New Compounds with Bioisosteric Replacement of Classic Choline Kinase Inhibitors Show Potent Antiplasmodial Activity
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
Affiliations
Francisco José Aguilar-Troyano
Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, Campus of Cartuja, 18071 Granada, Spain
Archimede Torretta
Center for Nano Science and Technology @PoliMi, Istituto Italiano di Tecnologia, Via Pascoli 70/3, 20133 Milano, Italy
Gianluca Rubbini
Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, Campus of Cartuja, 18071 Granada, Spain
Alberto Fasiolo
Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, Campus of Cartuja, 18071 Granada, Spain
Pilar María Luque-Navarro
Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, Campus of Cartuja, 18071 Granada, Spain
María Paz Carrasco-Jimenez
Department of Biochemistry and Molecular Biology I, Faculty of Sciences, 18071 Granada, Spain
Guiomar Pérez-Moreno
Department of Biochemistry and Molecular Pharmacology, Institute of Parasitology and Biomedicine “López-Neyra”, Spanish National Research Council, Parque Tecnológico de Ciencias de la Salud, Avenida del Conocimiento 17, 18016, Granada, Spain
Cristina Bosch-Navarrete
Department of Biochemistry and Molecular Pharmacology, Institute of Parasitology and Biomedicine “López-Neyra”, Spanish National Research Council, Parque Tecnológico de Ciencias de la Salud, Avenida del Conocimiento 17, 18016, Granada, Spain
Dolores González-Pacanowska
Department of Biochemistry and Molecular Pharmacology, Institute of Parasitology and Biomedicine “López-Neyra”, Spanish National Research Council, Parque Tecnológico de Ciencias de la Salud, Avenida del Conocimiento 17, 18016, Granada, Spain
Emilio Parisini
Center for Nano Science and Technology @PoliMi, Istituto Italiano di Tecnologia, Via Pascoli 70/3, 20133 Milano, Italy
Luisa Carlota Lopez-Cara
Department of Pharmaceutical and Organic Chemistry, Faculty of Pharmacy, Campus of Cartuja, 18071 Granada, Spain
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 Plasmodium falciparum 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.