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

Two new series of pyrazolyl-thiazolidinone/thiazole derivatives <b>16a–b</b> and <b>18a–j</b> were synthesised, merging the scaffolds of celecoxib and dasatinib. Compounds <b>16a</b>, <b>16b</b> and <b>18f</b> inhibit <b>COX-2</b> with S.I. 134.6, 26.08 and 42.13 respectively (celecoxib S.I. = 24.09). Compounds <b>16a,</b> <b>16b,</b> <b>18c,</b> <b>18d</b> and <b>18f</b> inhibit <b>MCF-7</b> with IC₅₀ = 0.73–6.25 μM (dasatinib IC₅₀ = 7.99 μM) and (doxorubicin IC50 = 3.1 μM) and inhibit <b>A549</b> with IC50 = 1.64–14.3 μM (dasatinib IC₅₀ = 11.8 μM and doxorubicin IC₅₀ = 2.42 μM) with S.I. <b>(F180/MCF7)</b> 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. <b>(F180/A549)</b> 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 <b>16a, 18c, 18d, 18f</b> 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.