New Compounds with Bioisosteric Replacement of Classic Choline Kinase Inhibitors Show Potent Antiplasmodial Activity Aguilar-Troyano, Francisco José Rubbini, Gianluca Fasiolo, Alberto Luque Navarro, Pilar María Carrasco Jiménez, María Paz Pérez Moreno, Guiomar Bosch-Navarrete, Cristina González Pacanowska, Dolores López Cara, Luisa Carlota Antimalarial drug Choline kinase inhibition This research was funded by Convocatoria 2019 Proyectos de I + D + i - RTI Tipo B “Ministerio de Ciencia e Innovación” grant number PID2019–109294RB-I00, University of Granada, Cei-BioticProject grant number CEI2013-MP-1, the Instituto de Salud Carlos III Subdirección General de Redes y Centros de Investigación Cooperativa-Red de Investigación Cooperativa en Enfermedades Tropicales (RICET: RD16/0027/0014), the Plan Nacional (SAF PID2019-109623RB-I002016-79957-R) and the Junta de Andalucía (BIO-199). Supplementary Materials: The following are available online at https://www.mdpi.com/article/10.3390/pharmaceutics13111842/s1, Figure S1. Pf CKIC50 Curves Inhibition of Pf CK. Figure S2. IC50Curves. Figure S3. Spectra. 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. 2024-04-30T07:11:46Z 2024-04-30T07:11:46Z 2021-11-02 journal article Aguilar-Troyano, F.J.; Torretta, A.; Rubbini, G.; Fasiolo, A.; Luque-Navarro, P.M.; Carrasco- Jimenez, M.P.; Pérez-Moreno, G.; Bosch-Navarrete, C.; González- Pacanowska, D.; Parisini, E.; et al. New Compounds with Bioisosteric Replacement of Classic Choline Kinase Inhibitors Show Potent Antiplasmodial Activity. Pharmaceutics 2021, 13, 1842. https://doi.org/10.3390/pharmaceutics 13111842 https://hdl.handle.net/10481/91266 10.3390/pharmaceutics 13111842 eng http://creativecommons.org/licenses/by-nc-nd/3.0/ open access Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License MDPI