Novel benzenesulfonamide derivatives as potential selective carbonic anhydrase IX, XII inhibitors with anti-proliferative activity: Design, synthesis and in silico studies.

As inhibitors of carbonic anhydrases (CAs) IX and XII, a novel series of 1,2,3-triazole benzenesulfonamide derivatives 17a-l containing pyrazolyl-thiazole moiety was designed, synthesized, and tested for anti-proliferative activity. Compounds 17e-h demonstrated more effective inhibitory activity than acetazolamide (IC50 63 nM CA IX and IC50 92 nM CA XII), with IC50 range of 25-52 nM against CA IX and IC50 range of 31-80 nM against CA XII. To verify selectivity against CA IX and CA XII, carbonic anhydrase inhibitory activity of compounds 17e-h against the physiological CA I and CA II isoforms was carried out. The results showed that compounds 17e-h induced lower inhibitory activity against CA I and CA II with IC50 range of 0.428-0.638 µM (CA I) and 0.095-0.164 µM (CA II), in addition to higher selectivity indices (CA I/CA IX S.I. 8.9-19.92, CA I/CA XII S.I. 5.78-16.06) and (CA II/CA IX S.I. 2.83-4.35, CA II/CA XII S.I. 2.05-3.15) when compared to that of acetazolamide, IC50 of 0.199 µM (CA I), 0.133 µM (CA II) (CA I/CA IX S.I. 3.15, CA I/CA XII S.I. 2.16) and (CA II/CA IX S.I. 2.11, CA II/CA XII S.I. 1.44). Concerning anti-proliferative activity of compounds 17e-h, investigations were done on HEPG-2 cell line with IC50 ranges of 3.44-15.03 µM in comparison, 5-FU and doxorubicin showed IC50 values of 11.80 and 9.53 µM, respectively. Furthermore IC50 of MCF-7 and MDA-MB-231 were determined under both normoxic and hypoxic conditions with IC50 values ranging from 3.18-8.26 µM MCF-7 (normoxic), 1.39-6.05 µM MCF-7 (hypoxic), 7.13-26.3 µM MDA-MB-231 (normoxic), 0.76-16.3 µM MDA-MB-231 (hypoxic) using acetazolamide and SLC-0111 as selective CA inhibition references. Moreover, compounds 17e-h demonstrated greater safety against the normal cell line, MCF-10A, with IC50 of 23.06-99.50 µM in comparison to 5-FU and doxorubicin IC50 of 59.8 and 71.8 µM respectively. They also demonstrated (MCF-7 S.I. range of 3.77-31.28) in contrast to doxorubicin (S.I. 13.72) and (HepG-2 S.I. range of 3.60-6.95) in comparison to doxorubicin (S.I. 7.53). In relation to CA IX, XII inhibition, molecular docking of and ADME studies of sulfonamide derivatives 17a-l with CA IX (PDB: 5FL6) and CA XII (PDB: 1JD0) was carried out. Additionally, molecular dynamic simulation was carried out for compounds 17e and 17g which maintained good stability inside the active sites of both enzymes, with average RMSDs of 2.3 Å and 2.1 Å, respectively.

Discovery of novel pyrazole based Urea/Thiourea derivatives as multiple targeting VEGFR-2, EGFRWT, EGFRT790M tyrosine kinases and COX-2 Inhibitors, with anti-cancer and anti-inflammatory activities.

A novel series of pyrazole derivatives with urea/thiourea scaffolds 16a-l as hybrid sorafenib/erlotinib/celecoxib analogs was designed, synthesized and tested for its VEGFR-2, EGFRWT, EGFRT790M tyrosine kinases and COX-2, pro-inflammatory cytokines TNF-α and IL-6 inhibitory activities. All the tested compounds showed excellent COX-2 selectivity index in range of 18.04-47.87 compared to celecoxib (S.I. = 26.17) and TNF-α and IL-6 inhibitory activities (IC50 = 5.0-7.50, 6.23-8.93 respectively, compared to celecoxib IC50 = 8.40 and 8.50, respectively). Screening was carried out against 60 human cancer cell lines by National Cancer Institute (NCI), compounds 16a, 16c, 16d and 16 g were the most potent inhibitors with GI% ranges of 100 %, 99.63-87.02 %, 98.98-43.10 % and 98.68-23.62 % respectively, and with GI50 values of 1.76-15.50 µM, 1.60-5.38 µM, 1.68-7.39 µM and 1.81-11.0 µM respectively, in addition, of showing good safety profile against normal cell line (F180). Moreover, compounds 16a, 16c, 16d and 16 g had cell cycle arrest at G2/M phase with induced necrotic percentage compared to sorafenib of 2.06 %, 2.47 %, 1.57 %, 0.88 % and 1.83 % respectively. Amusingly, compounds 16a, 16c, 16d and 16 g inhibited VEGFR-2 with IC50 of 25 nM, 52 nM, 324 nM and 110 nM respectively, compared to sorafenib (IC50 = 85 nM), and had excellent EGFRWT and EGFRT790M kinase inhibitory activities (IC50 = 94 nM, 128 nM, 160 nM, 297 nM), (10 nM, 25 nM, 36 nM and 48 nM) respectively, compared to both erlotinib and osimertinib (IC50 = 114 nM, 56 nM) and (70 nM, 37 nM) respectively and showed (EGFRwt/EGFRT790M S.I.) of (range: 4.44-9.40) compared to erlotinib (2.03) and osmertinib (1.89).

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).

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 1,2,4-triazole/pyrazole hybrids linked to oxime moiety as nitric oxide donor celecoxib analogs: Synthesis, cyclooxygenase inhibition anti-inflammatory, ulcerogenicity, anti-proliferative activities, apoptosis, molecular modeling and nitric oxide release studies.

Two new series of hybrid structures 16a-f and 19a-f containing 1,2,4-triazole moiety, pyrazole core with COX-2 pharmacophore and oxime as NO donor moiety were designed, synthesized and evaluated for anti-inflammatory, cytotoxic activities and NO release. All compounds were more selective for COX-2 isozyme especially the sulphamoyl derivatives (16b, 16e, 19b and 19e) had COX-2 selectivity indexes (S.I. = 9.78, 8.57, 10.78 and 10.47 respectively) in comparison to celecoxib (S.I. = 8.68). Similarly, 16b, 16e, 19b and 19e were the most potent anti-inflammatory derivatives with ED50 = 46.98-54.45 µmol/kg better than celecoxib (ED50 = 76.09 µmol/kg). Also, 16b, 16e, 19b and 19e were significantly less ulcerogenic (ulcer indexes = 2.79-3.95) upon comparison with ibuprofen (ulcer index = 20.25) and comparable with celecoxib (ulcer index = 2.93). Regarding anti-cancer activity, most of the target derivatives 16a-f and 19a-f showed good activities against A-549, MCF-7, HCT-116 and PC-3 cancer cell lines. Additionally, these derivatives examined against F180 fibroblasts to investigate their selectivity indexes. The sulphamoyl derivatives with internal oxime 19b and 19e were the most potent derivatives against all used cell lines especially PC-3 (IC50 = 1.48 and 0.33 µM respectively) with 11.75 and 39.4-fold respectively selectivity towards PC-3 than F180 fibroblasts. The mechanistic investigation of 19b and 19e revealed that both compounds arrested cell cycle at G2/M phase by 32.16 and 39.95 folds, up-regulated Bax expression by 6.83 and 14.52 folds and down-regulated the expression of the gene Bcl-2 by 0.57 and 0.36fold respectively. Also, 19b and 19e were good inhibitor for p38MAPK (0.65 for 19b and 0.58 for 19e) and VEGFR-2 (0.39 for 19b and 0.54 for 19e) in comparison with PC-3 control cell. All compounds 16a-f and 19a-f released NO in a slow rate (0.15-3.17%) and the four sulphamoyl derivatives 16b, 16e, 19b and 19e were the most NO releasers (3.06, 2.15, 3.17 and 2.54% respectively). Docking studies were carried out to explain the interaction of 16a-f and 19a-f with the target enzymes. Docking mode of final designed compounds with celecoxib (ID: 3LN1) represented that their triazole ring adopted as the core aryl in Y shaped structure. Regarding EGFR inhibition, docking was carried out with ID: 1M17. The internal oxime serious was more active as anticancer because of their ability to form extra HBs with receptor cleft.

Thiohydantoin derivatives incorporating a pyrazole core: Design, synthesis and biological evaluation as dual inhibitors of topoisomerase-I and cycloxygenase-2 with anti-cancer and anti-inflammatory activities.

A new series of hybrid structures 14a-l containing thiohydantoin as anti-cancer moiety and pyrazole core possessing SO2Me pharmacophore as selective COX-2 moiety was designed and synthesized to be evaluated for both anti-inflammatory and anti-cancer activities. The synthesized compounds were evaluated for their COX inhibition, in vivo anti-inflammatory activity, ulcerogenic liability, in vitro cytotoxic activity and human topoisomerase-1 inhibition. All compounds were more selective for COX-2 isozyme and showed good in vivo anti-inflammatory activity. Also, all derivatives were significantly less ulcerogenic (ulcer indexes = 2.64-3.87) than ibuprofen (ulcer index = 20.25) and were of acceptable ulcerogenicity when compared with the non-ulcerogenic reference drug celecoxib (ulcer index = 2.99). Regarding anti-cancer activity, most of the target derivatives showed activities against A-549, MCF-7 and HCT-116 cell lines (IC50 = 5.32-17.90, 3.67-19.04 and 3.19-14.87 µM respectively) in comparison with doxorubicin (IC50 = 0.20, 0.50 and 2.44 µM respectively). Compound 14a inhibited the human topoisomerase-1 with IC50 = 29.7 µg/ml while 14b and 14c showed more potent inhibitory activity with IC50 = 26.5 and 23.3 µg/ml. respectively in comparison with camptothecin (IC50 = 20.2 µg/ml). Additionally, COX-2 and human topoisomerase-1 docking studies were carried out to explain the interaction of the synthesized hybrid structures 14a-l with the target enzymes.