New Compounds with Bioisosteric Replacement of Classic Choline Kinase Inhibitors Show Potent Antiplasmodial Activity

In the fight against Malaria, new strategies need to be developed to avoid resistance of the parasite to pharmaceutics and other prevention barriers. Recently, a Host Directed Therapy approach based on the suppression of the starting materials uptake from the host by the parasite has provided excell...

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Autores principales:	Francisco José Aguilar-Troyano, Archimede Torretta, Gianluca Rubbini, Alberto Fasiolo, Pilar María Luque-Navarro, María Paz Carrasco-Jimenez, Guiomar Pérez-Moreno, Cristina Bosch-Navarrete, Dolores González-Pacanowska, Emilio Parisini, Luisa Carlota Lopez-Cara
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	antimalarial drug choline kinase inhibition Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/4ed42e0cc01e4a2db6f69fca8a4f731c
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spelling	oai:doaj.org-article:4ed42e0cc01e4a2db6f69fca8a4f731c2021-11-25T18:41:06ZNew Compounds with Bioisosteric Replacement of Classic Choline Kinase Inhibitors Show Potent Antiplasmodial Activity10.3390/pharmaceutics131118421999-4923https://doaj.org/article/4ed42e0cc01e4a2db6f69fca8a4f731c2021-11-01T00:00:00Zhttps://www.mdpi.com/1999-4923/13/11/1842https://doaj.org/toc/1999-4923In the fight against Malaria, new strategies need to be developed to avoid resistance of the parasite to pharmaceutics and other prevention barriers. Recently, a Host Directed Therapy approach based on the suppression of the starting materials uptake from the host by the parasite has provided excellent results. In this article, we propose the synthesis of bioisosteric compounds that are capable of inhibiting <i>Plasmodium falciparum</i> Choline Kinase and therefore to reduce choline uptake, which is essential for the development of the parasite. Of the 41 bioisosteric compounds reported herein, none showed any influence of the linker on the antimalarial and enzyme inhibitory activity, whereas an effect of the type of cationic heads used could be observed. SARs determined that the thienopyrimidine substituted in 4 by a pyrrolidine is the best scaffold, independently of the chosen linker. The decrease in lipophilicity seems to improve the antimalarial activity but to cause an opposite effect on the inhibition of the enzyme. While potent compounds with similar good inhibitory values have been related to the proposed mechanism of action, some of them still show discrepancies and further studies are needed to determine their specific molecular target.Francisco José Aguilar-TroyanoArchimede TorrettaGianluca RubbiniAlberto FasioloPilar María Luque-NavarroMaría Paz Carrasco-JimenezGuiomar Pérez-MorenoCristina Bosch-NavarreteDolores González-PacanowskaEmilio ParisiniLuisa Carlota Lopez-CaraMDPI AGarticleantimalarial drugcholine kinase inhibitionPharmacy and materia medicaRS1-441ENPharmaceutics, Vol 13, Iss 1842, p 1842 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	antimalarial drug choline kinase inhibition Pharmacy and materia medica RS1-441
spellingShingle	antimalarial drug choline kinase inhibition Pharmacy and materia medica RS1-441 Francisco José Aguilar-Troyano Archimede Torretta Gianluca Rubbini Alberto Fasiolo Pilar María Luque-Navarro María Paz Carrasco-Jimenez Guiomar Pérez-Moreno Cristina Bosch-Navarrete Dolores González-Pacanowska Emilio Parisini Luisa Carlota Lopez-Cara New Compounds with Bioisosteric Replacement of Classic Choline Kinase Inhibitors Show Potent Antiplasmodial Activity
description	In the fight against Malaria, new strategies need to be developed to avoid resistance of the parasite to pharmaceutics and other prevention barriers. Recently, a Host Directed Therapy approach based on the suppression of the starting materials uptake from the host by the parasite has provided excellent results. In this article, we propose the synthesis of bioisosteric compounds that are capable of inhibiting <i>Plasmodium falciparum</i> Choline Kinase and therefore to reduce choline uptake, which is essential for the development of the parasite. Of the 41 bioisosteric compounds reported herein, none showed any influence of the linker on the antimalarial and enzyme inhibitory activity, whereas an effect of the type of cationic heads used could be observed. SARs determined that the thienopyrimidine substituted in 4 by a pyrrolidine is the best scaffold, independently of the chosen linker. The decrease in lipophilicity seems to improve the antimalarial activity but to cause an opposite effect on the inhibition of the enzyme. While potent compounds with similar good inhibitory values have been related to the proposed mechanism of action, some of them still show discrepancies and further studies are needed to determine their specific molecular target.
format	article
author	Francisco José Aguilar-Troyano Archimede Torretta Gianluca Rubbini Alberto Fasiolo Pilar María Luque-Navarro María Paz Carrasco-Jimenez Guiomar Pérez-Moreno Cristina Bosch-Navarrete Dolores González-Pacanowska Emilio Parisini Luisa Carlota Lopez-Cara
author_facet	Francisco José Aguilar-Troyano Archimede Torretta Gianluca Rubbini Alberto Fasiolo Pilar María Luque-Navarro María Paz Carrasco-Jimenez Guiomar Pérez-Moreno Cristina Bosch-Navarrete Dolores González-Pacanowska Emilio Parisini Luisa Carlota Lopez-Cara
author_sort	Francisco José Aguilar-Troyano
title	New Compounds with Bioisosteric Replacement of Classic Choline Kinase Inhibitors Show Potent Antiplasmodial Activity
title_short	New Compounds with Bioisosteric Replacement of Classic Choline Kinase Inhibitors Show Potent Antiplasmodial Activity
title_full	New Compounds with Bioisosteric Replacement of Classic Choline Kinase Inhibitors Show Potent Antiplasmodial Activity
title_fullStr	New Compounds with Bioisosteric Replacement of Classic Choline Kinase Inhibitors Show Potent Antiplasmodial Activity
title_full_unstemmed	New Compounds with Bioisosteric Replacement of Classic Choline Kinase Inhibitors Show Potent Antiplasmodial Activity
title_sort	new compounds with bioisosteric replacement of classic choline kinase inhibitors show potent antiplasmodial activity
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/4ed42e0cc01e4a2db6f69fca8a4f731c
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New Compounds with Bioisosteric Replacement of Classic Choline Kinase Inhibitors Show Potent Antiplasmodial Activity

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