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

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.

GRAPHICAL ABSTRACT

Keywords:

• Pyrazole
• Thiazole
• COX-2 inhibition
• HER-2 inhibition
• EGFR inhibition

Acknowledgements

Prof. Dr. Wael A. A. Fadaly, Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Beni-Suef University would like to thank Dr. Ahmed Sami, Faculty of Graduate Studies for Advanced Sciences, Beni-Suef University for providing HPLC analysis for all final compounds 16a,b &18a–j.

Disclosure statement

The authors report no conflicts of interest.

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Funding

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