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Showing content from https://pubmed.ncbi.nlm.nih.gov/36101881/ below:

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

doi: 10.1016/j.molstruc.2022.134135. Online ahead of print. Synthesis, characterization, molecular docking, and anticancer activities of new 1,3,4-oxadiazole-5-fluorocytosine hybrid derivatives Saida Lachhab¹, Ali Oubella³, Mehdi Ahmad⁴, Johan Neyts⁵, Dirk Jochmans⁵, Winston Chiu⁵, Laura Vangeel⁵, Steven De Jonghe⁵, Hamid Morjani⁶, Mustapha Ait Ali¹, Mohamed Zahouily², Yogesh S Sanghvi⁷, Hassan B Lazrek¹

Affiliations

¹ Laboratory of Biomolecular and Medicinal chemistry, Faculty of Science Semlalia, University Cadi Ayyad, Marrakesh, Morocco.
² Laboratoire de Matériaux, Catalyse & Valorisation des Ressources Naturelles, URAC 24, Faculté des Sciences et Techniques, Université Hassan II, Casablanca B.P. 146, 20650, Morocco.
³ Laboratoire de Synthese Organique et de Physico-Chimie Moleculaire, Departement de Chimie, Faculte´ des Sciences, Semlalia BP 2390, Marrakech 40001, Morocco.
⁴ ICGM, Univ. Montpellier, CNRS, ENSCM, Montpellier, France.
⁵ Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
⁶ BioSpecT - EA7506 UFR de Pharmacie, Univ-Reims 51, rue Cognacq Jay 51096 Reims cedex, France.
⁷ Rasayan Inc. 2802 Crystal Ridge Road, Encinitas, CA 92024-6615, U.S.A.

PMID: 36101881
PMCID: PMC9459830
DOI: 10.1016/j.molstruc.2022.134135

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

Az-Eddine El Mansouri et al. J Mol Struct. 2022.

doi: 10.1016/j.molstruc.2022.134135. Online ahead of print. Authors Az-Eddine El Mansouri^{1 2}, Saida Lachhab¹, Ali Oubella³, Mehdi Ahmad⁴, Johan Neyts⁵, Dirk Jochmans⁵, Winston Chiu⁵, Laura Vangeel⁵, Steven De Jonghe⁵, Hamid Morjani⁶, Mustapha Ait Ali¹, Mohamed Zahouily², Yogesh S Sanghvi⁷, Hassan B Lazrek¹ Affiliations

¹ Laboratory of Biomolecular and Medicinal chemistry, Faculty of Science Semlalia, University Cadi Ayyad, Marrakesh, Morocco.
² Laboratoire de Matériaux, Catalyse & Valorisation des Ressources Naturelles, URAC 24, Faculté des Sciences et Techniques, Université Hassan II, Casablanca B.P. 146, 20650, Morocco.
³ Laboratoire de Synthese Organique et de Physico-Chimie Moleculaire, Departement de Chimie, Faculte´ des Sciences, Semlalia BP 2390, Marrakech 40001, Morocco.
⁴ ICGM, Univ. Montpellier, CNRS, ENSCM, Montpellier, France.
⁵ Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
⁶ BioSpecT - EA7506 UFR de Pharmacie, Univ-Reims 51, rue Cognacq Jay 51096 Reims cedex, France.
⁷ Rasayan Inc. 2802 Crystal Ridge Road, Encinitas, CA 92024-6615, U.S.A.

PMID: 36101881
PMCID: PMC9459830
DOI: 10.1016/j.molstruc.2022.134135

Item in Clipboard

Abstract

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 IC₅₀ values of 19.56 µM. Meanwhile, all tested compounds showed no anti-SARS-CoV-2 activity, with EC₅₀ >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.

Keywords: 1,3,4-oxadiazole hybrid; 5-fluorocytosine; anti- SARS-CoV-2; apoptosis induction; cytotoxic activity; molecular docking.

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Conflict of interest statement

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.

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Graphical abstract

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Graphical abstract
Scheme 1

Synthesis of alkylating agents 4a-g

Scheme 1

Synthesis of alkylating agents 4a-g

Scheme 1

Synthesis of alkylating agents 4a-g

Scheme 2

Synthesis of alkylating agents 4h

Scheme 2

Synthesis of alkylating agents 4h

Scheme 2

Synthesis of alkylating agents 4h

Scheme 3

Synthesis of 1,3,4-oxadiazole hybrids 5a-h

Scheme 3

Synthesis of 1,3,4-oxadiazole hybrids 5a-h

Scheme 3

Synthesis of 1,3,4-oxadiazole hybrids 5a-h

Figure 1

Design of the new 1,3,4-oxadiazole-5-fluorocytosine…

Figure 1

Design of the new 1,3,4-oxadiazole-5-fluorocytosine hybrid derivatives

Figure 1

Design of the new 1,3,4-oxadiazole-5-fluorocytosine hybrid derivatives

Figure 2

Annexin V-FITC/7-AAD double staining for…

Figure 2

Annexin V-FITC/7-AAD double staining for detection of apoptosis in HT-1080 and A549 cells…

Figure 2

Annexin V-FITC/7-AAD double staining for detection of apoptosis in HT-1080 and A549 cells after treatment with 20 µM of compound 5e as well as control (DMSO) for 24 hours. Compound 5e induces apoptosis.

Figure 3

Induction of caspase-3/7 activity in…

Figure 3

Induction of caspase-3/7 activity in response to compound 5e. HT-1080 and A-549 Cells…

Figure 3

Induction of caspase-3/7 activity in response to compound 5e. HT-1080 and A-549 Cells were treated with 20 µM of desired compound as well as DMSO (control) for 24 hours.

Figure 4

Flow cytometry analysis of cell…

Figure 4

Flow cytometry analysis of cell cycle phase distribution in HT-1080 and A-549 cell…

Figure 4

Flow cytometry analysis of cell cycle phase distribution in HT-1080 and A-549 cell lines after treatment of 20 µM of compound 5e in comparison with control for 24 hours.

Figure 5

The position of ligand 5e…

Figure 5

The position of ligand 5e in the hydrophobic cavity of caspase-3

Figure 5

The position of ligand 5e in the hydrophobic cavity of caspase-3

Figure 6

3D and 2D interactions of…

Figure 6

3D and 2D interactions of compound 5e with the amino acid residues of…

Figure 6

3D and 2D interactions of compound 5e with the amino acid residues of caspase-3

Figure 7

2D interactions of compounds 5g…

Figure 7

2D interactions of compounds 5g and 5h with the amino acid residues of…

Figure 7

2D interactions of compounds 5g and 5h with the amino acid residues of caspase-3

Figure 8

2D interactions of DOX with…

Figure 8

2D interactions of DOX with the amino acid residues of caspase-3

Figure 8

2D interactions of DOX with the amino acid residues of caspase-3