasing the number and diversity of hits available for assessment at the beginning of the discovery process will help to achieve this aim. RESULTS: We report the evaluation of multiple hits generated from a high-throughput screen to identify inhibitors of T. cruzi and from these studies the discovery of two novel series currently in lead optimization. Lead compounds from these series potently and selectively inhibit growth of T. cruzi in vitro and the most advanced compound is orally active in a subchronic mouse model of T. cruzi infection. CONCLUSION: High-throughput screening of novel compound collections has an important role to play in diversifying the trypanosomatid drug discovery portfolio. A new T. cruzi inhibitor series with good drug-like properties and promising in vivo efficacy has been identified through this process.
Subject(s)
Trypanocidal Agents/pharmacology , Trypanosoma cruzi/drug effects , Administration, Oral , Animals , Cell Line , Cell Survival/drug effects , Chagas Disease/drug therapy , Chagas Disease/mortality , Cytochrome P-450 CYP3A/metabolism , Cytochrome P-450 CYP3A Inhibitors , Disease Models, Animal , High-Throughput Screening Assays , Humans , Mice , Parasitic Sensitivity Tests , Rats , Structure-Activity Relationship , Survival Rate , Time Factors , Trypanocidal Agents/chemistry , Trypanocidal Agents/therapeutic useABSTRACT
We report the discovery of nontoxic fungicide fenarimol (1) as an inhibitor of Trypanosoma cruzi ( T. cruzi ), the causative agent of Chagas disease, and the results of structure-activity investigations leading to potent analogues with low nM IC(50)s in a T. cruzi whole cell in vitro assay. Lead compounds suppressed blood parasitemia to virtually undetectable levels after once daily oral dosing in mouse models of T. cruzi infection. Compounds are chemically tractable, allowing rapid optimization of target biological activity and drug characteristics. Chemical and biological studies undertaken in the development of the fenarimol series toward the goal of delivering a new drug candidate for Chagas disease are reported.
