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1.
Eur J Med Chem ; 271: 116434, 2024 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-38653067

RESUMEN

Diabetes mellitus is a chronic metabolic disorder characterized by improper expression/function of a number of key enzymes that can be regarded as targets for anti-diabetic drug design. Herein, we report the design, synthesis, and biological assessment of two series of thiazolidinone-based sulfonamides 4a-l and 5a-c as multitarget directed ligands (MTDLs) with potential anti-diabetic activity through targeting the enzymes: α-glucosidase and human carbonic anhydrase (hCA) II. The synthesized sulfonamides were evaluated for their inhibitory activity against α-glucosidase where most of the compounds showed good to potent activities. Compounds 4d and 4e showed potent inhibitory activities (IC50 = 0.440 and 0.3456 µM), comparable with that of the positive control (acarbose; IC50 = 0.420 µM). All the synthesized derivatives were also tested for their inhibitory activities against hCA I, II, IX, and XII. They exhibited different levels of inhibition against these isoforms. Compound 4d outstood as the most potent one against hCA II with Ki equals to 7.0 nM, more potent than the reference standard (acetazolamide; Ki = 12.0 nM). In silico studies for the most active compounds within the active sites of α-glucosidase and hCA II revealed good binding modes that can explain their biological activities. MM-GBSA refinements and molecular dynamic simulations were performed on the top-ranking docking pose of the most potent compound 4d to confirm the formation of stable complex with both targets. Compound 4d was screened for its in vivo antihyperglycemic efficacy by using the oral glucose tolerance test. Compound 4d decreased blood glucose level to 217 mg/dl, better than the standard acarbose (234 mg/dl). Hence, this revealed its synergistic mode of action on post prandial hyperglycemia and hepatic gluconeogenesis. Thus, these benzenesulfonamide thiazolidinone hybrids could be considered as promising multi-target candidates for the treatment of type II diabetes mellitus.


Asunto(s)
Bencenosulfonamidas , Anhidrasa Carbónica II , Inhibidores de Anhidrasa Carbónica , Diabetes Mellitus Tipo 2 , Inhibidores de Glicósido Hidrolasas , Hipoglucemiantes , Sulfonamidas , Tiazolidinas , alfa-Glucosidasas , Anhidrasa Carbónica II/antagonistas & inhibidores , Anhidrasa Carbónica II/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , alfa-Glucosidasas/metabolismo , Humanos , Sulfonamidas/química , Sulfonamidas/farmacología , Sulfonamidas/síntesis química , Inhibidores de Glicósido Hidrolasas/farmacología , Inhibidores de Glicósido Hidrolasas/química , Inhibidores de Glicósido Hidrolasas/síntesis química , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Hipoglucemiantes/síntesis química , Relación Estructura-Actividad , Inhibidores de Anhidrasa Carbónica/química , Inhibidores de Anhidrasa Carbónica/farmacología , Inhibidores de Anhidrasa Carbónica/síntesis química , Animales , Ligandos , Tiazolidinas/química , Tiazolidinas/farmacología , Tiazolidinas/síntesis química , Estructura Molecular , Ratas , Relación Dosis-Respuesta a Droga , Simulación del Acoplamiento Molecular , Diabetes Mellitus Experimental/tratamiento farmacológico , Masculino , Ratas Wistar
2.
Bioorg Chem ; 147: 107332, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38581966

RESUMEN

Activin receptor­like kinase-5 (ALK5) is an outstanding member of the transforming growth factor-ß (TGF-ß) family. (TGF-ß) signaling pathway integrates pleiotropic proteins that regulate various cellular processes such as growth, proliferation, and differentiation. Dysregulation within the signaling pathway can cause variety of diseases, such as fibrosis, cardiovascular disease, and especially cancer, rendering ALK5 a potential drug target. Hence, various small molecules have been designed and synthesized as potent ALK5 inhibitors. In this review, we shed light on the current ATP-competitive inhibitors of ALK5 through diverse heterocyclic based scaffolds that are in clinical or pre-clinical phases of development. Moreover, we focused on the binding interactions of the compounds to the ATP binding site and the structure-activity relationship (SAR) of each scaffold, revealing new scopes for designing novel candidates with enhanced selectivity and metabolic profiles.


Asunto(s)
Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas , Receptor Tipo I de Factor de Crecimiento Transformador beta , Humanos , Relación Estructura-Actividad , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/síntesis química , Receptor Tipo I de Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Receptor Tipo I de Factor de Crecimiento Transformador beta/metabolismo , Estructura Molecular , Animales
3.
Arch Pharm (Weinheim) ; 357(3): e2300599, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38100160

RESUMEN

Humanity is currently facing various diseases with significant mortality rates, particularly those associated with malignancies. Numerous enzymes and proteins have been identified as highly promising targets for the treatment of cancer. The poly(ADP-ribose) polymerases (PARPs) family comprises 17 members which are essential in DNA damage repair, allowing the survival of cancer cells. Unlike other PARP family members, PARP-1 and, to a lesser extent, PARP-2 show more than 90% activity in response to DNA damage. PARP-1 levels were shown to be elevated in various tumor cells, including breast, lung, ovarian, and prostate cancer and melanomas. Accordingly, novel series of phthalimide-tethered isatins (6a-n, 10a-e, and 11a-e) were synthesized as potential PARP-1 inhibitors endowed with anticancer activity. All the synthesized molecules were assessed against PARP-1, where compounds 6f and 10d showed nanomolar activities with IC50 = 15.56 ± 2.85 and 13.65 ± 1.42 nM, respectively. Also, the assessment of the antiproliferative effects of the synthesized isatins was conducted on four cancer cell lines: leukemia (K-562), liver (HepG2), and breast (MCF-7 and HCC1937) cancers. Superiorly, compounds 6f and 10d demonstrated submicromolar IC50 values against breast cancer MCF-7 (IC50 = 0.92 ± 0.18 and 0.67 ± 0.12 µM, respectively) and HCC1937 (IC50 = 0.88 ± 0.52 and 0.53 ± 0.11 µM, respectively) cell lines. In addition, compounds 6f and 10d induced arrest in the G2/M phase of the cell cycle as compared to untreated cells. Finally, in silico studies, including docking and molecular dynamic simulations, were performed to justify the biological results.


Asunto(s)
Isatina , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Masculino , Humanos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Relación Estructura-Actividad , Ftalimidas/farmacología , Línea Celular Tumoral
4.
Bioorg Chem ; 116: 105347, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34555628

RESUMEN

New diphenyl-1H-pyrazoles were synthesized and screened for CDK2 inhibition where 8d, 9b, 9c, and 9e exhibited promising activity (IC50 = 51.21, 41.36, 29.31, and 40.54 nM respectively) compared to R-Roscovitine (IC50 = 43.25 nM). Furthermore, preliminary anti-proliferative activity screening of some selected compounds on 60 cancer cell lines was performed at the (NCI/USA). Compounds 8a-c displayed promising growth inhibitory activity (mean %GI; 73.74, 94.32 and 74.19, respectively). Additionally, they were further selected by the NCI for five-dose assay, exhibiting pronounced activity against almost the full panel (GI50 ranges; 0.181-5.19, 1.07-4.12 and 1.07-4.82 µM, respectively) and (Full panel GI50 (MG-MID); 2.838, 2.306 and 2.770 µM, respectively). Screening the synthesized compounds 8a-c for inhibition of CDK isoforms revealed that compound 8a exhibited nearly equal inhibition to all the tested CDK isoforms, while compound 8b inhibits CDK4/D1 preferentially than the other isoforms and compound 8c inhibits CDK1, CDK2 and CDK4 more than CDK7. Flow cytometry cell cycle assay of 8a-c on Non-small cell lung carcinoma (NSCL HOP-92) cell line revealed S phase arrest by 8a and G1/S phase arrest by 8b and 8c. Apoptotic induction in HOP-92 cell line was also observed upon treatment with compounds 8a-c. Docking to CDK2 ATP binding site revealed similar interactions as the co-crystallized ligand R-Roscovitine (PDB code; 3ddq). These findings present compounds 8a-c as promising anti-proliferative agents.


Asunto(s)
Antineoplásicos/farmacología , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quinasas Ciclina-Dependientes/metabolismo , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirazoles/síntesis química , Pirazoles/química , Relación Estructura-Actividad
5.
Eur J Med Chem ; 218: 113389, 2021 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-33784602

RESUMEN

Novel series of diphenyl-1H-pyrazoles (4a-g) and pyrazolo[3,4-b]pyridines (5a-g and 7a-i) were synthesized and evaluated for their antiproliferative activity against breast cancer cell line (MCF7) and Hepatocellular carcinoma cell line (HepG2). The highest MCF7 growth inhibition activity was attained via compounds 4f and 7e (IC50 = 1.29 and 0.93 µM, respectively), while compounds 5b and 7f were the most active ones against HepG2 (IC50 = 1.57 and 1.33 µM, respectively) compared to doxorubicin (IC50 = 1.88 and 7.30 µM, respectively). Cell cycle analysis showed arrest at S and G2-M phases in MCF7 cells treated with 4f and 7e, and at G2-M and G1/S phases in HepG2 cells treated with 5b and 7f, respectively. Apoptotic effect of compounds 4f, 5b, 7e, and 7f was indicated via their pre-G1 early and late apoptotic effects and augmented levels of caspase-9/MCF7 and caspase-3/HepG2. A worthy safety profile was assessed for compounds 4f and 7e on MCF10A and compounds 5b and 7f on THLE2 treated normal cells. Furthermore, compounds 4f, 5b and 7f displayed a promising selective profile for CDK2 inhibition vs. CDK1, CDK4, and CDK7 isoforms as proved from their selectivity index. Docking in CDK2 ATP binding site, co-crystallized with R-Roscovitine, demonstrated analogous interactions and comparable binding energy with the native ligand. 2D QSAR sighted the possible structural features governing the CDK2 inhibition activity elicited by the studied pyrazolo[3,4-b]pyridines. These findings present compounds 4f, 5b, and 7f as selective CDK2 inhibitors with promising antiproliferative activity against MCF7 and HepG2 cancer cells.


Asunto(s)
Antineoplásicos/farmacología , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Piridinas/farmacología , Relación Estructura-Actividad Cuantitativa , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Quinasa 2 Dependiente de la Ciclina/metabolismo , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células Hep G2 , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirazoles/síntesis química , Pirazoles/química , Piridinas/síntesis química , Piridinas/química
6.
Bioorg Chem ; 94: 103411, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31711767

RESUMEN

A series of 1,2,4-triazolo[1,5-a]pyrimidine derivatives was designed, synthesized and screened for their antibacterial and antifungal activities as well as their safety profile. Compounds 2b, 3a, 6b, 8b, 8c, 8h, 9a,b, 10b, 11a,b and 12a,b showed high activity against Gram-positive and Gram-negative bacteria with MIC values ranging from 0.25 to 2.0 µg/mL. Many compounds were safe with no cytotoxicity against human embryonic kidney and red blood cells at concentration up to 32 µg/mL. Moreover, compound 9a showed the highest inhibitory activity against DNA Gyrase with IC50 = 0.68 µM compared to ciprofloxacin IC50 = 0.85 µM. Molecular docking at DNA Gyrase active site revealed binding mode and docking scores comparable to that of ciprofloxacin confirming their antibacterial activity via DNA Gyrase inhibition.


Asunto(s)
Antibacterianos/uso terapéutico , Simulación del Acoplamiento Molecular/métodos , Pirimidinas/química , Pirimidinas/síntesis química , Inhibidores de Topoisomerasa II/uso terapéutico , Antibacterianos/farmacología , Humanos , Inhibidores de Topoisomerasa II/farmacología
7.
Future Med Chem ; 11(23): 3029-3045, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31680552

RESUMEN

Aim: Nonsteroidal anti-inflammatory drugs are expansively used worldwide. However, their prolonged administration is associated with serious side effects, especially gastrointestinal ulceration. Materials & methods: New ibuprofen derivatives hybridized with H2S- or NO-donating moieties were synthesized and evaluated for their anti-inflammatory activity and ulcerogenic effect. COX-1/COX-2 isozymes selectivity test for the most promising derivatives was performed. Molecular docking studies were performed. Results: Most of the compounds showed promising anti-inflammatory activity comparable to that of ibuprofen (% edema inhibition = 76.6 and ulcer index = 21.26) with much better gastrointestinal tract tolerance (ulcer indices ranging from 0 to 14.67), especially compound 2 -H2S donor- (% edema inhibition = 75.5 and ulcer index = 11.75) and compound 16 -NO donor- (% edema inhibition = 65.4 and ulcer index = 8.66).


Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Sulfuro de Hidrógeno/química , Ibuprofeno/análogos & derivados , Donantes de Óxido Nítrico/química , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/toxicidad , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Edema/tratamiento farmacológico , Simulación del Acoplamiento Molecular , Estructura Molecular , Unión Proteica , Ratas , Úlcera Gástrica/inducido químicamente , Relación Estructura-Actividad
8.
Eur J Med Chem ; 184: 111747, 2019 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-31604164

RESUMEN

The present study reports on evaluation of anti-HCV activity and QSAR of certain arylidenethiazolidinone derivatives as potential inhibitors of HCV-NS5B polymerase. The pursued compounds involving, 5-aryliden-3-arylacetamidothiazolidin-2,4-diones 4-6(a-f), 5-arylidine-2-(N-arylacetamido)-iminothiazolidin-4-one (10) and their rigid counterparts 5-arylidinethiazolotriazines 13-15(a-f), were synthesized and their structures confirmed by spectral and elemental analyses. The results of NS5B polymerase inhibition assay revealed compound 4e, as the most active inhibitor (IC50 = 0.035 µM), which is four folds greater than that of the reference agent, VCH-759, (IC50 = 0.14 µM). Meanwhile, compounds 4b, 4c, 5a, and 5c, and 13b, 14e and 15c displayed equipotency to 2 folds higher activity than VCH-759 (IC50 values: 0.085, 0.14, 0.14, 0.10, 0.12, 0.09 and 0.07 µM, respectively). Assessment of the anti-HCV activity (GT1a) using human hepatoma cell line (Huh-7.5) illustrates superior activity of 4e (EC50 = 3.80 µM) relative to VCH-759 (EC50 = 5.29 µM). Cytotoxicity evaluation on, Transformed normal cell lines (Human Liver Epithelial-2, THLE-2 and Proximal Tubular Epithelial, RPTEC/TERT1), demonstrate enhanced safety profile of 4e (CC50 = 102.77, 161.37 µM, respectively) compared to VCH-759 (CC50 = 61.83, 81.28 µM, respectively). Molecular docking of the synthesized derivatives to NS5B polymerase allosteric site (PDB: 2HWH) showed similar binding modes to that of the co-crystallized ligand. Moreover, QSAR models were established for the studied thiazolidinones and thiazolotriazines to investigate the molecular characteristics contributing to the observed NS5B polymerase inhibition activity. The obtained results inspire further investigations of thiazolidinones and thiazolotriazine aiming at affording more potent, safe and orally active non-nucleoside NS5B polymerase inhibitors as anti-HCV drug candidates.


Asunto(s)
Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Inhibidores de Proteasas/farmacología , Relación Estructura-Actividad Cuantitativa , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/síntesis química , Antivirales/química , Línea Celular , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Hepacivirus/metabolismo , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/química , Tiazoles/síntesis química , Tiazoles/química , Tiazoles/farmacología , Tiazolidinas/síntesis química , Tiazolidinas/química , Tiazolidinas/farmacología , Triazinas/síntesis química , Triazinas/química , Triazinas/farmacología , Proteínas no Estructurales Virales/metabolismo
9.
Eur J Pharm Sci ; 140: 105101, 2019 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-31639436

RESUMEN

Gastric irritation and ulcerogenic effect of the acidic NSAIDs are of the most challenging problems in designing novel anti-inflammatory agents. In this study, the new prodrugs were prepared through Steglich esterification reaction between the carboxylic acid functional group of etodolac or tolfenamic acid and thymol. The structures were confirmed by IR, 1H NMR, 13C NMR, mass spectroscopy and elemental analysis. Their chemical stability in addition to a kinetic study of their hydrolysis in 20% liver homogenate and 10% buffered plasma were investigated. In vitro enzymatic hydrolysis showed half-life times 88.84 and 106.61 min for the prodrugs of etodolac and tolfenamic acid, respectively. Their ability to inhibit paw edema and their ulcerogenic potential were assessed in rats and compared to their parent drugs. the prodrugs were found to be stable in different pHs at room and body temperatures. Both prodrugs proved to possess high percentage of inhibition of paw edema (94.68 & 97.1%) in rats comparable to that of the parent drugs (90.33 & 93.23%) and, most importantly with lower ulcerogenic potential. The prodrugs are expected to be converted to their parent drugs rapidly in plasma and liver in vivo and proved to be safer than their parent drugs. The study opens a perspective chance that can be a backbone for further investigations.


Asunto(s)
Antiinflamatorios/síntesis química , Edema/tratamiento farmacológico , Etodolaco/síntesis química , Profármacos/síntesis química , Úlcera Gástrica/inducido químicamente , ortoaminobenzoatos/síntesis química , Animales , Antiinflamatorios/farmacología , Diseño de Fármacos , Estabilidad de Medicamentos , Etodolaco/farmacología , Femenino , Humanos , Concentración de Iones de Hidrógeno , Hidrólisis , Cinética , Hígado/metabolismo , Masculino , Estructura Molecular , Plasma/metabolismo , Profármacos/farmacología , Ratas , Ratas Wistar , Úlcera Gástrica/prevención & control , Relación Estructura-Actividad , Temperatura , ortoaminobenzoatos/farmacología
10.
Arch Pharm (Weinheim) ; 352(8): e1900002, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31353608

RESUMEN

A series of 1,2,4-triazolo[1,5-a]pyrimidine derivatives was designed, synthesized, and screened for their phosphodiesterase (PDE 4B) inhibitory activity and bronchodilation ability. Compound 7e showed 41.80% PDE 4B inhibition at 10 µM. Eight compounds were screened for their bronchodilator activity, where compounds 7f and 7e elicited promising bronchodilator activity with EC50 values of 18.6 and 57.1 µM, respectively, compared to theophylline (EC50 = 425 µM). Molecular docking at the PDE 4B active site revealed a binding mode and docking scores comparable to those of a reference ligand, consistent with their PDE 4B inhibition activity.


Asunto(s)
Broncodilatadores/farmacología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Diseño de Fármacos , Músculo Liso/efectos de los fármacos , Inhibidores de Fosfodiesterasa 4/farmacología , Pirimidinas/farmacología , Tráquea/efectos de los fármacos , Triazoles/farmacología , Animales , Broncodilatadores/síntesis química , Broncodilatadores/química , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Simulación del Acoplamiento Molecular , Estructura Molecular , Contracción Muscular/efectos de los fármacos , Inhibidores de Fosfodiesterasa 4/síntesis química , Inhibidores de Fosfodiesterasa 4/química , Pirimidinas/síntesis química , Pirimidinas/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Triazoles/síntesis química , Triazoles/química
11.
Eur J Med Chem ; 171: 332-342, 2019 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-30928706

RESUMEN

New pyrazole derivatives 2-5 were synthesized and evaluated for their COX-1 and COX-2 inhibitory activity in vitro. All compounds showed good inhibitory activity at a nanomolar level and most compounds exhibited selectivity towards COX-2 inhibition. Compounds 2a, 3b, 4a, 5b and 5e exhibited IC50 towards COX-2 enzyme of 19.87, 39.43, 61.24, 38.73 and 39.14 nM, respectively. Furthermore, compounds 3b, 4a, 5b and 5e exhibited a selectivity index of 22.21, 14.35, 17.47 and 13.10, respectively. The most active compounds were further subjected to in vivo anti-inflammatory assay. The tested compounds showed better or comparable activity to celecoxib as positive control. In order to explore their binding mode and selectivity behaviour, molecular docking in the active site of COX-2 was carried out for these derivatives. Analysis of the docked poses of the compounds showed that they adopt similar conformations to the highly selective COX-2 inhibitor, SC-558. The docking pose of compound 3b was confirmed by molecular dynamics. All the tested compounds exhibited potent inhibitory effect on the production of PGE2, in addition to their inhibition of COX-2 enzyme.


Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa/farmacología , Microsomas/efectos de los fármacos , Prostaglandina-Endoperóxido Sintasas/metabolismo , Pirazoles/farmacología , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Inhibidores de la Ciclooxigenasa/síntesis química , Inhibidores de la Ciclooxigenasa/química , Relación Dosis-Respuesta a Droga , Humanos , Microsomas/enzimología , Simulación del Acoplamiento Molecular , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Relación Estructura-Actividad
12.
Future Med Chem ; 10(1): 27-52, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-29235893

RESUMEN

AIM: In spite of the availability of different chemotherapies for cancer treatment, there is still a need for new candidates with higher efficacy and lower toxicity. METHODOLOGY: Aurones 7a-f, 8a-f and furoaurones 13a-f, 16a-c were synthesized. Some compounds were selected by the National Cancer Institute, USA, for cytotoxicity screening. RESULTS & DISCUSSION: The furoaurone derivative, 13a was the most active one exhibiting promising growth inhibition against leukemia, K562 and melanoma, MDA-MB-435 cells at concentration of 10 µM. It induced apoptosis in both cell lines by activation of CASP3 and inhibition of CDK2. Additionally, 13a showed good selectivity over normal kidney and liver cells. Simulation docking study was undertaken to gain insight into the possible binding mode of 13a in the CDK2 enzyme. CONCLUSION: The furoaurone 13a can be considered as a scaffold for further optimization to obtain more active hits. Graphical abstract [Formula: see text].


Asunto(s)
Antineoplásicos/farmacología , Benzofuranos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Benzofuranos/síntesis química , Benzofuranos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad
13.
Eur J Med Chem ; 138: 565-576, 2017 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-28704759

RESUMEN

A series of novel pyrazolo[3,4-d]pyrimidines bearing benzenesulfonamide moiety 5a-f, 6 and 7 were synthesized. Cytotoxic screening was conducted against MCF-7 and HepG2. 6-(4-Methoxyphenyl)-4-oxopyrazolopyrimidine derivative 5e and 4-imino-6-oxopyrazolopyrimidine derivative 6 revealed potent cytotoxic activity with IC50 1.4 µM (MCF-7) and 0.4 µM (HepG2), respectively compared to that of doxorubicin, (IC50 = 1.02 µM and 0.9 µM, respectively). Compounds 5e and 6 were subjected to cell cycle analysis and apoptosis assay after 24 h and 48 h treatment. Compound 5e arrested cell at G1 phase, while 6 arrested cell at S and G2/M phases, respectively. The apoptotic effect of both compounds were evidenced by pre G1 apoptosis as its percentage increased by time (7.38%, 11.61%) and (13.92%, 16.71%), respectively. Apoptosis induction capability was confirmed by the effect on early and late apoptosis and augmentation of caspase-3 level. Furthermore, compound 6 inhibited CDK2 enzyme with IC50 = 0.19 µM and increased levels of its regulators, P21 and P27 by 10.06% and 8.5%, respectively. Moreover, a molecular docking study of compound 6 on CDK2 enzyme was adopted to explore binding interaction with amino acid residues of its active site.


Asunto(s)
Antineoplásicos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Pirimidinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Quinasa 2 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 2 Dependiente de la Ciclina/metabolismo , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células Hep G2 , Humanos , Células MCF-7 , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirazoles/síntesis química , Pirazoles/química , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-Actividad
14.
Artículo en Inglés | MEDLINE | ID: mdl-28622543

RESUMEN

Four simple, accurate, sensitive and economic Attenuated Total Reflectance-Fourier Transform Infrared Spectroscopic (ATR-FTIR) methods have been developed for the quantitative estimation of some non-steroidal anti-inflammatory drugs. The first method involves the determination of Etodolac by direct measurement of the absorbance at 1716cm-1. In the second method, the second derivative of the IR spectra of Tolfenamic acid and its reported degradation product (2-chlorobenzoic acid) was used and the amplitudes were measured at 1084.27cm-1 and 1056.02cm-1 for Tolfenamic acid and 2-chlorobenzoic acid, respectively. The third method used the first derivative of the IR spectra of Bumadizone and its reported degradation product, N,N-diphenylhydrazine and the amplitudes were measured at 2874.98cm-1 and 2160.32cm-1 for Bumadizone and N,N-diphenylhydrazine, respectively. The fourth method depends on measuring the amplitude of Diacerein at 1059.18cm-1 and of rhein, its reported degradation product, at 1079.32cm-1 in their first derivative spectra. The four methods were successfully applied on the pharmaceutical formulations by extracting the active constituent in chloroform and the extract was directly measured in liquid phase mode using a specific cell. Moreover, validation of these methods was carried out following International Conference of Harmonisation (ICH) guidelines.


Asunto(s)
Antiinflamatorios no Esteroideos/análisis , Antiinflamatorios no Esteroideos/química , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Espectroscopía Infrarroja por Transformada de Fourier/normas , Clorobenzoatos/análisis , Clorobenzoatos/química , Cloroformo , Etodolaco/análisis , Etodolaco/química , Modelos Químicos , Sensibilidad y Especificidad , ortoaminobenzoatos/análisis , ortoaminobenzoatos/química
15.
Eur J Med Chem ; 90: 221-31, 2015 Jan 27.
Artículo en Inglés | MEDLINE | ID: mdl-25461322

RESUMEN

Based on the reported anticancer activity of coumarin and pyrazoline derivatives, the present investigation dealt with the design and synthesis of coumarin derivatives bearing diversely substituted pyrazoline moieties 7-10. The non-cyclic isosteres 11a-e of compounds 10a-e were synthesized for comparative reasons. The target compounds were synthesized from 8-acetyl-7-methoxycoumarin that underwent Claisen-Schmidt condensation with various aldehydes to give the chalcones 6a-e, followed by reaction with hydrazine hydrate, phenyl hydrazine or semicarbazide under the appropriate conditions. Cytotoxicity of the synthesized compounds was evaluated in vitro against liver HepG2 cell line. Compounds were active in the nanomolar range. The most active compounds were investigated for their telomerase inhibition and proapoptotic activities.


Asunto(s)
Antineoplásicos/farmacología , Cromonas/farmacología , Inhibidores Enzimáticos/farmacología , Telomerasa/antagonistas & inhibidores , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cromonas/síntesis química , Cromonas/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Células Hep G2 , Humanos , Estructura Molecular , Relación Estructura-Actividad , Telomerasa/metabolismo
16.
Eur J Med Chem ; 60: 187-98, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23291120

RESUMEN

Two groups of coumarin-pyrazoline hybrids were synthesized. The target compounds were obtained by cyclization of the coumarin chalcones with various substituted hydrazines to produce the corresponding pyrazolines through 1,4-addition on α,ß-unsaturated carbonyl system. Selected compounds were investigated for their anticancer activity toward 60 cancer cell lines according to US NCI protocol where breast cancer MCF7 and colon cancer HCT-116 were the most susceptible to the influence of compounds 7d, 8c and 9c. Encouraged by this, all final compounds were screened against colorectal cell line HCT-116. The tested compounds exhibited high potency with IC(50) ranging from 0.01 µM to 2.8 µM. Moreover, compound 9c which possessed the highest cytotoxicity proved to have weak enzyme inhibitory activity against PI3K (p110α/p85α).


Asunto(s)
Antineoplásicos/farmacología , Cumarinas/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Cumarinas/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Humanos , Células MCF-7 , Estructura Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirazoles/química , Relación Estructura-Actividad
17.
Bioorg Med Chem ; 19(20): 6087-97, 2011 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-21908192

RESUMEN

The main objective of the present work depends on the hybridization of coumarin moiety as a vasorelaxant scaffold and pyrimidine ring with known potential cardiovascular activity in order to prepare some new potent antihypertensive candidates. Hence, two groups of pyrimidinyl coumarin derivatives were synthesized and evaluated for their vasorelaxing activity. These compounds were prepared via two routes; either preparation of the guanidinocoumarin 4 followed by a cocktail of cyclization reactions to yield a different array of 6-(substituted pyrimidin-2-yl)aminocoumarins 5-17, or through cyclization of the precursor chalcones 22a-g with guanidine hydrochloride to generate the corresponding final compounds, 8-(6-aryl-2-aminopyrimidin-4-yl)-7-methoxycoumarins 23a-g. The effect of these compounds and the coumarin intermediates 3, 4, 21 and 22a-g on nor-epinephrine induced contracture in thoracic rat aortic rings was investigated using prazocin as reference drug. Several derivatives showed promising activities either equal or even better than that of prazocin (IC(50) 0.487 mM). The most prospective compounds; the pyrimidinylamino coumarin derivatives 8, 17 (IC(50) 0.411, IC(50) 0.421 mM) and the chalcones 22b, 22e (IC(50) 0.371, 0.374 mM) that displayed the highest activity can be a base for lead optimization and simple but efficient design of new compounds. 2D-QSAR analysis was applied to find a correlation between the experimental vasorelaxant activities of the newly synthesized coumarin derivatives and their different physicochemical parameters. The result of this study showed that the increase in aqueous solubility while retaining good hydrophobic character of the overall molecule is the key for maintaining high relaxation activity.


Asunto(s)
Cumarinas/síntesis química , Cumarinas/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Vasodilatadores/síntesis química , Vasodilatadores/farmacología , Animales , Cumarinas/química , Masculino , Estructura Molecular , Pirimidinas/química , Ratas , Ratas Wistar , Relación Estructura-Actividad , Vasodilatadores/química
18.
Eur J Med Chem ; 45(9): 4104-12, 2010 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-20573425

RESUMEN

Ulcerative colitis is a chronically recurrent inflammatory bowel disease of unknown origin. The present work describes design and synthesis of 3-aminofurosalicylic acid 4, azo-conjugates with aniline 2a, 4-ASA 2b or sulphapyridine 2c as well as N-arylsulphonamido 5, chlorosulphonyl 6, aminosulphonyl 7 and N-arylaminosulphonyl derivatives 8 (positional isosters of 5). All the synthesized compounds were evaluated for their anti-ulcerogenic effect on acetic acid-induced ulcerative colitis in rats. It was noticed that oral treatment with sulphasalazine (a reference drug) and the tested compounds 2a, 2c, 4 and 5c in equimolar doses significantly reduced the intensity of lesion score, ulcer area, ulcer index and wet weight/length ratio compared to the control group. On the other hand, compounds 2b, 5a, 5b and 7 had a lower anti-ulcerogenic efficacy. Also, the antimicrobial activity of the synthesized compounds was screened in vitro using the agar diffusion assay technique. In addition, docking of the tested compounds into cycloxygenase II using molecular operating environment (MOE) was performed in order to rationalize the obtained biological results and their mechanism of action.


Asunto(s)
Benzofuranos/química , Colitis Ulcerosa/tratamiento farmacológico , Diseño de Fármacos , Ácido Salicílico/síntesis química , Ácido Salicílico/farmacología , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/química , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Araquidonato 5-Lipooxigenasa/metabolismo , Bacterias/efectos de los fármacos , Ciclooxigenasa 2/química , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/química , Inhibidores de la Ciclooxigenasa 2/farmacología , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Interacciones Hidrofóbicas e Hidrofílicas , Dosificación Letal Mediana , Inhibidores de la Lipooxigenasa/síntesis química , Inhibidores de la Lipooxigenasa/química , Inhibidores de la Lipooxigenasa/farmacología , Inhibidores de la Lipooxigenasa/uso terapéutico , Masculino , Ratones , Modelos Moleculares , Conformación Proteica , Ratas , Ácido Salicílico/química , Ácido Salicílico/uso terapéutico , Estómago/efectos de los fármacos
19.
Arch Pharm (Weinheim) ; 341(11): 725-33, 2008 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-18973170

RESUMEN

In an attempt to find a new class of antibacterial agents, we have synthesized thirty new coumarin (2H-benzopyran-2-one) analogues. These derivatives include substituted azetidin-2-ones (beta-lactam) 3a-f, pyrrolidin-2-ones 4a-f, 2H-1,3,4-oxadiazoles 5a-f, and thiazolidin-4-ones 6a-f attached to 4-phenyl-2H-benzopyran-2-one through an oxyacetamido or an oxymethyl bridge. The target compounds were synthesized starting from 2-oxo-4-phenyl-2H-benzo[b]pyran-7-yl-oxyacetic acid hydrazides 2a-f. The new compounds were evaluated as DNA gyrase-B inhibitors through molecular modeling and docking techniques using the Molsoft ICM 3.4-8C program. The synthesized compounds were also screened for antibacterial activity against four different species of Gram-positive and Gram-negative bacteria; as well as screening against C. albicans for antifungal activity. The molecular modeling data were in accordance with the antimicrobial screening results.


Asunto(s)
Antibacterianos/síntesis química , Cumarinas/síntesis química , Diseño de Fármacos , Inhibidores de Topoisomerasa II , Antibacterianos/farmacología , Candida albicans/efectos de los fármacos , Simulación por Computador , Cumarinas/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Modelos Moleculares , Unión Proteica
20.
Eur J Med Chem ; 42(8): 1117-27, 2007 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-17346862

RESUMEN

The synthesis of 9- and 6-alkylaminomethyl furoflavones 5a, b, 9a-c, 13a, b, 15a-g and 18 from the naturally occurring chromones visnagin and khellin. Gastroprotective potency of these compounds in the ethanol damage model was determined. The results indicate that, through appropriate substitution, furoflavones can be obtained that are gastroprotective.


Asunto(s)
Antiulcerosos/síntesis química , Flavonas/síntesis química , Sustancias Protectoras/síntesis química , Úlcera Gástrica/prevención & control , Animales , Antiulcerosos/farmacología , Cromonas/química , Etanol , Flavonas/farmacología , Khellin/análogos & derivados , Khellin/química , Sustancias Protectoras/farmacología , Ratas , Úlcera Gástrica/inducido químicamente , Relación Estructura-Actividad
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