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 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.

New 1,2,3-triazole/1,2,4-triazole hybrids linked to oxime moiety as nitric oxide donor selective COX-2, aromatase, B-RAFV600E and EGFR inhibitors celecoxib analogs: design, synthesis, anti-inflammatory/anti-proliferative activities, apoptosis and molecular modeling study.

A new series of bis-triazole 19a-l was synthesised for the purpose of being hybrid molecules with both anti-inflammatory and anti-cancer activities and assessed for cell cycle arrest, NO release. Compounds 19c, 19f, 19h, 19 l exhibited COX-2 selectivity indexes in the range of 18.48 to 49.38 compared to celecoxib S.I. = 21.10), inhibit MCF-7 with IC50 = 9-16 µM compared to tamoxifen (IC50 = 27.9 µM). and showed good inhibitory activity against HEP-3B with IC50 = 4.5-14 µM compared to sorafenib (IC50 = 3.5 µM) (HEP-3B). Moreover, derivatives 19e, 19j, 19k, 19 l inhibit HCT-116 with IC50 = 5.3-13.7 µM compared to 5-FU with IC50 = 4.8 µM (HCT-116). Compounds 19c, 19f, 19h, 19 l showed excellent inhibitory activity against A549 with IC50 = 3-4.5 µM compared to 5-FU with IC50 = 6 µM (A549). Compounds 19c, 19f, 19h, 19 l inhibit aromatase (IC50 of 22.40, 23.20, 22.70, 30.30 µM), EGFR (IC50 of 0.112, 0.205, 0.169 and 0.066 µM) and B-RAFV600E (IC50 of 0.09, 0.06, 0.07 and 0.05 µM).

Synthesis of novel halogenated triarylpyrazoles as selective COX-2 inhibitors: Anti-inflammatory activity, histopatholgical profile and in-silico studies.

A novel series of halogenated triarylpyrazoles 12a-l was designed and synthesized. All target compounds showed good in vitro COX-2 inhibitory activity (IC50 = 0.043-0.17 µM) over COX-1 (IC50 = 7.8 - 15.4 µM) relative to celecoxib (COX-1/IC50 = 9.87, COX-2/IC50 = 0.055), with acceptable selectivity index values (SI = 50.6-253.1). Also, they displayed moderate to potent in vivo anti-inflammatory activity (% edema inhibition = 16.9-87.9) comparable to celecoxib (% edema inhibition = 46.6-72.1) as standard drug. Three fluorinated pyrazoles 12a, 12g and 12j, exhibited superior anti-inflammatory activity at all time intervals (% edema inhibition = 42.1-87.9) with better gastric profile (UI = 1.25-2.5) than the traditional NSAID; indomethacin (UI = 14) and were close to the selective COX-2 inhibitor; celecoxib (UI = 1.75). In-silico docking and ADME studies of 12a, 12g and 12j supported the obtained biological data and pointed out their potential use for the development of bio-available, safe and potent anti-inflammatory drugs.

Design, synthesis of celecoxib-tolmetin drug hybrids as selective and potent COX-2 inhibitors.

Three novel series of diarylpyrazole 10b-d and triarylpyrazole derivatives 11a-d &12a-d were synthesized through Vilsmier-Haack condition. The structures of prepared compounds were determined through IR, 1H NMR, 13C NMR, Mass spectral and elemental analysis. Docking of the synthesized compounds over COX-2 active site ensure their selectivity. Moreover, the target compounds were evaluated for both in vitro and in vivo inhibitory activity. All compounds were more selective for COX-2 isozyme than COX-1 isozyme and with excellent anti-inflammatory activity. Compounds 11b, 11d and 12b showed the highest anti-inflammatory activity (67.4%, 62.7%, 61.4% respectively), lower ulcerogenic liability (UI = 2.00, 2.75, 3.25 respectively) than indomethacin (UI = 14) and comparable to celecoxib (UI = 1.75) which were confirmed from the histopatholgical study.

Synthesis and Biological Evaluation of New Diarylpyrazole and Triarylimidazoline Derivatives as Selective COX-2 Inhibitors.

New series of diarylpyrazoles 8a-f and triarylimidazoline-5-ones 11a-g were synthesized and evaluated for their in vitro cyclooxygenase-1 (COX-1) and COX-2 inhibitory activity and in vivo anti-inflammatory activity. The synthesized compounds showed good selectivity for COX-2; compounds 8a, 8d, 8f, 11a, and 11c exhibited the highest COX-2 selectivity indexes (SI = 4.77-5.43) compared to the reference drug celecoxib (SI = 7.8). All compounds showed good in vivo anti-inflammatory activity, especially compounds 8a, 8f, 11c, and 11d, which also showed some similarities to the time interval pattern of celecoxib at all different time intervals (1, 3, and 6 h).

Synthesis, cyclooxygenase inhibition, anti-inflammatory evaluation and ulcerogenic liability of novel triarylpyrazoline derivatives as selective COX-2 inhibitors.

A new series of triarylpyrazoline derivatives 8a-p containing the most important COX-2 pharmacophore (SO2CH3 or/and SO2NH2) were synthesized by reaction of propen-1-one derivatives 6a-h with different phenyl hydrazine hydrochloride derivatives 7a-b in aqueous ethanol. All prepared compounds were evaluated for their in vitro COX-1/COX-2 inhibitory activity and the in vivo anti-inflammatory activity. All compounds were more selective for COX-2 isozyme than COX-1 isozyme and showed good in vivo anti-inflammatory activity. Compounds 8g, 8j and 8o showed the highest anti-inflammatory activity and were less ulcerogenic (Ulcer Index=6.85, 7.7, 5.92, respectively) than indomethacin (Ulcer Index=12.3) and comparable to celecoxib (Ulcer Index=4.85).