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Synthesis and antiplasmodial activity of regioisomers and epimers of second-generation dual acting ivermectin hybrids

With its strong effect on vector-borne diseases, and insecticidal effect on mosquito vectors of malaria, inhibition of sporogonic and blood-stage development of Plasmodium falciparum, as well as in vitro and in vivo impairment of the P. berghei development inside hepatocytes, ivermectin (IVM) contin...

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Autores principales: Singh, Lovepreet, Fontinha, Diana, Francisco, Denise, Prudêncio, Miguel, Singh, Kamaljit
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8755717/
https://www.ncbi.nlm.nih.gov/pubmed/35022455
http://dx.doi.org/10.1038/s41598-021-04532-w
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author Singh, Lovepreet
Fontinha, Diana
Francisco, Denise
Prudêncio, Miguel
Singh, Kamaljit
author_facet Singh, Lovepreet
Fontinha, Diana
Francisco, Denise
Prudêncio, Miguel
Singh, Kamaljit
author_sort Singh, Lovepreet
collection PubMed
description With its strong effect on vector-borne diseases, and insecticidal effect on mosquito vectors of malaria, inhibition of sporogonic and blood-stage development of Plasmodium falciparum, as well as in vitro and in vivo impairment of the P. berghei development inside hepatocytes, ivermectin (IVM) continues to represent an antimalarial therapeutic worthy of investigation. The in vitro activity of the first-generation IVM hybrids synthesized by appending the IVM macrolide with heterocyclic and organometallic antimalarial pharmacophores, against the blood-stage and liver-stage infections by Plasmodium parasites prompted us to design second-generation molecular hybrids of IVM. Here, a structural modification of IVM to produce novel molecular hybrids by using sub-structures of 4- and 8-aminoquinolines, the time-tested antiplasmodial agents used for treating the blood and hepatic stage of Plasmodium infections, respectively, is presented. Successful isolation of regioisomers and epimers has been demonstrated, and the evaluation of their in vitro antiplasmodial activity against both the blood stages of P. falciparum and the hepatic stages of P. berghei have been undertaken. These compounds displayed structure-dependent antiplasmodial activity, in the nM range, which was more potent than that of IVM, its aglycon or primaquine, highlighting the superiority of this hybridization strategy in designing new antiplasmodial agents.
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spelling pubmed-87557172022-01-13 Synthesis and antiplasmodial activity of regioisomers and epimers of second-generation dual acting ivermectin hybrids Singh, Lovepreet Fontinha, Diana Francisco, Denise Prudêncio, Miguel Singh, Kamaljit Sci Rep Article With its strong effect on vector-borne diseases, and insecticidal effect on mosquito vectors of malaria, inhibition of sporogonic and blood-stage development of Plasmodium falciparum, as well as in vitro and in vivo impairment of the P. berghei development inside hepatocytes, ivermectin (IVM) continues to represent an antimalarial therapeutic worthy of investigation. The in vitro activity of the first-generation IVM hybrids synthesized by appending the IVM macrolide with heterocyclic and organometallic antimalarial pharmacophores, against the blood-stage and liver-stage infections by Plasmodium parasites prompted us to design second-generation molecular hybrids of IVM. Here, a structural modification of IVM to produce novel molecular hybrids by using sub-structures of 4- and 8-aminoquinolines, the time-tested antiplasmodial agents used for treating the blood and hepatic stage of Plasmodium infections, respectively, is presented. Successful isolation of regioisomers and epimers has been demonstrated, and the evaluation of their in vitro antiplasmodial activity against both the blood stages of P. falciparum and the hepatic stages of P. berghei have been undertaken. These compounds displayed structure-dependent antiplasmodial activity, in the nM range, which was more potent than that of IVM, its aglycon or primaquine, highlighting the superiority of this hybridization strategy in designing new antiplasmodial agents. Nature Publishing Group UK 2022-01-12 /pmc/articles/PMC8755717/ /pubmed/35022455 http://dx.doi.org/10.1038/s41598-021-04532-w Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Singh, Lovepreet
Fontinha, Diana
Francisco, Denise
Prudêncio, Miguel
Singh, Kamaljit
Synthesis and antiplasmodial activity of regioisomers and epimers of second-generation dual acting ivermectin hybrids
title Synthesis and antiplasmodial activity of regioisomers and epimers of second-generation dual acting ivermectin hybrids
title_full Synthesis and antiplasmodial activity of regioisomers and epimers of second-generation dual acting ivermectin hybrids
title_fullStr Synthesis and antiplasmodial activity of regioisomers and epimers of second-generation dual acting ivermectin hybrids
title_full_unstemmed Synthesis and antiplasmodial activity of regioisomers and epimers of second-generation dual acting ivermectin hybrids
title_short Synthesis and antiplasmodial activity of regioisomers and epimers of second-generation dual acting ivermectin hybrids
title_sort synthesis and antiplasmodial activity of regioisomers and epimers of second-generation dual acting ivermectin hybrids
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8755717/
https://www.ncbi.nlm.nih.gov/pubmed/35022455
http://dx.doi.org/10.1038/s41598-021-04532-w
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