RESUMEN
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).
Asunto(s)
Antineoplásicos , Proliferación Celular , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB , Inhibidores de Proteínas Quinasas , Pirazoles , Tiourea , Urea , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Humanos , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/síntesis química , Pirazoles/química , Pirazoles/farmacología , Pirazoles/síntesis química , Relación Estructura-Actividad , Proliferación Celular/efectos de los fármacos , Tiourea/farmacología , Tiourea/química , Tiourea/síntesis química , Estructura Molecular , Urea/farmacología , Urea/química , Urea/análogos & derivados , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/síntesis química , Línea Celular Tumoral , Ciclooxigenasa 2/metabolismo , Descubrimiento de Drogas , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/síntesis químicaRESUMEN
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.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina , Antiinflamatorios , Antihipertensivos , Inhibidores de la Ciclooxigenasa 2 , Pirazoles , Tetrazoles , Pirazoles/farmacología , Pirazoles/química , Animales , Antihipertensivos/farmacología , Antihipertensivos/química , Antihipertensivos/síntesis química , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/química , Inhibidores de la Enzima Convertidora de Angiotensina/síntesis química , Tetrazoles/farmacología , Tetrazoles/química , Antiinflamatorios/farmacología , Antiinflamatorios/química , Antiinflamatorios/síntesis química , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/química , Ratas , Diseño de Fármacos , Masculino , Antifibróticos/farmacología , Antifibróticos/química , Ciclooxigenasa 2/metabolismo , Presión Sanguínea/efectos de los fármacos , Humanos , Peptidil-Dipeptidasa A/metabolismoRESUMEN
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.
Asunto(s)
Antineoplásicos , Tiazoles , Celecoxib/farmacología , Ciclooxigenasa 2/metabolismo , Dasatinib/farmacología , Tiazoles/farmacología , Simulación del Acoplamiento Molecular , Antiinflamatorios/farmacología , Doxorrubicina , Apoptosis , Relación Estructura-Actividad , Estructura Molecular , Antineoplásicos/farmacología , Ensayos de Selección de Medicamentos AntitumoralesRESUMEN
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).
Asunto(s)
Antineoplásicos , Donantes de Óxido Nítrico , Ciclooxigenasa 2/metabolismo , Celecoxib , Estructura Molecular , Donantes de Óxido Nítrico/farmacología , Relación Estructura-Actividad , Aromatasa/metabolismo , Línea Celular Tumoral , Antiinflamatorios/farmacología , Triazoles/farmacología , Receptores ErbB/metabolismo , Apoptosis , Fluorouracilo , Simulación del Acoplamiento Molecular , Antineoplásicos/farmacologíaRESUMEN
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.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Ciclooxigenasa 2/metabolismo , Edema/tratamiento farmacológico , Hidrocarburos Halogenados/farmacología , Pirazoles/farmacología , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Carragenina , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/química , Relación Dosis-Respuesta a Droga , Edema/inducido químicamente , Edema/patología , Humanos , Hidrocarburos Halogenados/síntesis química , Hidrocarburos Halogenados/química , Simulación del Acoplamiento Molecular , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Ratas , Úlcera Gástrica/tratamiento farmacológico , Úlcera Gástrica/patología , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Antineoplásicos/farmacología , Celecoxib/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Celecoxib/síntesis química , Celecoxib/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Masculino , Modelos Moleculares , Estructura Molecular , Óxido Nítrico/metabolismo , Oximas/química , Oximas/farmacología , Células PC-3 , Pirazoles/química , Pirazoles/farmacología , Ratas , Ratas Wistar , Úlcera Gástrica/tratamiento farmacológico , Relación Estructura-Actividad , Triazoles/química , Triazoles/farmacologíaRESUMEN
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 indexesâ¯=â¯2.64-3.87) than ibuprofen (ulcer indexâ¯=â¯20.25) and were of acceptable ulcerogenicity when compared with the non-ulcerogenic reference drug celecoxib (ulcer indexâ¯=â¯2.99). Regarding anti-cancer activity, most of the target derivatives showed activities against A-549, MCF-7 and HCT-116 cell lines (IC50â¯=â¯5.32-17.90, 3.67-19.04 and 3.19-14.87⯵M respectively) in comparison with doxorubicin (IC50â¯=â¯0.20, 0.50 and 2.44⯵M respectively). Compound 14a inhibited the human topoisomerase-1 with IC50â¯=â¯29.7⯵g/ml while 14b and 14c showed more potent inhibitory activity with IC50â¯=â¯26.5 and 23.3⯵g/ml. respectively in comparison with camptothecin (IC50â¯=â¯20.2⯵g/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.
Asunto(s)
Antiinflamatorios/farmacología , Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Pirazoles/farmacología , Tiohidantoínas/farmacología , Antiinflamatorios/síntesis química , Antiinflamatorios/metabolismo , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Dominio Catalítico , Línea Celular Tumoral , Ciclooxigenasa 1/química , Ciclooxigenasa 1/metabolismo , ADN-Topoisomerasas de Tipo I/química , ADN-Topoisomerasas de Tipo I/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Unión Proteica , Pirazoles/síntesis química , Pirazoles/metabolismo , Tiohidantoínas/síntesis química , Tiohidantoínas/metabolismoRESUMEN
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 15â¯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.â¯=â¯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 activityâ¯=â¯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 activityâ¯=â¯49.50 for α-glucosidase and d-saccharic acid 1,4-lactone monohydrate with % inhibitory activityâ¯=â¯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.
Asunto(s)
Antiinflamatorios/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de Glicósido Hidrolasas/farmacología , PPAR gamma/agonistas , Pirroles/farmacología , Tiazolidinas/farmacología , Animales , Antiinflamatorios/efectos adversos , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Dominio Catalítico , Celecoxib/química , Celecoxib/farmacología , Celulasas/metabolismo , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/química , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/efectos adversos , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/química , Diseño de Fármacos , Inhibidores de Glicósido Hidrolasas/efectos adversos , Inhibidores de Glicósido Hidrolasas/síntesis química , Inhibidores de Glicósido Hidrolasas/química , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , PPAR gamma/química , Pirroles/efectos adversos , Pirroles/síntesis química , Pirroles/química , Ratas , Ovinos , Úlcera Gástrica/inducido químicamente , Relación Estructura-Actividad , Tiazolidinas/efectos adversos , Tiazolidinas/síntesis química , Tiazolidinas/química , alfa-Glucosidasas/metabolismoRESUMEN
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 (UIâ¯=â¯2.00, 2.75, 3.25 respectively) than indomethacin (UIâ¯=â¯14) and comparable to celecoxib (UIâ¯=â¯1.75) which were confirmed from the histopatholgical study.
Asunto(s)
Antiinflamatorios/uso terapéutico , Celecoxib/uso terapéutico , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Inflamación/tratamiento farmacológico , Tolmetina/uso terapéutico , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/metabolismo , Dominio Catalítico , Celecoxib/análogos & derivados , Celecoxib/metabolismo , Celecoxib/farmacología , Ciclooxigenasa 2/química , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/metabolismo , Diseño de Fármacos , Mucosa Gástrica/patología , Humanos , Indometacina/farmacología , Simulación del Acoplamiento Molecular , Unión Proteica , Ratas , Tolmetina/análogos & derivados , Tolmetina/metabolismoRESUMEN
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.â¯=â¯9.87, 9.50 and 9.22 respectively) and showed good anti-inflammatory potency (ED50â¯=â¯15.06, 42.51 and 50.43⯵mol/kg respectively) in comparison with celecoxib (COX-2 S.I.â¯=â¯8.61, ED50â¯=â¯82.2⯵mol/kg). Also, compounds 14a-c were less ulcerogenic (ulcer indexesâ¯=â¯2.72-3.72) than ibuprofen (ulcer indexâ¯=â¯20.25) and comparable to celecoxib (ulcer indexâ¯=â¯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.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Ciclooxigenasa 2/metabolismo , Pirazoles/farmacología , Úlcera Gástrica/tratamiento farmacológico , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/química , Relación Dosis-Respuesta a Droga , Edema/tratamiento farmacológico , Humanos , Modelos Moleculares , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Ratas , Relación Estructura-ActividadRESUMEN
A new series of 1,3,5-triaryl-4,5-dihydro-1H-pyrazole 10a-l was designed and synthesized via cyclization of chalcones 8a-f with 4-amino/methanesulfonylphenylhydrazine hydrochloride 9a-b. All the synthesized compounds were evaluated for their cyclooxygenase (COX) inhibition, anti-inflammatory activity, ulcerogenic liability and analgesic activity. All compounds were more COX-2 inhibitors than COX-1. While most compounds showed good anti-inflammatory activity, the trimethoxy derivatives (10a, 10b, 10g and 10h) were the most potent derivatives (ED50=55.78, 53.99, 67.65 and 69.20µmol/kg respectively) in comparison with celecoxib (ED50=82.15µmol/kg). Compounds 10a, 10b, 10g and 10h (ulcer index=2.68, 1.20, 2.63 and 2.66 respectively) showed less ulceration effect than celecoxib (ulcer index=2.90). Also, Compounds 10a, 10b, 10g and 10h showed analgesic activity higher than celecoxib and comparable to that of ibuprofen. In addition, molecular docking studies were performed for compounds 10a, 10b, 10g and 10h and the results were in agreement with that obtained from the in vitro COX inhibition assays.
Asunto(s)
Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/uso terapéutico , Inhibidores de la Ciclooxigenasa/química , Inhibidores de la Ciclooxigenasa/uso terapéutico , Pirazoles/química , Pirazoles/uso terapéutico , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/farmacología , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa/síntesis química , Inhibidores de la Ciclooxigenasa/farmacología , Edema/tratamiento farmacológico , Edema/enzimología , Femenino , Humanos , Masculino , Mesilatos/síntesis química , Mesilatos/química , Mesilatos/farmacología , Mesilatos/uso terapéutico , Ratones , Modelos Moleculares , Simulación del Acoplamiento Molecular , Pirazoles/síntesis química , Pirazoles/farmacología , Ratas Wistar , OvinosRESUMEN
A new series of 1,2-diaryl-4-substituted-benzylidene-5-4H-imidazolone derivatives 10a-h was designed and synthesized for evaluation as selective COX-2 inhibitors, anti-inflammatory agents and as analgesic agents. All compounds were more selective for COX-2 isozyme and showed good in vivo anti-inflammatory activity. Compounds 10a, 10b, 10e and 10f were the most COX-2 selective compounds (S.I.=10.76, 10.87, 8.69 and 9.14 respectively), the most potent anti-inflammatory derivatives (ED50=65.7, 60.2, 76.3 and 107.4µmol/kg respectively) in comparison with Celecoxib (COX-2 S.I.=8.61, ED50=82.2µmol/kg) and were less ulcerogenic (ulcer indexes=1.22-3.02) than Ibuprofen (ulcer index=20.25) and comparable to Celecoxib (ulcer index=2.93). The four derivatives (10a, 10b, 10e and 10f) showed considerable analgesic activities which are clearly parallel to their anti-inflammatory activities.
Asunto(s)
Analgésicos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Edema/tratamiento farmacológico , Imidazoles/farmacología , Dolor/tratamiento farmacológico , Analgésicos/síntesis química , Analgésicos/química , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Carragenina , Bovinos , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa/síntesis química , Inhibidores de la Ciclooxigenasa/química , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Edema/inducido químicamente , Humanos , Imidazoles/síntesis química , Imidazoles/química , Estructura Molecular , Dimensión del Dolor , Ratas , Relación Estructura-ActividadRESUMEN
Two new series of 1,3,5-triarylpyrazolines 10a-m and 1,5-diarylpyrazoles 14a-d were synthesized. 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 and showed good in vivo anti-inflammatory activity. Compound 10k was the most COX-2 selective compound (S.I.=5.91) and the most potent anti-inflammatory derivative (ED50=99µmol/kg) which is approximately five folds more potent than ibuprofen (ED50=499µmol/kg) and had half potency of celecoxib (ED50=47µmol/kg). All compounds were less ulcerogenic (Ulcer Indexes=1.20-5.00) than ibuprofen (Ulcer Index=20.25) and comparable to celecoxib (Ulcer Index=2.90).
Asunto(s)
Antiinflamatorios/química , Antiinflamatorios/farmacología , Inhibidores de la Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/farmacología , Pirazoles/química , Pirazoles/farmacología , Antiinflamatorios/síntesis química , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/síntesis química , Humanos , Pirazoles/síntesis química , Úlcera/inducido químicamenteRESUMEN
A new series of 1,5-diarylpyrazoles 10a-l was designed and synthesized for evaluation as COX inhibitors and as anti-inflammatory agents. All compounds were more selective for COX-2 isozyme and showed good in vivo anti-inflammatory activity. Compound 10e was the most COX-2 selective compound (S.I. = 10.67) and the most potent anti-inflammatory derivative (ED50 = 46 µmol/kg) which is approximately 11-folds more potent than ibuprofen (ED50 = 499 µmol/kg) and had 2/3 potency of celecoxib (ED50 = 31 µmol/kg). All compounds were less ulcerogenic (ulcer indexes = 1.20-4.61) than ibuprofen (ulcer index = 20.25) and comparable to celecoxib (ulcer index = 2.90).
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Ciclooxigenasa 2/metabolismo , Pirazoles/farmacología , Úlcera Gástrica/inducido químicamente , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/química , Relación Dosis-Respuesta a Droga , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Relación Estructura-ActividadRESUMEN
A new series of 1,3,5-triarylpyrazolines 13a-l was synthesized and all prepared compounds were evaluated for their in vitro COX-1/COX-2 inhibitory activity and in vivo anti-inflammatory activity. All test compounds were more selective for the COX-2 isozyme and showed good in vivo anti-inflammatory activity. Compound 13h was the most COX-2 selective compound (COX-2 selectivity index (SI) = 10.23) and the most potent anti-inflammatory derivative (ED50 = 60.1 µmol/kg) in comparison with celecoxib (COX-2 SI = 9.29 and ED50 = 81.4 µmol/kg). All screened compounds were less ulcerogenic (ulcer indexes (UI) = 0.33-1.33) than aspirin (UI = 2.33) and comparable to celecoxib (UI = 0.33).