New pyrazolyl-thiazolidinone/thiazole derivatives as celecoxib/dasatinib analogues with selective COX-2, HER-2 and EGFR inhibitory effects: design, synthesis, anti-inflammatory/anti-proliferative activities, apoptosis, molecular modelling and ADME studies

Wael A A Fadaly; Taha H Zidan; Nesma M Kahk; Fatma E A Mohamed; Marwa M Abdelhakeem; Rehab G Khalil; Mohamed T M Nemr

doi:10.1080/14756366.2023.2281262

New pyrazolyl-thiazolidinone/thiazole derivatives as celecoxib/dasatinib analogues with selective COX-2, HER-2 and EGFR inhibitory effects: design, synthesis, anti-inflammatory/anti-proliferative activities, apoptosis, molecular modelling and ADME studies

J Enzyme Inhib Med Chem. 2023 Dec;38(1):2281262. doi: 10.1080/14756366.2023.2281262. Epub 2023 Nov 27.

Authors

Wael A A Fadaly¹, Taha H Zidan¹, Nesma M Kahk¹, Fatma E A Mohamed¹, Marwa M Abdelhakeem¹, Rehab G Khalil², Mohamed T M Nemr³

Affiliations

¹ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt.
² Immunology Division, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt.
³ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.

Abstract

Two new series of pyrazolyl-thiazolidinone/thiazole derivatives 16a-b and 18a-j were synthesised, merging the scaffolds of celecoxib and dasatinib. Compounds 16a, 16b and 18f inhibit COX-2 with S.I. 134.6, 26.08 and 42.13 respectively (celecoxib S.I. = 24.09). Compounds 16a, 16b, 18c, 18d and 18f inhibit MCF-7 with IC₅₀ = 0.73-6.25 μM (dasatinib IC₅₀ = 7.99 μM) and (doxorubicin IC50 = 3.1 μM) and inhibit A549 with IC50 = 1.64-14.3 μM (dasatinib IC₅₀ = 11.8 μM and doxorubicin IC₅₀ = 2.42 μM) with S.I. (F180/MCF7) of 33.15, 7.13, 18.72, 13.25 and 8.28 respectively higher than dasatinib (4.03) and doxorubicin (3.02) and S.I. (F180/A549) of 14.75, 12.96, 4.16, 7.07 and 18.88 respectively higher than that of dasatinib (S.I. = 2.72) and doxorubicin (S.I = 3.88). Derivatives 16a, 18c, 18d, 18f inhibit EGFR and HER-2 IC50 for EGFR of 0.043, 0.226, 0.388, 0.19 μM respectively and for HER-2 of 0.032, 0.144, 0.195, 0.201 μM respectively.

Keywords: COX-2 inhibition; EGFR inhibition; HER-2 inhibition; Pyrazole; Thiazole.

MeSH terms

Anti-Inflammatory Agents / pharmacology
Antineoplastic Agents* / pharmacology
Apoptosis
Celecoxib / pharmacology
Cyclooxygenase 2 / metabolism
Dasatinib / pharmacology
Doxorubicin
Drug Screening Assays, Antitumor
Molecular Docking Simulation
Molecular Structure
Structure-Activity Relationship
Thiazoles* / pharmacology

Substances

Celecoxib
Cyclooxygenase 2
Dasatinib
Thiazoles
Anti-Inflammatory Agents
Doxorubicin
Antineoplastic Agents

Grants and funding

The author(s) reported there is no funding associated with the work featured in this article.