Synthesis, anti-inflammatory, cyclooxygenases inhibitions assays and histopathological study of poly-substituted 1,3,5-triazines: Confirmation of regiospecific pyrazole cyclization by HMBC

Heba A H Elshemy; Eman K A Abdelall; Amany A Azouz; Abeer Moawad; Waleed A M Ali; Nesreen M Safwat

doi:10.1016/j.ejmech.2016.12.030

Synthesis, anti-inflammatory, cyclooxygenases inhibitions assays and histopathological study of poly-substituted 1,3,5-triazines: Confirmation of regiospecific pyrazole cyclization by HMBC

Eur J Med Chem. 2017 Feb 15:127:10-21. doi: 10.1016/j.ejmech.2016.12.030. Epub 2016 Dec 23.

Authors

Heba A H Elshemy¹, Eman K A Abdelall², Amany A Azouz³, Abeer Moawad⁴, Waleed A M Ali⁵, Nesreen M Safwat⁶

Affiliations

¹ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt.
² Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt. Electronic address: eman.ahmed@pharm.bsu.edu.eg.
³ Department of Pharmacology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt.
⁴ Department of Pharmacognosy, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt.
⁵ Biochemistry Lab, Cairo General Hospital, Cairo, Egypt.
⁶ Department of Pathology, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef, 62514, Egypt.

PMID: 28038322
DOI: 10.1016/j.ejmech.2016.12.030

Abstract

Three novel triazines series were prepared. These series are pyrazolines (4a and 4b), pyrazoles (6a, 6b and 8a-d) and isoxazoles (7a and 7b). Such series were designed as COX-2 inhibitors. All compounds were characterized by using spectroscopic methods and elemental analysis. Regarding COX-2, compounds 5b, 4a and 3b were the most active with IC₅₀ in the range of 0.55-0.87 μM. Most of synthesized compounds were relatively more potent to celecoxib (0.78 μM), diclofenac (2.94 μM) and indomethacin (7.24 μM). A molecular modeling study was performed for the most active compounds. Histopathological evaluation also was done to estimate the safety of compounds. Finally, structure elucidation of pyrazole 8 was studied by 2D NMR.

Keywords: Anti-inflammatory activity; COX-2 inhibitors; Enaminone; HMBC; Histopathology; S-Triazines.

MeSH terms

Animals
Anti-Inflammatory Agents, Non-Steroidal / adverse effects
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
Anti-Inflammatory Agents, Non-Steroidal / metabolism
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Chemistry Techniques, Synthetic
Cyclization
Cyclooxygenase 2 / chemistry
Cyclooxygenase 2 / metabolism
Cyclooxygenase 2 Inhibitors / adverse effects
Cyclooxygenase 2 Inhibitors / chemical synthesis*
Cyclooxygenase 2 Inhibitors / metabolism
Cyclooxygenase 2 Inhibitors / pharmacology*
Drug Design
Male
Molecular Docking Simulation
Protein Conformation
Pyrazoles / chemistry*
Rats
Stereoisomerism
Structure-Activity Relationship
Triazines / adverse effects
Triazines / chemical synthesis*
Triazines / metabolism
Triazines / pharmacology*
Ulcer / chemically induced

Substances

Anti-Inflammatory Agents, Non-Steroidal
Cyclooxygenase 2 Inhibitors
Pyrazoles
Triazines
Cyclooxygenase 2