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

Fiche publication

Date publication

septembre 2022

Journal

Journal of molecular structure

Auteurs

Membres identifiés du Cancéropôle Est :
Pr MORJANI Hamid

Tous les auteurs :
El Mansouri AE, Lachhab S, Oubella A, Ahmad M, Neyts J, Jochmans D, Chiu W, Vangeel L, De Jonghe S, Morjani H, Ali MA, Zahouily M, Sanghvi YS, Lazrek HB

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/36101881

Résumé

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 (-) 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 showed marked growth inhibition against all cell lines tested, particularly in HT-1080, with IC values of 19.56 µM. Meanwhile, all tested compounds showed no anti-SARS-CoV-2 activity, with EC >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 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 activated caspase-3 via the formation of a stable complex protein-ligand.