Εξειδίκευση τύπου :	Άρθρο σε επιστημονικό περιοδικό
Τίτλος:	Design, synthesis and biological evaluation of antiparasitic dinitroaniline-ether phospholipid hybrids
Δημιουργός/Συγγραφέας:	Roussaki, Marina Magoulas, George E Fotopoulou, Theano Santarem, Nuno Barrias, Emile Pöhner, Ina Luelmo, Sara Afroudakis, Pantelis Georgikopoulou, Kalliopi Nevado, Paloma Tejera Eick, Julia Bifeld, Eugenia Corral, María J Jiménez-Antón, María Dolores Ellinger, Bernhard Kuzikov, Maria Fragiadaki, Irini Scoulica, Effie Gul, Sheraz Clos, Joachim [EL] Προύσης, Κυριάκος[EN] Prousis, Kyriakos Torrado, Juan J Alunda, José María Wade, Rebecca C de Souza, Wanderley Cordeiro da Silva, Anabela [EL] Καλογεροπούλου, Θεοδώρα[EN] Calogeropoulou, Theodora
Ημερομηνία:	2023-06-19
Γλώσσα:	Αγγλικά
ISSN:	00452068
DOI:	10.1016/j.bioorg.2023.106615
Άλλο:	37244229
Περίληψη:	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.
Τίτλος πηγής δημοσίευσης:	Bioorganic chemistry
Τόμος/Κεφάλαιο:	138
Θεματική Κατηγορία:	[EL] Οργανική χημεία[EN] Organic chemistry [EL] Φαρμακευτική χημεία[EN] Pharmaceutical chemistry [EL] Δομική Βιολογία[EN] Structural Biology [EL] Βιοτεχνολογία[EN] Biotechnology
Λέξεις-Κλειδιά:	Alkylphosphocholines Antiparasitic hybrid compounds Dinitroanilines Leishmania sp. Molecular docking trypanosomatid tubulin Trypanosomatids Humans Antiparasitic Agents Phospholipid Ethers Choline Antiprotozoal Agents Trypanosoma cruzi Chagas Disease
Ηλεκτρονική διεύθυνση στον εκδότη (link):	https://doi.org/10.1016/j.bioorg.2023.106615
Εμφανίζεται στις συλλογές:	Ινστιτούτο Χημικής Βιολογίας - Επιστημονικό έργο