Design, synthesis and biological evaluation of antiparasitic dinitroaniline-ether phospholipid hybrids

Abstract:

A series of nine novel ether phospholipid-dinitroaniline hybrids were synthesized in an effort to deliver more potent antiparasitic agents with improved safety profile compared to miltefosine. The compounds were evaluated for their in vitro antiparasitic activity against L. infantum, L.donovani, L. amazonensis, L. major and L. tropica promastigotes, L. infantum and L. donovani intracellular amastigotes, Trypanosoma brucei brucei and against different developmental stages of Trypanosoma cruzi. The nature of the oligomethylene spacer between the dinitroaniline moiety and the phosphate group, the length of the side chain substituent on the dinitroaniline and the choline or homocholine head group were found to affect both the activity and toxicity of the hybrids. The early ADMET profile of the derivatives did not reveal major liabilities. Hybrid 3, bearing an 11-carbon oligomethylene spacer, a butyl side chain and a choline head group, was the most potent analogue of the series. It exhibited a broad spectrum antiparasitic profile against the promastigotes of New and Old World Leishmania spp., against intracellular amastigotes of two L. infantum strains and L. donovani, against T. brucei and against T. cruzi Y strain epimastigotes, intracellular amastigotes and trypomastigotes. The early toxicity studies revealed that hybrid 3 showed a safe toxicological profile while its cytotoxicity concentration (CC50) against THP-1 macrophages being >100 μM. Computational analysis of binding sites and docking indicated that the interaction of hybrid 3 with trypanosomatid α-tubulin may contribute to its mechanism of action. Furthermore, compound 3 was found to interfere with the cell cycle in T. cruzi epimastigotes, while ultrastructural studies using SEM and TEM in T. cruzi showed that compound 3 affects cellular processes that result in changes in the Golgi complex, the mitochondria and the parasite’s plasma membrane. The snapshot pharmacokinetic studies showed low levels of 3 after 24 h following oral administration of 100 mg/Kg, while, its homocholine congener compound 9 presented a better pharmacokinetic profile.

SEEK ID: https://fairdomhub.org/publications/668

DOI: 10.1016/j.bioorg.2023.106615

Projects: NMTrypI - New Medicines for Trypanosomatidic Infections

Publication type: Journal

Journal: Bioorganic Chemistry

Citation: Bioorganic Chemistry 138:106615

Date Published: 1st Sep 2023

Registered Mode: by DOI

Authors: Marina Roussaki, George E. Magoulas, Theano Fotopoulou, Nuno Santarem, Emile Barrias, Ina Pöhner, Sara Luelmo, Pantelis Afroudakis, Kalliopi Georgikopoulou, Paloma Tejera Nevado, Julia Eick, Eugenia Bifeld, María J. Corral, María Dolores Jiménez-Antón, Bernhard Ellinger, Maria Kuzikov, Irini Fragiadaki, Effie Scoulica, Sheraz Gul, Joachim Clos, Kyriakos C. Prousis, Juan J. Torrado, José María Alunda, Rebecca C. Wade, Wanderley de Souza, Anabela Cordeiro da Silva, Theodora Calogeropoulou

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Roussaki, M., Magoulas, G. E., Fotopoulou, T., Santarem, N., Barrias, E., Pöhner, I., Luelmo, S., Afroudakis, P., Georgikopoulou, K., Nevado, P. T., Eick, J., Bifeld, E., Corral, M. J., Jiménez-Antón, M. D., Ellinger, B., Kuzikov, M., Fragiadaki, I., Scoulica, E., Gul, S., … Calogeropoulou, T. (2023). Design, synthesis and biological evaluation of antiparasitic dinitroaniline-ether phospholipid hybrids. In Bioorganic Chemistry (Vol. 138, p. 106615). Elsevier BV. https://doi.org/10.1016/j.bioorg.2023.106615
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Created: 26th May 2023 at 09:13

Last updated: 26th May 2023 at 09:20

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