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1.
Expert Opin Drug Discov ; 19(6): 741-753, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38715393

RESUMEN

INTRODUCTION: Benznidazole, the drug of choice for treating Chagas Disease (CD), has significant limitations, such as poor cure efficacy, mainly in the chronic phase of CD, association with side effects, and parasite resistance. Understanding parasite resistance to benznidazole is crucial for developing new drugs to treat CD. AREAS COVERED: Here, the authors review the current understanding of the molecular basis of benznidazole resistance. Furthermore, they discuss the state-of-the-art methods and critical outcomes employed to evaluate the efficacy of potential drugs against T. cruzi, aiming to select better compounds likely to succeed in the clinic. Finally, the authors describe the different strategies employed to overcome resistance to benznidazole and find effective new treatments for CD. EXPERT OPINION: Resistance to benznidazole is a complex phenomenon that occurs naturally among T. cruzi strains. The combination of compounds that inhibit different metabolic pathways of the parasite is an important strategy for developing a new chemotherapeutic protocol.


Asunto(s)
Enfermedad de Chagas , Descubrimiento de Drogas , Resistencia a Medicamentos , Nitroimidazoles , Tripanocidas , Trypanosoma cruzi , Trypanosoma cruzi/efectos de los fármacos , Nitroimidazoles/farmacología , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/parasitología , Tripanocidas/farmacología , Humanos , Animales , Descubrimiento de Drogas/métodos , Desarrollo de Medicamentos
2.
Eur J Med Chem ; 256: 115445, 2023 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-37156183

RESUMEN

An early hit-to-lead optimization of a novel pyrazinylpiperazine series against L. infantum and L. braziliensis has been performed after an extensive SAR focusing on the benzoyl fragment of hit (4). Deletion of the meta-Cl of (4) led to the obtention of the para-hydroxyl derivative (12), on which the design of most monosubstituted derivatives of the SAR was based. Further optimization of the series, involving disubstituted benzoyl fragments and the hydroxyl substituent of (12), allowed the obtention of a total of 15 compounds with increased antileishmanial potency (IC50 < 10 µM), nine of which displayed activity in the low micromolar range (IC50 < 5 µM). This optimization ultimately identified the ortho, meta-dihydroxyl derivative (46) as an early lead for this series (IC50 (L. infantum) = 2.8 µM, IC50 (L. braziliensis) = 0.2 µM). Additional assessment of some selected compounds against other trypanosomatid parasites revealed that this series is selective towards Leishmania parasites, and in silico ADMET predictions revealed satisfactory profiles for these compounds, allowing further lead optimization of the pyrazinylpiperazine class against Leishmania.


Asunto(s)
Antiprotozoarios , Leishmania braziliensis , Leishmania infantum , Antiprotozoarios/farmacología , Radical Hidroxilo
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