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Antileishmanial activity of terpenylquinones on Leishmania infantum and their effects on Leishmania topoisomerase IB
Leishmania is the aethiological agent responsible for the visceral leishmaniasis, a serious parasite-borne disease widely spread all over the World. The emergence of resistant strains makes classical treatments less effective; therefore, new and better drugs are necessary. Naphthoquinones are intere...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904838/ https://www.ncbi.nlm.nih.gov/pubmed/31678841 http://dx.doi.org/10.1016/j.ijpddr.2019.10.004 |
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author | Pérez-Pertejo, Yolanda Escudero-Martínez, José M. Reguera, Rosa M. Balaña-Fouce, Rafael García, Pablo A. Jambrina, Pablo G. San Feliciano, Arturo Castro, María-Ángeles |
author_facet | Pérez-Pertejo, Yolanda Escudero-Martínez, José M. Reguera, Rosa M. Balaña-Fouce, Rafael García, Pablo A. Jambrina, Pablo G. San Feliciano, Arturo Castro, María-Ángeles |
author_sort | Pérez-Pertejo, Yolanda |
collection | PubMed |
description | Leishmania is the aethiological agent responsible for the visceral leishmaniasis, a serious parasite-borne disease widely spread all over the World. The emergence of resistant strains makes classical treatments less effective; therefore, new and better drugs are necessary. Naphthoquinones are interesting compounds for which many pharmacological properties have been described, including leishmanicidal activity. This work shows the antileishmanial effect of two series of terpenyl-1,4-naphthoquinones (NQ) and 1,4-anthraquinones (AQ) obtained from natural terpenoids, such as myrcene and myrceocommunic acid. They were evaluated both in vitro and ex vivo against the transgenic iRFP-Leishmania infantum strain and also tested on liver HepG2 cells to determine their selectivity indexes. The results indicated that NQ derivatives showed better antileishmanial activity than AQ analogues, and among them, compounds with a diacetylated hydroquinone moiety provided better results than their corresponding quinones. Regarding the terpenic precursor, compounds obtained from the monoterpenoid myrcene displayed good antiparasitic efficiency and low cytotoxicity for mammalian cells, whereas those derived from the diterpenoid showed better antileishmanial activity without selectivity. In order to explore their mechanism of action, all the compounds have been tested as potential inhibitors of Leishmania type IB DNA topoisomerases, but only some compounds that displayed the quinone ring were able to inhibit the recombinant enzyme in vitro. This fact together with the docking studies performed on LTopIB suggested the existence of another mechanism of action, alternative or complementary to LTopIB inhibition. In silico druglikeness and ADME evaluation of the best leishmanicidal compounds has shown good predictable druggability. |
format | Online Article Text |
id | pubmed-6904838 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-69048382019-12-20 Antileishmanial activity of terpenylquinones on Leishmania infantum and their effects on Leishmania topoisomerase IB Pérez-Pertejo, Yolanda Escudero-Martínez, José M. Reguera, Rosa M. Balaña-Fouce, Rafael García, Pablo A. Jambrina, Pablo G. San Feliciano, Arturo Castro, María-Ángeles Int J Parasitol Drugs Drug Resist Regular Article Leishmania is the aethiological agent responsible for the visceral leishmaniasis, a serious parasite-borne disease widely spread all over the World. The emergence of resistant strains makes classical treatments less effective; therefore, new and better drugs are necessary. Naphthoquinones are interesting compounds for which many pharmacological properties have been described, including leishmanicidal activity. This work shows the antileishmanial effect of two series of terpenyl-1,4-naphthoquinones (NQ) and 1,4-anthraquinones (AQ) obtained from natural terpenoids, such as myrcene and myrceocommunic acid. They were evaluated both in vitro and ex vivo against the transgenic iRFP-Leishmania infantum strain and also tested on liver HepG2 cells to determine their selectivity indexes. The results indicated that NQ derivatives showed better antileishmanial activity than AQ analogues, and among them, compounds with a diacetylated hydroquinone moiety provided better results than their corresponding quinones. Regarding the terpenic precursor, compounds obtained from the monoterpenoid myrcene displayed good antiparasitic efficiency and low cytotoxicity for mammalian cells, whereas those derived from the diterpenoid showed better antileishmanial activity without selectivity. In order to explore their mechanism of action, all the compounds have been tested as potential inhibitors of Leishmania type IB DNA topoisomerases, but only some compounds that displayed the quinone ring were able to inhibit the recombinant enzyme in vitro. This fact together with the docking studies performed on LTopIB suggested the existence of another mechanism of action, alternative or complementary to LTopIB inhibition. In silico druglikeness and ADME evaluation of the best leishmanicidal compounds has shown good predictable druggability. Elsevier 2019-10-22 /pmc/articles/PMC6904838/ /pubmed/31678841 http://dx.doi.org/10.1016/j.ijpddr.2019.10.004 Text en © 2019 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Regular Article Pérez-Pertejo, Yolanda Escudero-Martínez, José M. Reguera, Rosa M. Balaña-Fouce, Rafael García, Pablo A. Jambrina, Pablo G. San Feliciano, Arturo Castro, María-Ángeles Antileishmanial activity of terpenylquinones on Leishmania infantum and their effects on Leishmania topoisomerase IB |
title | Antileishmanial activity of terpenylquinones on Leishmania infantum and their effects on Leishmania topoisomerase IB |
title_full | Antileishmanial activity of terpenylquinones on Leishmania infantum and their effects on Leishmania topoisomerase IB |
title_fullStr | Antileishmanial activity of terpenylquinones on Leishmania infantum and their effects on Leishmania topoisomerase IB |
title_full_unstemmed | Antileishmanial activity of terpenylquinones on Leishmania infantum and their effects on Leishmania topoisomerase IB |
title_short | Antileishmanial activity of terpenylquinones on Leishmania infantum and their effects on Leishmania topoisomerase IB |
title_sort | antileishmanial activity of terpenylquinones on leishmania infantum and their effects on leishmania topoisomerase ib |
topic | Regular Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904838/ https://www.ncbi.nlm.nih.gov/pubmed/31678841 http://dx.doi.org/10.1016/j.ijpddr.2019.10.004 |
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