2. Academic Validation
  3. Design, synthesis, biological evaluation and molecular docking of new uracil analogs-1,2,4-oxadiazole hybrids as potential anticancer agents

Design, synthesis, biological evaluation and molecular docking of new uracil analogs-1,2,4-oxadiazole hybrids as potential anticancer agents

  • Bioorg Med Chem Lett. 2020 Oct 1;30(19):127438. doi: 10.1016/j.bmcl.2020.127438.
Az-Eddine El Mansouri 1,  Ali Oubella 2,  Mohamed Maatallah 3,  Moulay Youssef AitItto 3,  Mohamed Zahouily 4,  Hamid Morjani 5,  Hassan B Lazrek 6
Affiliations

Affiliations

  • 1 Laboratoire de Materiaux, Catalyse & Valorisation des Ressources Naturelles, URAC 24, Faculte des Sciences et Techniques, Universite Hassan II, Casablanca, Morocco; Laboratory of Biomolecular and Medicinal Chemistry, Department of Chemistry, Faculty of Science Semlalia, BP 2390, Marrakech 40001, Morocco. Electronic address: az-eddine.elmansouri@edu.uca.ac.ma.
  • 2 Laboratoire de Synthese Organique et de Physico-Chimie Moleculaire, Departement de Chimie, Faculté des Sciences, Semlalia BP 2390, Marrakech 40001, Morocco.
  • 3 Laboratoire de Chimie théorique, Faculty of Science Semlalia, BP 2390, Marrakech 40001, Morocco.
  • 4 Laboratoire de Materiaux, Catalyse & Valorisation des Ressources Naturelles, URAC 24, Faculte des Sciences et Techniques, Universite Hassan II, Casablanca, Morocco; Moroccan Foundation for Advanced Science, Innovation and Research (MAScIR), VARENA Center, Rue Mohamed El Jazouli, Madinat Al Irfane, 10100 Rabat, Morocco. Electronic address: mzahouily@gmail.com.
  • 5 BioSpecT - EA7506 UFR de Pharmacie, Univ-Reims 51, rue Cognacq Jay, 51096 Reims cedex, France. Electronic address: hamid.morjani@univ-reims.fr.
  • 6 Laboratory of Biomolecular and Medicinal Chemistry, Department of Chemistry, Faculty of Science Semlalia, BP 2390, Marrakech 40001, Morocco. Electronic address: hblazrek50@gmail.com.
PMID: 32736079 DOI: 10.1016/j.bmcl.2020.127438
Abstract

A new series of uracil analogues-1,2,4-oxadiazole hybrid derivatives were synthesized by a new, simple, and efficient method using for the first time HAP-SO3H as an heterogenous acid catalyst for the condensation and cyclization between amidoxime and aldehyde. The new derivatives were characterized by HRMS, FT-IR, 1H NMR, and 13C NMR spectroscopy techniques. The synthesized 1,2,4-oxadiazole hybrids were evaluated for their cytotoxic activity in five human Cancer cell lines: melanoma (A-375), fibrosarcoma (HT-1080), breast (MCF-7 and MDA-MB-231), and lung carcinoma (A-549). Data showed that compounds 22 and 23 were potent cytotoxic agents against HT-1080 and MFC-7 cells with IC50 inferior to 1 µM. The possible mechanism of Apoptosis induction by the derivatives was investigated using Annexin V staining, Caspase-3/7 activity, mitochondrial membrane potential measurement, and analysis cell cycle progression. The compound 22 induced Apoptosis through Caspase-3/7 activation and S-phase arrest in HT-1080 and A549 cells. The molecular docking showed that compound 22 activated the Caspase-3 by forming a stable protein-ligand complex.

Keywords

1,2,4-Oxadiazole; Anticancer activity; Apoptosis; Heterogeneous catalyst; Hybrid molecules; Molecular docking; Uracil analogues.

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