Identification of Pyrazolo[3,4-e][1,4]thiazepin based CYP51 inhibitors as potential Chagas disease therapeutic alternative: In vitro and in vivo evaluation, binding mode prediction and SAR exploration

Article


Ferreira de Almeida Fiuza, Ludmila, Peres, Raiza Brandão, Simões-Silva, Marianne Rocha, da Silva, Patricia Bernardino, Batista, Denise da Gama Jaen, da Silva, Cristiane França, Nefertiti Silva da Gama, Aline, Reddy, T. and Soeiro, Maria de Nazaré Correia 2018. Identification of Pyrazolo[3,4-e][1,4]thiazepin based CYP51 inhibitors as potential Chagas disease therapeutic alternative: In vitro and in vivo evaluation, binding mode prediction and SAR exploration. European Journal of Medicinal Chemistry. 149, pp. 257-268.
AuthorsFerreira de Almeida Fiuza, Ludmila, Peres, Raiza Brandão, Simões-Silva, Marianne Rocha, da Silva, Patricia Bernardino, Batista, Denise da Gama Jaen, da Silva, Cristiane França, Nefertiti Silva da Gama, Aline, Reddy, T. and Soeiro, Maria de Nazaré Correia
Abstract

American trypanosomiasis or Chagas disease (CD) is a vector borne pathology caused by the parasite Trypanosoma cruzi (T. cruzi), which remains a serious global health problem. The current available treatment for CD is limited to two nitroderivatives with limited efficacy and several side effects. The rational design of ergosterol synthetic route inhibitors (e.g. CYP51 inhibitors) represents a promising strategy for fungi and trypanosomatids, exhibiting excellent anti-T.cruzi activity in pre-clinical assays. In the present work, we evaluate through different approaches (molecular docking, structure activity relationships, CYP51 inhibitory assay, and phenotypic screenings in vitro and in vivo) the potency and selectivity of a novel CYP51 inhibitor (compound 1) and its analogues against T.cruzi infection. Regarding anti-parasitic effect, compound 1 was active in vitro with EC50 3.86 and 4.00 μM upon intracellular (Tulahuen strain) and bloodstream forms (Y strain), respectively. In vivo assays showed that compound 1 reduced in 43% the parasitemia peak but, unfortunately failed to promote animal survival. In order to promote an enhancement at the potency and pharmacological properties, 17 new analogues were purchased and screened in vitro. Our findings demonstrated that five compounds were active against intracellular forms, highlighting compounds 1e and 1f, with EC50 2.20 and 2.70 μM, respectively, and selectivity indices (SI) = 50 and 36, respectively. Against bloodstream trypomastigotes, compound 1f reached an EC50 value of 20.62 μM, in a similar range to Benznidazole, but with low SI (3). Although improved the solubility of compound 1, the analogue 1f did not enhance the potency in vitro neither promote better in vivo efficacy against mouse model of acute T.cruzi infection arguing for the synthesis of novel pyrazolo[3,4-e][1,4]thiazepin derivatives aiming to contribute for alternative therapies for CD.

JournalEuropean Journal of Medicinal Chemistry
Journal citation149, pp. 257-268
ISSN0223-5234
Year2018
PublisherElsevier
Accepted author manuscript
License
Digital Object Identifier (DOI)doi:10.1016/j.ejmech.2018.02.020
Web address (URL)https://doi.org/10.1016/j.ejmech.2018.02.020
Publication dates
Online23 Feb 2018
Publication process dates
Deposited06 Apr 2018
Accepted06 Feb 2018
Accepted06 Feb 2018
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