RESUMEN
Recent clinical trials investigating treatment of chronic indeterminate Chagas disease with two re-purposed azole anti-fungal drugs, posaconazole and ravuconazole, revealed their inferiority to the current standard-of-care benznidazole and highlighted the inadequacy of the existing pre-clinical testing paradigm for this disease. A very limited number of controlled clinical trials for Chagas disease have been conducted to date. The selection of these compounds for clinical evaluation relied heavily on pre-clinical data obtained from in vitro screens and animal studies. This chapter reviews the evolution of CYP51 as a target for Trypanosoma cruzi growth inhibition and also explores the impact of clinical trial data on contemporary Chagas disease drug discovery. Advances in pre-clinical profiling assays, the current compound landscape and progress towards the identification of new drug targets to re-invigorate research are reviewed.
Asunto(s)
Enfermedad de Chagas/tratamiento farmacológico , Descubrimiento de Drogas , Inhibidores de 14 alfa Desmetilasa/uso terapéutico , Ensayos Clínicos como Asunto , Humanos , Nitroimidazoles/uso terapéuticoRESUMEN
Reductive coupling of α,ß-unsaturated acid chlorides A with alkynoyls B provides convergent access to Nazarov cyclization precursors, α-carboxy divinyl ketones C. Cyclization of C gives an intermediate oxyallyl cation intermediate D, which can be trapped with tethered arenes (Ar). The resultant products can be further cyclized through nucleophilic displacement of suitable leaving groups X by tethered OH groups to give lactones (in a subsequent step). Where X is a suitable chiral auxiliary (e.g., oxazolidinone) this strategy affords access to homochiral cyclopentanoids.
Asunto(s)
Alquinos/química , Cloruros/química , Ciclopentanos/síntesis química , Compuestos Policíclicos/síntesis química , Compuestos de Vinilo/química , Ciclización , Ciclopentanos/química , Estructura MolecularRESUMEN
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.
Asunto(s)
Enfermedad de Chagas/tratamiento farmacológico , Pirimidinas/farmacología , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Enfermedad de Chagas/parasitología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Pirimidinas/administración & dosificación , Pirimidinas/química , Relación Estructura-Actividad , Tripanocidas/administración & dosificación , Tripanocidas/químicaRESUMEN
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.
Asunto(s)
Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Administración Oral , Animales , Línea Celular , Supervivencia Celular/efectos de los fármacos , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/mortalidad , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A , Modelos Animales de Enfermedad , Ensayos Analíticos de Alto Rendimiento , Humanos , Ratones , Pruebas de Sensibilidad Parasitaria , Ratas , Relación Estructura-Actividad , Tasa de Supervivencia , Factores de Tiempo , Tripanocidas/química , Tripanocidas/uso terapéuticoRESUMEN
Chagas disease, caused by the eukaryotic (protozoan) parasite Trypanosoma cruzi, is an alarming emerging global health problem with no clinical drugs available to treat the chronic stage. Azole inhibitors of sterol 14α-demethylase (CYP51) were proven effective against Chagas, and antifungal drugs posaconazole and ravuconazole have entered clinical trials in Spain, Bolivia, and Argentina. Here we present the x-ray structures of T. cruzi CYP51 in complexes with two alternative drug candidates, pyridine derivatives (S)-(4-chlorophenyl)-1-(4-(4-(trifluoromethyl)phenyl)-piperazin-1-yl)-2-(pyridin-3-yl)ethanone (UDO; Protein Data Bank code 3ZG2) and N-[4-(trifluoromethyl)phenyl]-N-[1-[5-(trifluoromethyl)-2-pyridyl]-4-piperi-dyl]pyridin-3-amine (UDD; Protein Data Bank code 3ZG3). These compounds have been developed by the Drugs for Neglected Diseases initiative (DNDi) and are highly promising antichagasic agents in both cellular and in vivo experiments. The binding parameters and inhibitory effects on sterol 14α-demethylase activity in reconstituted enzyme reactions confirmed UDO and UDD as potent and selective T. cruzi CYP51 inhibitors. Comparative analysis of the pyridine- and azole-bound CYP51 structures uncovered the features that make UDO and UDD T. cruzi CYP51-specific. The structures suggest that although a precise fit between the shape of the inhibitor molecules and T. cruzi CYP51 active site topology underlies their high inhibitory potency, a longer coordination bond between the catalytic heme iron and the pyridine nitrogen implies a weaker influence of pyridines on the iron reduction potential, which may be the basis for the observed selectivity of these compounds toward the target enzyme versus other cytochrome P450s, including human drug-metabolizing P450s. These findings may pave the way for the development of novel CYP51-targeted drugs with optimized metabolic properties that are very much needed for the treatment of human infections caused by eukaryotic microbial pathogens.
Asunto(s)
Inhibidores de 14 alfa Desmetilasa/química , Antiprotozoarios/química , Enfermedad de Chagas/enzimología , Proteínas Protozoarias/antagonistas & inhibidores , Proteínas Protozoarias/química , Esterol 14-Desmetilasa/química , Trypanosoma cruzi/enzimología , Inhibidores de 14 alfa Desmetilasa/uso terapéutico , Antiprotozoarios/uso terapéutico , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/genética , Cristalografía por Rayos X , Humanos , Proteínas Protozoarias/genética , Proteínas Protozoarias/metabolismo , Esterol 14-Desmetilasa/genética , Esterol 14-Desmetilasa/metabolismo , Tiazoles/química , Triazoles/química , Trypanosoma cruzi/genéticaRESUMEN
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.
Asunto(s)
Enfermedad de Chagas/tratamiento farmacológico , Pirimidinas/química , Pirimidinas/farmacología , Tripanocidas/química , Tripanocidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Animales , Línea Celular , Enfermedad de Chagas/metabolismo , Enfermedad de Chagas/parasitología , Modelos Animales de Enfermedad , Cromatografía de Gases y Espectrometría de Masas , Concentración 50 Inhibidora , Masculino , Ratones , Resonancia Magnética Nuclear Biomolecular , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tripanocidas/síntesis química , Tripanocidas/farmacocinéticaRESUMEN
Oxazolidinones are powerful promoters of the Nazarov reaction, enabling the cyclization of conventionally resistant substrates to be achieved under mild conditions. They exert excellent regio- and torquoselective control in both the conventional Nazarov reaction giving cyclopentenones and in the "interrupted" Nazarov reaction, giving more highly substituted multistereocenter containing products.
Asunto(s)
Ciclopentanos/síntesis química , Oxazolidinonas/química , Catálisis , Ciclización , Ciclopentanos/química , Estructura Molecular , EstereoisomerismoRESUMEN
A structure-activity relationship (SAR) guided design of novel tubulin polymerization inhibitors has resulted in a series of benzo[b]furans with exceptional potency toward cancer cells and activated endothelial cells. The potency of early lead compounds has been substantially improved through the synergistic effect of introducing a conformational bias and additional hydrogen bond donor to the pharmacophore. Screening of a focused library of potent tubulin polymerization inhibitors for selectivity against cancer cells and activated endothelial cells over quiescent endothelial cells has afforded 7-hydroxy-6-methoxy-2-methyl-3-(3,4,5-trimethoxybenzoyl)benzo[b]furan (BNC105, 8) as a potent and selective antiproliferative. Because of poor solubility, 8 is administered as its disodium phosphate ester prodrug 9 (BNC105P), which is rapidly cleaved in vivo to return the active 8. 9 exhibits both superior vascular disrupting and tumor growth inhibitory properties compared with the benchmark agent combretastatin A-4 disodium phosphate 5 (CA4P).
Asunto(s)
Anisoles/farmacología , Aorta/efectos de los fármacos , Benzofuranos/farmacología , Proliferación Celular/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Neovascularización Fisiológica/efectos de los fármacos , Moduladores de Tubulina/farmacología , Anisoles/síntesis química , Anisoles/química , Aorta/citología , Benzofuranos/síntesis química , Benzofuranos/química , Células Cultivadas , Endotelio Vascular/citología , Humanos , Relación Estructura-Actividad , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/químicaRESUMEN
A convenient method for the synthesis of 2-bromo-3-aroyl-benzo[b]furans from readily accessible precursors has been developed. The 2-bromo group has been employed as a versatile synthetic handle in both palladium-mediated couplings and direct nucleophilic substitutions to give access to a wide range of 2-substituted-3-aroyl-benzo[b]furans.
Asunto(s)
Compuestos de Aluminio/síntesis química , Benzofuranos/síntesis química , Bromo/química , Compuestos de Aluminio/química , Benzofuranos/química , Estructura MolecularRESUMEN
The complex tetracyclic carbon skeleton of colombiasin A is conveniently accessed through an enantioselective intermolecular Diels-Alder-sulfoxide elimination-intramolecular Diels-Alder (DA-E-IMDA) sequence.