Synthesis, characterization, molecular docking, and anticancer activities of new 1,3,4-oxadiazole-5-fluorocytosine hybrid derivatives.

Autor: El Mansouri AE; Laboratory of Biomolecular and Medicinal chemistry, Faculty of Science Semlalia, University Cadi Ayyad, Marrakesh, Morocco.; Laboratoire de Matériaux, Catalyse & Valorisation des Ressources Naturelles, URAC 24, Faculté des Sciences et Techniques, Université Hassan II, Casablanca B.P. 146, 20650, Morocco., Lachhab S; Laboratory of Biomolecular and Medicinal chemistry, Faculty of Science Semlalia, University Cadi Ayyad, Marrakesh, Morocco., Oubella A; Laboratoire de Synthese Organique et de Physico-Chimie Moleculaire, Departement de Chimie, Faculte´ des Sciences, Semlalia BP 2390, Marrakech 40001, Morocco., Ahmad M; ICGM, Univ. Montpellier, CNRS, ENSCM, Montpellier, France., Neyts J; Rega Institute for Medical Research, KU Leuven, Leuven, Belgium., Jochmans D; Rega Institute for Medical Research, KU Leuven, Leuven, Belgium., Chiu W; Rega Institute for Medical Research, KU Leuven, Leuven, Belgium., Vangeel L; Rega Institute for Medical Research, KU Leuven, Leuven, Belgium., De Jonghe S; Rega Institute for Medical Research, KU Leuven, Leuven, Belgium., Morjani H; BioSpecT - EA7506 UFR de Pharmacie, Univ-Reims 51, rue Cognacq Jay 51096 Reims cedex, France., Ali MA; Laboratory of Biomolecular and Medicinal chemistry, Faculty of Science Semlalia, University Cadi Ayyad, Marrakesh, Morocco., Zahouily M; Laboratoire de Matériaux, Catalyse & Valorisation des Ressources Naturelles, URAC 24, Faculté des Sciences et Techniques, Université Hassan II, Casablanca B.P. 146, 20650, Morocco., Sanghvi YS; Rasayan Inc. 2802 Crystal Ridge Road, Encinitas, CA 92024-6615, U.S.A., Lazrek HB; Laboratory of Biomolecular and Medicinal chemistry, Faculty of Science Semlalia, University Cadi Ayyad, Marrakesh, Morocco.
Jazyk: angličtina
Zdroj: Journal of molecular structure [J Mol Struct] 2022 Sep 09, pp. 134135. Date of Electronic Publication: 2022 Sep 09.
DOI: 10.1016/j.molstruc.2022.134135
Abstrakt: Analogs of pyrimidine and 1,3,4-oxadiazole are two well established class of molecules proven as potent antiviral and anticancer agents in the pharmaceutical industry. We envisioned designing new molecules where these two heterocycles were conjugated with the goal of enhancing biological activity. In this vein, we synthesized a series of novel pyrimidine-1,3,4-oxadiazole conjugated hybrid molecules as potential anticancer and antiviral agents. Herein, we present a new design for 5-fluorocytosine-1,3,4-oxadiazole hybrids ( 5a - h ) connected via a methylene bridge. An efficient synthesis of new derivatives was established, and all compounds were fully characterized by NMR and MS. Eight compounds were evaluated for their cytotoxic activity against fibrosarcoma (HT-1080), breast (MCF-7 and MDA-MB-231), lung carcinoma (A-549), and for their antiviral activity against SARS-CoV-2. Among all compounds tested, the compound 5e showed marked growth inhibition against all cell lines tested, particularly in HT-1080, with IC 50 values of 19.56 µM. Meanwhile, all tested compounds showed no anti-SARS-CoV-2 activity, with EC 50 >100 µM. The mechanism of cell death was investigated using Annexin V staining, caspase-3/7 activity, and analysis of cell cycle progression. The compound 5e induced apoptosis by the activation of caspase-3/7 and cell-cycle arrest in HT-1080 and A-549 cells at the G2M phase. The molecular docking suggested that the compound 5e activated caspase-3 via the formation of a stable complex protein-ligand.
Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(© 2022 Published by Elsevier B.V.)
Databáze: MEDLINE
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