Design, synthesis, chemical characterization, biological evaluation, and docking study of new 1,3,4-oxadiazole homonucleoside analogs

• Published in: Nucleosides, nucleotides & nucleic acids Vol. 39; no. 8; pp. 1088 - 1107
• Main Authors: El Mansouri, Az-Eddine, Maatallah, Mohamed, Ait Benhassou, Hassan, Moumen, Abdeladim, Mehdi, Ahmad, Snoeck, Robert, Andrei, Graciela, Zahouily, Mohamed, Lazrek, Hassan B.
• Format: Journal Article
• Language: English
• Published: PHILADELPHIA Taylor & Francis 02.08.2020; Taylor & Francis Ltd
• Subjects: 1,3,4-Oxadiazole; Acyclovir; anticancer activity; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; antiviral activity; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Binding sites; Biochemistry & Molecular Biology; Cell Line, Tumor; Cell Proliferation - drug effects; Chemical Sciences; Cytotoxicity; Drug Design; Drug Screening Assays, Antitumor; Epidermal growth factor receptors; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - metabolism; ErbB-2 protein; Herpesvirus 3, Human - drug effects; HL-60 Cells; homonucleosides; Humans; Life Sciences & Biomedicine; Material chemistry; MCF-7 Cells; Microbial Sensitivity Tests; molecular docking; Molecular Docking Simulation; Molecular Structure; NMR; Nuclear magnetic resonance; Nucleosides - chemical synthesis; Nucleosides - chemistry; Nucleosides - pharmacology; Oxadiazoles - chemical synthesis; Oxadiazoles - chemistry; Oxadiazoles - pharmacology; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Receptor, ErbB-2 - antagonists & inhibitors; Receptor, ErbB-2 - metabolism; Science & Technology; Sulfur; Tumor cell lines; Varicella; THIOGLYCOSIDES; EGFR/HER2; antiviral activity; EGFR; 4-Oxadiazole; KINASE DOMAIN; BREAST-CANCER; 1; NUCLEOSIDE; 3; molecular docking; INHIBITION; THERAPY; homonucleosides; RESISTANCE; anticancer activity; DERIVATIVES; 1,3,4-Oxadiazole
• ISSN: 1525-7770; 1532-2335
• DOI: 10.1080/15257770.2020.1761982

Herein, we report the synthetic strategies and characterization of some novel 1,3,4-oxadiazole homonucleoside analogs that are relevant to potential antitumor and cytotoxic activities. The structure of all compounds is confirmed using various spectroscopic methods such as 1 H-NMR, 13 C-NMR, HRMS, and FTIR. These compounds were evaluated against three human cancer cell lines (MCF-7, SKBR3, and HL60 Cell Line). Preliminary investigations showed that the cytotoxic activity was markedly dependent on the nucleobase. Introduction of 5-Iodouracil 4g and theobromine 6b proved to be extremely beneficial even they were more potent than the reference drug (DOX). Also, the synthesized compounds were tested for their antiviral activities against the human varicella-zoster virus (VZV). The product 4h was (6-azauracil derivative) more potent to the reference (acyclovir) against the deficient TK − VZV strain by about 2-fold. Finally, molecular docking suggested that the anticancer activities of compounds 6b and 4g mediated by inhibiting dual proteins EGFR/HER2 with low micromolar inhibition constant Ki range. The 1,3,4-oxadiazole homonucleosides showed a strong affinity to binding sites of target proteins by forming H-bond, carbon-hydrogen bond, Pi-anion, Pi-sulfur, Pi-sigma, alkyl, and Pi-alkyl interactions.