Vicinal diaryl pyrazole with tetrazole/urea scaffolds as selective angiotensin converting enzyme-1/cyclooxygenase-2 inhibitors: Design, synthesis, anti-hypertensive, anti-fibrotic, and anti-inflammatory.

As a hybrid weapon, two novel series of pyrazoles, 16a-f and 17a-f, targeting both COX-2 and ACE-1-N-domain, were created and their anti-inflammatory, anti-hypertensive, and anti-fibrotic properties were evaluated. In vitro, 17b and 17f showed COX-2 selectivity (SI = 534.22 and 491.90, respectively) compared to celecoxib (SI = 326.66) and NF-κB (IC50 1.87 and 2.03 µM, respectively). 17b (IC50 0.078 µM) and 17 f (IC50 0.094 µM) inhibited ACE-1 comparable to perindopril (PER) (IC50 0.048 µM). In vivo, 17b decreased systolic blood pressure by 18.6%, 17b and 17f increased serum NO levels by 345.8%, and 183.2%, respectively, increased eNOS expression by 0.97 and 0.52 folds, respectively and reduced NF-κB-p65 and P38-MAPK expression by -0.62, -0.22, -0.53, and -0.24 folds, respectively compared to  l-NAME (-0.34, -0.45 folds decline in NF-κB-p65 and P38-MAPK, respectively). 17b reduced ANG-II expression which significantly reversed the cardiac histological changes induced by L-NAME.

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).

Design, synthesis, and pharmacological evaluation of novel and selective COX-2 inhibitors based on celecoxib scaffold supported with in vivo anti-inflammatory activity, ulcerogenic liability, ADME profiling and docking study.

Four new series of 1,2,4 triazole derivatives 4a,b 5a-d, 6a-f, and 7a,b possessing methylsulphonylphenyl moiety as COX-2 pharmacophore were designed and synthesized. The target compounds were prepared and evaluated in-vitro against COX-1 and COX-2 enzymes. Compounds 4a, 5b, 6a, and 7a showed the highest selectivity towards the COX-2 enzyme (S.I. = 8.64-14.58) in comparison to celecoxib (S.I. = . 6.44). Interestingly, compounds 4a, 6a, and 7a showed good anti-inflammatory activity with edema inhibition (54.17, 53.03, and 50.29 %, in order) relative to the reference drug celecoxib (49.60%) after 3 h. Additionally, these potent derivatives 4a, 5b, 6a and 7a were significantly less ulcerogenic (U.I. = 2.27-2.97) than both reference drugs celecoxib (U.I. = 2.99) and indomethacin (U.I. = 20.25). Besides, a histopathological study of the stomach was also included. Moreover, docking simulation for the most selective compounds 4a, 5b, 6a, and 7a inside COX-2 active site was performed to explain their binding mode. Finally, an ADME study was applied and proved the promising activity of the new compounds as a new oral anti-inflammatory agent. In conclusion, the above findings reveal that newly developed compounds 4a, 6a, and 7a represent a potential selective COX-2 NSAID candidate with minimum gastrointestinal risks.

Optimization of pyrazole-based compounds with 1,2,4-triazole-3-thiol moiety as selective COX-2 inhibitors cardioprotective drug candidates: Design, synthesis, cyclooxygenase inhibition, anti-inflammatory, ulcerogenicity, cardiovascular evaluation, and molecular modeling studies.

The cardiovascular side effects associated with COX-2 selective drugs were the worst for coxibs leading to their withdrawal from the market a few years after their discovery. Therefore, the design of new series of pyrazole (4a,b 5a,b, 7a,b, 9a,b, 10a-h, and 11a-f) substituted with a triazole moiety as selective COX-2 inhibitors with cardioprotective effect was aimed in this paper. The target compounds were prepared and evaluated in-vitro against COX-1 and COX-2 enzymes. Compound 5-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-4H-1,2,4-triazole-3-thiol (7a) showed the highest selectivity towards COX-2 enzyme (S.I. = 27.56) and was the most active anti-inflammatory agent. Interestingly, its cardiovascular profile showed the cardiac biomarkers (ALP, AST, CK-MB, and LDH), as well as inflammatory cytokines named (TNF-α and IL-6) nearly similar to the control. Besides, a histopathological study of the heart muscle and the stomach was also included. The results confirmed that compound 7a has a more favorable cardio profile than celecoxib. Moreover, docking simulation for the most selective compounds 4b, 7a, 10e, 11c, and 11e inside COX-2 active site was performed to explain their binding mode. Finally, an ADME study was applied and proved the promising activity of the new compounds as a new oral anti-inflammatory agent. In conclusion, the newly developed compound 7a represents a potential selective COX-2 NSAID candidate with minimum cardiovascular risks.

Design, synthesis, biological assessment and in silico ADME prediction of new 2-(4-(methylsulfonyl) phenyl) benzimidazoles as selective cyclooxygenase-2 inhibitors.

A novel series of benzimidazole derivatives wherein 4-(methylsulfonyl) phenyl pharmacophore attached via its C-2 position was designed and synthesized. These compounds were evaluated in vitro as cyclooxygenase-1(COX-1)/cyclooxygenese-2(COX-2) inhibitors. Furthermore, the synthesized compounds were also in vivo evaluated for their anti-inflammatory activity and ulcerogenic liability. Examination of histopathological lesions was also performed to evaluate the cariogenic effect of most active compounds. In silico prediction of physicochemical properties, ADME, and drug-likeness profiles were also studied. Several compounds as 11b, 11k, 12b, and 12d showed selective inhibition to (COX-2) isozyme. Compound 11b showed the most potent (COX-2) inhibitory activity with (IC50 = 0.10 µM) and selectivity index (SI = 134); the tested compounds also have shown good anti-inflammatory activity. Regarding the ulcerogenic liability, compound 11b was also safest one (Ulcer Index) (UI = 0.83). The results of the molecular docking studies is closely related to the results of the in vitro COX-2 inhibitory activities.

New indomethacin analogs as selective COX-2 inhibitors: Synthesis, COX-1/2 inhibitory activity, anti-inflammatory, ulcerogenicity, histopathological, and docking studies.

New indomethacin analogs 4a-g, 5, 6, 8a, and 8b were synthesized to overcome the nonselectivity and ulcer liability of indomethacin. All newly synthesized compounds were more potent against cyclooxygenase 2 (COX-2; IC50 value range: 0.09-0.4 µÐœ) as compared with celecoxib (IC50 = 0.89 µÐœ). Compounds 4a, 4b, 4d, 5, and 6 showed the highest COX-2 selectivity index (SI range = 4.07-6.33) as compared with indomethacin (SI = 1.14) and celecoxib (SI = 3.52). Additionally, 4a, 4b, 4d, 5, and 7 showed good anti-inflammatory activity with edema inhibition (79.36-88.8%), relative to celecoxib (78.96%) and indomethacin (90.43%), after 5 h. Also, ulcerogenic effects and histopathological examination were assessed for the most potent analogs, 4b, 4d, 5, and 6, to determine their safety. The results can shed light on indomethacin analog 5 as a remarkable anti-inflammatory lead compound with a good safety profile (ulcer index = 10.62) close to the nonulcerogenic drug celecoxib (ulcer index = 10.53) and better than indomethacin (ulcer index = 18.50). Docking studies were performed in the COX-2 active site for the most active compounds, to test their selectivity and to confirm their mechanism of action.

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, molecular docking and antiproliferative activity of some novel benzothiazole derivatives targeting EGFR/HER2 and TS.

Multi-targeted anticancer drugs are in focus as a promising research topic. A new series of benzothiazoles hybridized with pyrimidine moiety was designed and synthesized using the lead compound 4a. Various chemical modifications on the pyrimidine ring of 4a at four different positions were done in a trial to get new multi-targeted anticancer agents. The structures of the newly synthesized compounds were established on their elemental analyses and spectral data. All final synthesized derivatives were submitted to the National Cancer Institute (NCI), USA, to be screened for their in vitro anticancer activity. Further evaluation for the cytotoxic activity of the most active compounds was performed using the MTT assay method. Compounds 4d, 8d, 8h, 8i and 17 were then selected for examining their in vitro enzyme inhibitory activities against EGFR, HER2 and TS enzymes using lapatinib and 5FU as standards. Furthermore, cell cycle analysis and apoptosis induction detection were also evaluated. Finally, molecular docking studies were carried out for compounds 4d, 8d, 8h, 8i and 17 to interpret their observed enzymatic activities based on the ligand-protein interactions.

Synthesis and biological evaluation of 2-(4-methylsulfonyl phenyl) indole derivatives: multi-target compounds with dual antimicrobial and anti-inflammatory activities.

Three series of 2-(4-methylsulfonylphenyl) indole derivatives have been designed and synthesized. The synthesized compounds were assessed for their antimicrobial, COX inhibitory and anti-inflammatory activities. Compound 7g was identified to be the most potent antibacterial candidate against strains of MRSA, E. coli, K. pneumoniae, P. aeruginosa, and A. baumannii, respectively, with safe therapeutic dose. Compounds 7a-k, 8a-c, and 9a-c showed good anti-inflammatory activity with excessive selectivity towards COX-2 in comparison with reference drugs indomethacin and celecoxib. Compounds 9a-c were found to release moderate amounts of NO to decrease the side effects associated with selective COX-2 inhibitors. A molecular modeling study for compounds 7b, 7h, and 7i into COX-2 active site was correlated with the results of in vitro COX-2 inhibition assays.

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.

New pyrazole derivatives possessing amino/methanesulphonyl pharmacophore with good gastric safety profile: Design, synthesis, cyclooxygenase inhibition, anti-inflammatory activity and histopathological studies.

New series of pyrazole derivatives Va-c, VIa-c, VIIa-f, and VIII possessing amino/methanesulphonyl moiety as COX-2 pharmacophore were designed and synthesized. All compounds were evaluated for both in vitro COX inhibition and in vivo anti-inflammatory activities and all of them were more potent against COX-2 than COX-1 isozyme and showed good in vivo anti-inflammatory activity. Compounds Va, VIa, VIc and VIIa-c showed good COX-2 SI (246.8-353.8) in comparison with the COX-2 selective drug; celecoxib (326.7). Also, they showed good anti-inflammatory activity with edema inhibition (51-86 and 83-96%) relative to celecoxib (60.6 and 82.8%) after 3 and 5 h respectively. Additionally, these potent derivatives Va, VIa, VIc and VIIa-c were significantly less ulcerogenic (ulcer indexes = 0.7-2.0) than indomethacin (ulcer index = 21.3) and were of acceptable ulcerogenicity when compared with the non-ulcerogenic reference drug celecoxib (ulcer index = 1.3). The obtained ulcerogenic liability data revealed the gastric safety of these derivatives which was confirmed by the histopathological studies. Docking study was performed for all synthesized derivatives to explain their interaction with COX-2 receptor active site.

Treatment of breast cancer with engineered novel pH-sensitive triaryl-(Z)-olefin niosomes containing hydrogel: an in vitro and in vivo study.

Triaryl-(Z)-olefin (TZO) was synthesized as a Tamoxifen (TMX) analogue for breast cancer treatment to avoid developing the resistance and toxicity of TMX. TZO was synthesized using McMurry olefination reaction and has anti-cancer activity better than TMX by two folds. In this paper, in situ pH-sensitive TZO-loaded noisome hydrogel was prepared for delivering and targeting TZO to its site of activity. Equi-molar of cholesterol and span 60 was used to prepare TZO-loaded niosomes using the Hand Shaking Method. The central composite experimental design was used to prepare differently in situ pH-sensitive TZO-loaded niosomes formulae. The formulae were done by incorporated TZO-loaded niosomes into different concentrations of chitosan and Glyceryl monooleate (GCM). Increasing the chitosan and GCM concentrations resulted in significantly increasing the viscosity and significantly decreasing the release of TZO from different formulae. The formula composed of (0.61% w/v) of chitosan and (0.23% w/v) of GCM was chosen as an optimum formula to evaluate the efficacy of TZO using Ehrlich carcinoma mice model. A significant anti-tumour effect was shown in comparison with TMX. Briefly, in situ pH-sensitive TZO-loaded niosomes could be an effective treatment for breast cancer.

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.

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.

Design, synthesis, modeling studies and biological evaluation of thiazolidine derivatives containing pyrazole core as potential anti-diabetic PPAR-γ agonists and anti-inflammatory COX-2 selective inhibitors.

Nowadays, diabetes and its associated inflammatory complications are important public health problems worldwide. Market limitations of drugs with dual actions as anti-inflammatory (AI) and anti-diabetic have been led to a temptation for focusing on the discovery and development of new compounds with potential AI and anti-diabetic activities. Herein, we synthesized two new series containing pyrazole ring with vicinal diaryl rings as selective COX-2 moiety and thiazolidindione (series 12a-f) or thiazolidinone (series 13a-f) as anti-diabetic moiety and the two moieties were linked together with methylene or methylenehydrazone functionality. The two series were evaluated for their COX inhibition, AI activity and ulcerogenic liability and for the anti-diabetic activity; 12a-f and 13a-f were assessed in vitro against α-glucosidase, ß- glucosidase, in vivo hypoglycemic activity (one day and 15 days studies) in addition to PPARγ activation study. Four compounds (12c, 12f, 13b and 13f) had higher COX-2 S.I. (8.69-9.26) than the COX-2 selective drug celecoxib (COX-2 S.I. = 8.60) and showed the highest AI activities and the lowest ulcerogenicity than other derivatives. Also, two thiazolidindione derivatives 12e and 12f and two thiazolidinone derivatives 13b and 13c showed higher inhibitory activities against α- and ß-glucosidase (% inhibitory activity = 62.15, 55.30, 65.37, 59.08 for α-glucosidase and 57.42, 60.07, 58.19, 66.90 for ß-glucosidase respectively) than reference compounds (acarbose with % inhibitory activity = 49.50 for α-glucosidase and d-saccharic acid 1,4-lactone monohydrate with % inhibitory activity = 53.42 for ß-glucosidase) and also showed good PPAR-γ activation and good hypoglycemic effect in comparison to pioglitazone and rosiglitazone. Moreover, Shape comparison and docking studies were carried out to understand their interaction and similarity with standard drugs.

New advances in synthesis and clinical aspects of pyrazolo[3,4-d]pyrimidine scaffolds.

Pyrazolo[3,4-d]pyrimidine ring system constitute an important class of heterocyclic compounds which can serve as a promising scaffold exhibiting many pharmacological activities. This ring system received much attention as it is a purine isostere by replacing imidazole ring in purine with pyrazole moiety in pyrazolo[3,4-d]pyrimidine. Here we concentrate on new advances in the synthesis of this important ring and other clinical aspects in an attempt to sheld the light to assist in discovery of new pyrazolo[3,4-d]pyrimidine derivatives.

Evaluation and optimization of pH-responsive niosomes as a carrier for efficient treatment of breast cancer.

Tamoxifen citrate (TXC) is commonly indicated to prevent cell multiplication and development of breast cancer. However, it is usually associated with limited activity and development of toxicity and resistance. This study aimed to describe an in situ pH-responsive niosomes as a carrier for localized and sustained delivery of TXC. The thin film hydration method was utilized to produce TXC niosomes using sorbitan monostearate and cholesterol of 1:1 Molar ratio. The produced formula displayed nano-spherical shape with entrapment efficiency (EE) of 88.90 ± 0.72% and drug release of 49.2 ± 1.51% within 8 h. This formula was incorporated into chitosan/glyceryl monooleate (CH/GMO) as a localized in situ pH-responsive hydrogel delivery system. Different formulae were produced by Design-Expert software based on user-defined response surface design utilizing different chitosan concentration (A) and GMO concentration (B) characterized for mean viscosity (R2) and in vitro release studies (R1). The results displayed that R1 was significantly antagonistic with both of A and B while R2 was significantly synergistic with both of them. The optimum formula was selected and capped with gold as an ideal candidate for computed tomography (CT) to evaluate the efficacy and tissue distribution of TXC utilizing Ehrlich carcinoma mice model. The optimum formula showed localized TXC in a tumour and consequently a significant anti-tumour efficacy compared with free TXC. Based on these outcomes, the novel in situ pH-responsive TXC-loaded noisome could be a promising formula for the efficient treatment of breast cancer.

Design, synthesis and anticancer evaluation of novel spirobenzo[h]chromene and spirochromane derivatives with dual EGFR and B-RAF inhibitory activities.

A novel series of spirobenzo[h]chromene and spirochromane derivatives was designed, synthesized and evaluated as potential anticancer agents against MCF-7 (human breast carcinoma), HT-29 (human colorectal adenocarcinoma) and A549 (human lung carcinoma) cell lines using MTT assay. Eight compounds 7, 8e, 13a-e and 16 showed a better anticancer activity than that of sorafenib, the multi-kinase inhibitor with IC50 values between 1.78 and 5.47 µM or erlotinib with IC50 values over 20 µM. Representative compounds 8e, 13c and 16 were selected for further mechanistic investigation via EGFR, B-RAF and tubulin polymerization assays. Compound 16 was the most potent EGFR inhibitor (IC50 = 1.2 µM), yet compounds 8e, 13c and 16 displayed moderate tubulin polymerization inhibition effects. Molecular docking studies of those compounds revealed their possible binding modes into the active sites of both EGFR and B-RAF kinases. The newly developed compounds represent a therapeutically promising approach for the treatment of different types of cancer.

Non-acidic 1,3,4-trisubstituted-pyrazole derivatives as lonazolac analogs with promising COX-2 selectivity, anti-inflammatory activity and gastric safety profile.

Twelve new compounds of 1,3,4-trisubstituted-pyrazole derivatives possessing two cyclooxygenase-2 (COX-2) pharmacophoric moieties (SO2Me or/and SO2NH2) 11a-c, 12a-c, 13a-c and 14a-c were designed and synthesized to be evaluated for their COX inhibition, anti-inflammatory activity, ulcerogenic liability. All compounds were more selective for COX-2 isozyme and showed good in vivo anti-inflammatory activity. The bisaminosulphonyl derivatives (14a-c) were the most COX-2 selective compounds (S.I. = 9.87, 9.50 and 9.22 respectively) and showed good anti-inflammatory potency (ED50 = 15.06, 42.51 and 50.43 µmol/kg respectively) in comparison with celecoxib (COX-2 S.I. = 8.61, ED50 = 82.2 µmol/kg). Also, compounds 14a-c were less ulcerogenic (ulcer indexes = 2.72-3.72) than ibuprofen (ulcer index = 20.25) and comparable to celecoxib (ulcer index = 2.93). In addition, to explain the preferential (COX-2) inhibitory and selectivity, the designed compounds were subjected to molecular docking studies. It was found that compound 14c with the highest COX-2 activity and selectivity exhibited a binding pattern and interactions similar to that of celecoxib with formation of more hydrogen-bond features.

Design, Synthesis and Cytotoxicity Evaluation of New 3, 5-Disubstituted-2-Thioxoimidazolidinones.

BACKGROUND: Some 2-thioxoimidazolidinones have been reported as anti-prostate and anti-breast cancer agents through their inhibitory activity on topoisomerase I that is considered as a potential chemotherapeutic target. OBJECTIVE: A new series of 3,5-disubstituted-2-thioxoimidazolidinone derivatives 10a-f and their S-methyl analogs 11a-f were designed, synthesized and evaluated for cytotoxicity against human prostate cancer cell line (PC-3), human breast cancer cell line (MCF-7) and non-cancerous human lung fibroblast cell line (WI-38). Results and Method: While compounds 10a-f showed a broad range of activities against PC-3 and MCF-7 cell lines (IC50 = 34.0 - 186.9 and 24.6 - 147.5 µM respectively), the S-methyl analogs 11a-f showed (IC50 = 22.7 - 198.5 and 16.9 - 188.2 µM respectively) in comparison with 5-fluorouracil (IC50 = 60.7 and 40.7 µM respectively). 11c (IC50 = 22.7 and 29.2 µM) and 11f (IC50 = 28.7 and 16.9 µM) were the most potent among all compounds against both PC-3 and MCF-7 respectively with no cytotoxicity against WI-38. CONCLUSION: The newly synthesized compounds showed good activity against PC-3 and MCF-7 cell lines in comparison with 5-fluorouracil. Compounds 11c and 11f bound with human topoisomerase I similar to its known inhibitors and significantly inhibited its DNA relaxation activity in a dose dependent manner which may rationalize their molecular mechanism as cytotoxic agents.