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
Copyright © 2018 Elsevier Masson SAS. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2018 |
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| Erschienen: |
2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:149 |
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| Enthalten in: |
European journal of medicinal chemistry - 149(2018) vom: 10. Apr., Seite 257-268 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ferreira de Almeida Fiuza, Ludmila [VerfasserIn] |
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| Links: |
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| Themen: |
14-alpha Demethylase Inhibitors |
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| Anmerkungen: |
Date Completed 21.03.2018 Date Revised 21.03.2018 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ejmech.2018.02.020 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM281590877 |
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| 245 | 1 | 0 | |a Identification of Pyrazolo[3,4-e][1,4]thiazepin based CYP51 inhibitors as potential Chagas disease therapeutic alternative |b In vitro and in vivo evaluation, binding mode prediction and SAR exploration |
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| 520 | |a Copyright © 2018 Elsevier Masson SAS. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a CYP51 inhibitors and SAR studies | |
| 650 | 4 | |a Chagas disease | |
| 650 | 4 | |a Trypanosoma cruzi | |
| 650 | 7 | |a 14-alpha Demethylase Inhibitors |2 NLM | |
| 650 | 7 | |a Pyrazolones |2 NLM | |
| 650 | 7 | |a Thiazepines |2 NLM | |
| 700 | 1 | |a Peres, Raiza Brandão |e verfasserin |4 aut | |
| 700 | 1 | |a Simões-Silva, Marianne Rocha |e verfasserin |4 aut | |
| 700 | 1 | |a da Silva, Patricia Bernardino |e verfasserin |4 aut | |
| 700 | 1 | |a Batista, Denise da Gama Jaen |e verfasserin |4 aut | |
| 700 | 1 | |a da Silva, Cristiane França |e verfasserin |4 aut | |
| 700 | 1 | |a Nefertiti Silva da Gama, Aline |e verfasserin |4 aut | |
| 700 | 1 | |a Krishna Reddy, Tummala Rama |e verfasserin |4 aut | |
| 700 | 1 | |a Soeiro, Maria de Nazaré Correia |e verfasserin |4 aut | |
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