Exploring COX-1 and COX-2 inhibitors disubstituted 1,2,4-oxadiazole based phenol / aniline: synthesis, X-ray structure, Hirshfeld analysis and molecular docking

Mohammad Salah Ayoup; Saied M. Soliman; David B. Cordes; Aidan P. McKay; Faisal Mohammed  Alkahtani; Yasair S.   Al-Faiyz; Elbadawy A. Kamoun; Mohamed S. Nafie

doi:10.1016/j.molstruc.2026.147144

Exploring COX-1 and COX-2 inhibitors disubstituted 1,2,4-oxadiazole based phenol / aniline: synthesis, X-ray structure, Hirshfeld analysis and molecular docking

Mohammad Salah Ayoup^*
, Saied M. Soliman^*
, David B. Cordes
, Aidan P. McKay
, Faisal Mohammed Alkahtani
, Yasair S. Al-Faiyz
, Elbadawy A. Kamoun
, Mohamed S. Nafie

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Synthesis of three derivatives as a single crystal from 3,5-diaryl-1,2,4-oxadiazole based phenol and/ or aniline 4-6 were accomplished by cyclization of the corresponding amidoxime with salicylate or anthranilate ester. The molecular and supramolecular structures of the synthesized crystals are explored based on X-ray crystallography. All three compounds showed both hydrogen bonding and aromatic π-π stacking interactions to different extents. All compounds were investigated for their in vitro ability to inhibit the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes, and their inhibitory ability was compared to that of Celecoxib. Compound 4 and 5 showed moderate inhibition activity, while the 1,2,4-oxadiazole based dianiline 6 provided remarkable inhibition activity for (COX-2) enzymes. Furthermore; Molecular docking Compound 6 exhibited a favorable binding mode within the active site of cyclooxygenase-2 (COX-2, PDB ID: 3LN1), supporting its potential as a selective COX-2 inhibitor.

Original language	English
Article number	147144
Journal	Journal of Molecular Structure
Volume	In Press
Early online date	24 Jul 2026
DOIs	https://doi.org/10.1016/j.molstruc.2026.147144
Publication status	E-pub ahead of print - 24 Jul 2026

Keywords

1,2,4-oxadiazole
COX-1/COX-2 inhibitors
X-ray structure
Hirshfeld analysis

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Copyright © 2026 the Authors. This work has been made available online in accordance with the University of St Andrews Open Access policy. This accepted manuscript is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The final published version of this work is available at https://doi.org/10.1016/j.molstruc.2026.147144
Accepted author manuscript, 2 MBLicence: CC BY

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Ayoup, M. S., Soliman, S. M., Cordes, D. B., McKay, A. P., Alkahtani, F. M., Al-Faiyz, Y. S., Kamoun, E. A., & Nafie, M. S. (2026). Exploring COX-1 and COX-2 inhibitors disubstituted 1,2,4-oxadiazole based phenol / aniline: synthesis, X-ray structure, Hirshfeld analysis and molecular docking. Journal of Molecular Structure, In Press, Article 147144. Advance online publication. https://doi.org/10.1016/j.molstruc.2026.147144

@article{77c7fc31c6c949158dde485b13bc7615,

title = "Exploring COX-1 and COX-2 inhibitors disubstituted 1,2,4-oxadiazole based phenol / aniline: synthesis, X-ray structure, Hirshfeld analysis and molecular docking",

abstract = "Synthesis of three derivatives as a single crystal from 3,5-diaryl-1,2,4-oxadiazole based phenol and/ or aniline 4-6 were accomplished by cyclization of the corresponding amidoxime with salicylate or anthranilate ester. The molecular and supramolecular structures of the synthesized crystals are explored based on X-ray crystallography. All three compounds showed both hydrogen bonding and aromatic π-π stacking interactions to different extents. All compounds were investigated for their in vitro ability to inhibit the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes, and their inhibitory ability was compared to that of Celecoxib. Compound 4 and 5 showed moderate inhibition activity, while the 1,2,4-oxadiazole based dianiline 6 provided remarkable inhibition activity for (COX-2) enzymes. Furthermore; Molecular docking Compound 6 exhibited a favorable binding mode within the active site of cyclooxygenase-2 (COX-2, PDB ID: 3LN1), supporting its potential as a selective COX-2 inhibitor.",

keywords = "1,2,4-oxadiazole, COX-1/COX-2 inhibitors, X-ray structure, Hirshfeld analysis",

author = "Ayoup, \{Mohammad Salah\} and Soliman, \{Saied M.\} and Cordes, \{David B.\} and McKay, \{Aidan P.\} and Alkahtani, \{Faisal Mohammed\} and Al-Faiyz, \{Yasair S.\} and Kamoun, \{Elbadawy A.\} and Nafie, \{Mohamed S.\}",

note = "Funding: The authors acknowledge support for the St Andrews Single-Crystal X-Ray Diffraction Service from an EPSRC Core Equipment Grant (UKRI381) and the University of St Andrews Strategic Equipment Fund. Also, the authors acknowledge the Deanship of Scientific Research, Vice Presidency for Graduate Studies and Scientific Research at King Faisal University, Saudi Arabia, for financial support under the annual funding track [KFU263715]”",

year = "2026",

month = jul,

day = "24",

doi = "10.1016/j.molstruc.2026.147144",

language = "English",

volume = "In Press",

journal = "Journal of Molecular Structure",

issn = "0022-2860",

publisher = "Elsevier",

}

Ayoup, MS, Soliman, SM, Cordes, DB, McKay, AP, Alkahtani, FM, Al-Faiyz, YS, Kamoun, EA & Nafie, MS 2026, 'Exploring COX-1 and COX-2 inhibitors disubstituted 1,2,4-oxadiazole based phenol / aniline: synthesis, X-ray structure, Hirshfeld analysis and molecular docking', Journal of Molecular Structure, vol. In Press, 147144. https://doi.org/10.1016/j.molstruc.2026.147144

TY - JOUR

T1 - Exploring COX-1 and COX-2 inhibitors disubstituted 1,2,4-oxadiazole based phenol / aniline

T2 - synthesis, X-ray structure, Hirshfeld analysis and molecular docking

AU - Ayoup, Mohammad Salah

AU - Soliman, Saied M.

AU - Cordes, David B.

AU - McKay, Aidan P.

AU - Alkahtani, Faisal Mohammed

AU - Al-Faiyz, Yasair S.

AU - Kamoun, Elbadawy A.

AU - Nafie, Mohamed S.

N1 - Funding: The authors acknowledge support for the St Andrews Single-Crystal X-Ray Diffraction Service from an EPSRC Core Equipment Grant (UKRI381) and the University of St Andrews Strategic Equipment Fund. Also, the authors acknowledge the Deanship of Scientific Research, Vice Presidency for Graduate Studies and Scientific Research at King Faisal University, Saudi Arabia, for financial support under the annual funding track [KFU263715]”

PY - 2026/7/24

Y1 - 2026/7/24

N2 - Synthesis of three derivatives as a single crystal from 3,5-diaryl-1,2,4-oxadiazole based phenol and/ or aniline 4-6 were accomplished by cyclization of the corresponding amidoxime with salicylate or anthranilate ester. The molecular and supramolecular structures of the synthesized crystals are explored based on X-ray crystallography. All three compounds showed both hydrogen bonding and aromatic π-π stacking interactions to different extents. All compounds were investigated for their in vitro ability to inhibit the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes, and their inhibitory ability was compared to that of Celecoxib. Compound 4 and 5 showed moderate inhibition activity, while the 1,2,4-oxadiazole based dianiline 6 provided remarkable inhibition activity for (COX-2) enzymes. Furthermore; Molecular docking Compound 6 exhibited a favorable binding mode within the active site of cyclooxygenase-2 (COX-2, PDB ID: 3LN1), supporting its potential as a selective COX-2 inhibitor.

AB - Synthesis of three derivatives as a single crystal from 3,5-diaryl-1,2,4-oxadiazole based phenol and/ or aniline 4-6 were accomplished by cyclization of the corresponding amidoxime with salicylate or anthranilate ester. The molecular and supramolecular structures of the synthesized crystals are explored based on X-ray crystallography. All three compounds showed both hydrogen bonding and aromatic π-π stacking interactions to different extents. All compounds were investigated for their in vitro ability to inhibit the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes, and their inhibitory ability was compared to that of Celecoxib. Compound 4 and 5 showed moderate inhibition activity, while the 1,2,4-oxadiazole based dianiline 6 provided remarkable inhibition activity for (COX-2) enzymes. Furthermore; Molecular docking Compound 6 exhibited a favorable binding mode within the active site of cyclooxygenase-2 (COX-2, PDB ID: 3LN1), supporting its potential as a selective COX-2 inhibitor.

KW - 1,2,4-oxadiazole

KW - COX-1/COX-2 inhibitors

KW - X-ray structure

KW - Hirshfeld analysis

U2 - 10.1016/j.molstruc.2026.147144

DO - 10.1016/j.molstruc.2026.147144

M3 - Article

SN - 0022-2860

VL - In Press

JO - Journal of Molecular Structure

JF - Journal of Molecular Structure

M1 - 147144

ER -

Exploring COX-1 and COX-2 inhibitors disubstituted 1,2,4-oxadiazole based phenol / aniline: synthesis, X-ray structure, Hirshfeld analysis and molecular docking

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