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1.
BMC Chem ; 18(1): 208, 2024 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-39449145

RESUMO

New Series of N-Manniche bases 3,4 (a-c) and 5,6 (a-b) were synthesized through the reaction of benzaldehyde and amine with 3-methyl-4-(aryldiazenyl)-1H-pyrazol-5-ol derivatives 2(a-c), they were fully characterized by FT-IR, (1H, 13C) NMR data in addition to their mass spectra. The Structural Activity Relationship of the target compounds were examined for their cytotoxicity. Some newly synthesized compounds showed promising antiproliferation properties when tested against HepG2 cancer cells. Compounds 4a, 5a, and 6b showed potent cytotoxicity against HepG2 with IC50 values of 4.4, 3.46 and 2.52 µM compared to Sorafenib (IC50 = 2.051 µM) and Roscovitine (IC50 = 4.18 µM). Furthermore, they were safe against the THLE2 cells with higher IC50 values. Compound 6b exhibited promising dual VEGFR2/CDK-2 inhibition activities; it had an IC50 value of 0.2 µM with VEGFR2 inhibition of 93.2%, and it had an IC50 value of 0.458 µM with CDK-2 inhibition of 88.7%. In comparison to the untreated control group (0.95%), compounds 5a (38.32%) and 6b (42.9%) considerably increased the cell population in total apoptosis. In addition, compounds 5a and 6b arrested the cell population at G0-G1 and S phases, respectively. Molecular docking experiments confirmed the virtual binding mechanism of the most active drugs, which were found to have good binding affinities with both receptor active sites.

2.
RSC Med Chem ; 2024 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-39345715

RESUMO

VEGFR2 inhibition has been established as a therapeutic approach for managing cancer. A series of curcumin-based analogues were designed, synthesized, and screened for their anticancer activity against MCF-7 and HepG-2 cell lines and WISH normal cells. Compounds 4b, 4d, 4e, and 4f showed potent cytotoxicity against MCF-7 with IC50 values of 0.49, 0.14, 0.01, and 0.32 µM, respectively, compared to curcumin (IC50 = 13.8 µM) and sorafenib (IC50 = 2.13 µM). Interestingly, compound 4e, the most active compound, exhibited potent VEGFR2 inhibition with an IC50 value of 11.6 nM (96.5% inhibition) compared to sorafenib with an IC50 value of 30 nM (94.8% inhibition). Additionally, compound 4e significantly induced apoptotic cell death in MCF-7 cells by 41.1% compared to a control group (0.8%), halting cell division during the G2/M phase by 39.8% compared to the control (21.7%). Molecular docking-coupled dynamics simulations highlighted the bias of the VEGFR2 pocket towards compound 4e compared to other synthesized compounds. Predicting superior binding affinities and relevant interactions with the pocket's key residues recapitulated in vitro findings towards higher inhibition activity for compound 4e. Furthermore, compound 4e with adequate pharmacokinetic and drug-likeness profiles in terms of ADME and safety characteristics can serve as a promising clinical candidate for future lead optimization and development. Notably, 4e-Fe2O3-humic acid NPs exhibited potent cytotoxicity with IC50 values of 2.41 and 13.4 ng mL-1 against MCF-7 and HepG-2 cell lines, respectively. Hence, compound 4e and its Fe2O3-humic acid-NPs could be further developed as promising anti-breast cancer agents.

3.
Bioorg Chem ; 111: 104909, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33895603

RESUMO

In the present study, a novel generation of selective aldose reductase ALR2 inhibitors with significant hypoglycemic activities was designed and modulated based on rhodanine scaffold joined to an acetamide linker in between two lipophilic moieties. The synthesis of the novel compounds was accomplished throughout simple chemical pathways. Molecular docking was performed on B-cell membrane protein SUR1, aldehyde reductase ALR1 and aldose reductase ALR2 active sites. Compounds 10B, 11B, 12B, 15C, 16C, 26F and 27F displayed the highest hypoglycemic activities with 80.7, 85.2, 87, 82.3, 83.5, 81.4 and 85.3% reduction in blood glucose levels, respectively. They were more potent than the standard hypoglycemic agent repaglinide with 65.4% reduction in blood glucose level. Compounds 12B and 15C with IC50 0.29 and 0.35 µM were more potent than the standard ALR2 inhibitor epalrestat with IC50 0.40 µM. They were selective towards ALR2 over ALR1 134 and 116 folds, respectively. Molecular docking studies matched with the in-vitro and in-vivo results to elucidate the dual activities of both compounds 12B and 15C as potent antagonists for ALR2 over ALR1 and good agonists for the SUR1 protein.


Assuntos
Aldeído Redutase/antagonistas & inibidores , Benzamidas/farmacologia , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Aldeído Redutase/metabolismo , Benzamidas/síntese química , Benzamidas/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
4.
Pharmaceuticals (Basel) ; 14(1)2020 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-33374155

RESUMO

Dual targeting of epidermal growth factor receptor (EGFR) and human EGFR-related receptor 2 (HER2) is a proven approach for the treatment of lung cancer. With the aim of discovering effective dual EGFR/HER2 inhibitors targeting non-small cell lung cancer cell line H1299, three series of thieno[2,3-d][1,2,3]triazine and acetamide derivatives were designed, synthesized, and biologically evaluated. The synthesized compounds displayed IC50 values ranging from 12 to 54 nM against H1299, which were superior to that of gefitinib (2) at 40 µM. Of the synthesized compounds, 2-(1H-pyrazolo[3,4-b]pyridin-3-ylamino)-N-(3-cyano4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)acetamide (21a) achieved the highest in vitro cytotoxic activity against H1299, with an IC50 value of 12.5 nM in situ, and 0.47 and 0.14 nM against EGFR and HER2, respectively, values comparable to the IC50 of the approved drug imatinib (1). Our synthesized compounds were promising, demonstrating high selectivity and affinity for EGFR/HER2, especially the hinge region forming a hydrophobic pocket, which was mediated by hydrogen bonding as well as hydrophobic and electrostatic interactions, as indicated by molecular modeling. Moreover, the designed compounds showed good affinity for T790M EGFR, one of the main mutants resulting in acquired drug resistance. Furthermore, both pharmacokinetic and physicochemical properties of the designed compounds were within the appropriate range for human usage as predicted by the in Silico ADME study. The designed compound (21a) might serve as an encouraging lead compound for the discovery of promising anti-lung cancer agents targeting EGFR/HER2.

5.
Arch Pharm (Weinheim) ; 353(2): e1900108, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31894866

RESUMO

Two series of thieno[2,3-d][1,2,3]triazine derivatives were designed, synthesized, and biologically evaluated as potential epidermal growth factor receptor (EGFR) inhibitors targeting the non-small-cell lung cancer cell line H1299. Most of the synthesized compounds displayed IC50 values ranging from 25 to 58 nM against H1299, which are superior to that of gefitinib (40 µM). 3-(5,6,7,8-Tetrahydro-7H-cyclohexa[4:5]thieno[2,3-d]-1,2,3-triazin-4-ylamino)benzene-1,3-diamine (6b) achieved the highest cytotoxic activity against H1299 with an IC50 value of 25 nM; it had the ability to decrease the EGFR concentration in H1299 cells from 7.22 to 2.67 pg/ml. In vitro, the IC50 value of compound 6b was 0.33 nM against EGFR, which is superior to that of gefitinib at 1.9 nM and erlotinib at 4 nM. The three-dimensional quantitative structure-activity relationships and molecular modeling studies revealed comparable binding modes of compound 6b, gefitinib, and erlotinib in the EGFR active site. The in silico ADME (absorption, distribution, metabolism, and excretion) prediction parameters of this compound revealed promising pharmacokinetic and physicochemical properties. Moreover, DFT (density functional theory) calculations showed the high reactivity of compound 6b toward the EGFR compared with other compounds. The designed compound 6b might serve as an encouraging lead compound for the discovery of promising anti-lung cancer agents targeting EGFR.


Assuntos
Antineoplásicos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Relação Quantitativa Estrutura-Atividade , Triazinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Modelos Moleculares , Estrutura Molecular , Triazinas/síntese química , Triazinas/química , Células Tumorais Cultivadas
6.
Bioorg Med Chem ; 27(15): 3383-3389, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31221611

RESUMO

Novel non-sulfonylureas derivatives bearing an acetamide linker between a spirohydantoin scaffold and a phenyl ring were prepared and their hypoglycemic activity was estimated in vivo. Their abilities to discriminate in vitro between aldehyde reductase (ALR1) and aldose reductase (ALR2) were determined. The molecular docking and the in silico prediction studies were performed to rationalize the obtained biological results and to predict the physicochemical properties and drug-likeness scores of the new compounds. N-(2,4-Dichlorophenyl)-2-(2',4'-dioxospiro[fluorene-9,5'-imidazolidine]-3'-yl)acetamide (3e) displayed an 84% reduction in blood glucose level superior to that of repaglinide 66% and showed an IC50 value of 0.37 µM against ALR2 that is superior to that of sorbinil 3.14 µM. Compound (3e) was selective 96 fold towards ALR2 which is closely related to serious diabetic complications. Based on the identification of this hit candidate, a new generation of safe and effective antidiabetic agents could be designed.


Assuntos
Aldeído Redutase/antagonistas & inibidores , Complicações do Diabetes/tratamento farmacológico , Diabetes Mellitus Experimental/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Hipoglicemiantes/farmacologia , Compostos de Sulfonilureia/farmacologia , Aldeído Redutase/metabolismo , Animais , Complicações do Diabetes/metabolismo , Diabetes Mellitus Experimental/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Compostos de Sulfonilureia/síntese química , Compostos de Sulfonilureia/química
7.
Bioorg Chem ; 79: 131-144, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29751319

RESUMO

Novel derivatives of spiroimidazolidinedione were synthesized and evaluated as hypoglycemic agents through binding to sulfonylurea receptor 1 (SUR1) in pancreatic beta-cells. Their selectivity index was calculated against both aldehyde reductase (ALR1) and aldose reductase (ALR2). Aldehyde reductase is a key enzyme in the polyol pathway that is involved in the etiology of the secondary diabetic complications. All structures were confirmed by microanalysis and by IR, 1H NMR, 13C NMR and EI-MS spectroscopy. The investigated compounds were subjected to molecular docking and an in silico prediction study to determine their free energy of binding (ΔG) values and predict their physicochemical properties and drug-likeness scores. Compound 1'-(5-chlorothiophene-2-ylsulfonyl)spiro[cyclohexane-1,5'-imidazolidine]-2',4'-dione showed IC50 0.47 µM and 79% reduction in blood glucose level with a selectivity index 127 for ALR2.


Assuntos
Aldeído Redutase/antagonistas & inibidores , Inibidores Enzimáticos/química , Hidantoínas/química , Hipoglicemiantes/química , Sulfonamidas/química , Aldeído Redutase/química , Animais , Domínio Catalítico , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular
8.
J Med Chem ; 60(24): 10257-10267, 2017 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-29185746

RESUMO

Three series of biarylpyrazole imidazole and triazoles are described, which vary in the linker between the biaryl pyrazole and imidazole/triazole group. The imidazole and triazole series with the short -CH2- linker displayed promising antimycobacterial activity, with the imidazole-CH2- series (7) showing low MIC values (6.25-25 µg/mL), which was also influenced by lipophilicity. Extending the linker to -C(O)NH(CH2)2- resulted in a loss of antimycobacterial activity. The binding affinity of the compounds with CYP121A1 was determined by UV-visible optical titrations with KD values of 2.63, 35.6, and 290 µM, respectively, for the tightest binding compounds 7e, 8b, and 13d from their respective series. Both binding affinity assays and docking studies of the CYP121A1 inhibitors suggest type II indirect binding through interstitial water molecules, with key binding residues Thr77, Val78, Val82, Val83, Met86, Ser237, Gln385, and Arg386, comparable with the binding interactions observed with fluconazole and the natural substrate dicyclotyrosine.


Assuntos
Inibidores das Enzimas do Citocromo P-450/química , Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/química , Mycobacterium tuberculosis/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Antituberculosos/química , Antituberculosos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Inibidores das Enzimas do Citocromo P-450/síntese química , Sistema Enzimático do Citocromo P-450/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Pirazóis/química , Bibliotecas de Moléculas Pequenas/farmacologia , Espectrofotometria Ultravioleta
9.
Arch Pharm (Weinheim) ; 350(9)2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28792072

RESUMO

Some novel 2,6-disubstituted pyridazine-3(2H)-one derivatives were synthesized and evaluated for in vitro cyclooxygenase-2 (COX-2) inhibitory efficacy. Compounds 2-{[3-(2-methylphenoxy)-6-oxopyridazin-1(6H)-yl]methyl}-1H-isoindole-1,3(2H)-dione (5a), 2-propyl-6-(o-tolyloxy)pyridazin-3(2H)-one (6a), and 2-benzyl-6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridazin-3(2H)-one (16a) showed the most potent COX-2 inhibitory activity with IC50 values of 0.19, 0.11, and 0.24 µM, respectively. The synthesized compounds with the highest COX-2 selectivity indices were evaluated for their anti-inflammatory, analgesic, and ulcerogenic activities. Compounds 6a and 16a demonstrated the most potent and consistent anti-inflammatory activity over the synthesized compounds, which was significantly higher than that of celecoxib in the carrageenin rat paw edema model and with milder ulcer scoring than that of indomethacin in the ulcerogenicity screening.


Assuntos
Analgésicos não Narcóticos/síntese química , Analgésicos não Narcóticos/farmacologia , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Piridazinas/síntese química , Piridazinas/farmacologia , Úlcera Gástrica/induzido quimicamente , Analgésicos não Narcóticos/toxicidade , Animais , Anti-Inflamatórios não Esteroides/toxicidade , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Edema/induzido quimicamente , Edema/prevenção & controle , Masculino , Ratos
10.
Bioorg Med Chem Lett ; 27(11): 2377-2383, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28427813

RESUMO

COX-2 is an inducible enzyme mediating inflammatory responses. Selective targeting of COX-2 is useful for developing anti-inflammatory agents devoid of ulcerogenic activity. Herein, we report the design and synthesis of a series of pyrazoles and pyrazolo[1,2-a]pyridazines with selective COX-2 inhibitory activity and in vivo anti-inflammatory effect. Both series were accessed through acid-catalyzed ultrasound-assisted reactions. The most active compounds in this study are two novel molecules, 11 and 16, showing promising selectivity and decent IC50 of 16.2 and 20.1nM, respectively. These compounds were also docked into the crystal structure of COX-2 enzyme (PDB ID: 3LN1) to understand their mode of binding. Finally, Mulliken charges and electrostatic surface potential were calculated for both compound 11 and celecoxib using DFT method to get insights into the molecular determinants of activity of this compound. These results could lead to the development of novel COX-2 inhibitors with improved selectivity.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Pirazóis/farmacologia , Piridazinas/farmacologia , Quinonas/farmacologia , Ondas Ultrassônicas , Animais , Anti-Inflamatórios não Esteroides/síntese química , Sítios de Ligação/efeitos dos fármacos , Celecoxib/química , Ciclização , Inibidores de Ciclo-Oxigenase 2/síntese química , Ensaios Enzimáticos , Interações Hidrofóbicas e Hidrofílicas , Simulação de Acoplamento Molecular , Pirazóis/síntese química , Piridazinas/síntese química , Teoria Quântica , Quinonas/síntese química , Spodoptera
11.
Pak J Pharm Sci ; 27(4): 885-92, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25015456

RESUMO

Methods for the synthesis of new heterocyclic systems of thieno (3,2-d)- (1,2,3)-triazine derivatives and N-(3-cyano-5,6-dihydro-4H-cyclopenta (b) thiophene derivatives have been developed. The newly synthesized compounds were tested in vitro against human breast carcinoma cell line (MCF-7). Compounds 7 and 9 have shown the highest activity among the two synthesized series. The results of this study have led to the identification of two lead compounds with good inhibitory activities that can confirm the design of the next generation inhibitors of tyrosine kinase with fewer side effects such as hepatotoxicity and resistance.


Assuntos
Antineoplásicos/síntese química , Tiofenos/síntese química , Antineoplásicos/farmacologia , Humanos , Células MCF-7 , Espectroscopia de Ressonância Magnética , Proteínas Tirosina Quinases/antagonistas & inibidores , Relação Estrutura-Atividade , Tiofenos/farmacologia
12.
Chem Pharm Bull (Tokyo) ; 62(7): 675-94, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24990505

RESUMO

Cobalamin-dependant cytosolic enzyme methionine synthase (MetS) catalyses the transfer of a methyl group from the methyltetrahydrofolate (MTHF) to homocysteine (Hcy) to produce methionine and tetrahydrofolate (THF). MetS is over-expressed in the cytosol of certain breast and prostate tumour cells. Methionine used as a source of one carbon atom for the building of the DNA of the tumour cells, structural protein and enzymes. In this study, we designed, synthesized and evaluated the cytotoxic activity of a series of substituted methyl 2-(2-(4-oxo-3-aryl-3,4-dihydroquinazolin-2-ylthio)acetamido)acetate and dipeptide that mimic the substructure of MTHF. These inhibitors were docked in to the MTHF binding domain in such the same way as MTHF in its binding domain. The free energies of the binding were calculated and compared to the IC50 values. This series has been developed by dicyclohexylcarbodiimide (DCC) and azide coupling methods of amino acid esters with carboxylic acid derivatives, respectively. Compound methyl 3-hydroxy-2-(2-(3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylthio)acetamido)propanoate exhibited the highest IC50 value 20 µg/mL against PC-3 cell line and scored the lowest free energy of the binding (-207.19 kJ/mol).


Assuntos
5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/antagonistas & inibidores , Antineoplásicos/síntese química , Inibidores Enzimáticos/síntese química , Simulação de Acoplamento Molecular , Quinazolinas/química , 5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/metabolismo , Antineoplásicos/química , Antineoplásicos/toxicidade , Sítios de Ligação , Linhagem Celular Tumoral , Bases de Dados de Proteínas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/toxicidade , Ácido Fólico/análogos & derivados , Ácido Fólico/química , Ácido Fólico/metabolismo , Humanos , Cinética , Fígado/enzimologia , Estrutura Terciária de Proteína , Termodinâmica
13.
Chem Pharm Bull (Tokyo) ; 62(5): 454-66, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24789927

RESUMO

In this study, four series of 4-anilinoquinazoline derivatives were designed and synthesized as potential anti-proliferative agents. Mechanism of anticancer activity was explained through molecular docking of the target compounds into epidermal growth factor receptor tyrosine kinase (EGFR-TK) active site which displayed comparable binding mode of certain compounds to that of lapatinib. Moreover, the newly synthesized compounds were tested for their anti-proliferative activity on breast carcinoma cell line (MCF-7). 6-(4-Benzylpiperazin-1-ylsulfonyl)-4-(4-bromoanilino)quinazoline (14g) exhibited the most potent inhibitory activity (IC50=5.52 µM).


Assuntos
Antineoplásicos/farmacologia , Receptores ErbB/antagonistas & inibidores , Modelos Moleculares , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Domínio Catalítico/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/metabolismo , Humanos , Células MCF-7 , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Quinazolinas/síntese química , Quinazolinas/química , Relação Estrutura-Atividade
14.
Bioorg Med Chem ; 22(1): 550-8, 2014 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-24268539

RESUMO

Methionine synthase catalyzes the transfer of a methyl group from 5-methyltetrahydrofolate to homocysteine, producing methionine and tetrahydrofolate. Benzimidazole and deazatetrahydrofolates derivatives have been shown to inhibit methionine synthase by competing with the substrate 5-methyltetrahydrofolate. In this study, a novel series of substituted benzimidazoles and quinoxalines were designed and assessed for inhibitory activity against purified rat liver methionine synthase using a radiometric enzyme assay. Compounds 3g, 3j, and 5c showed the highest activity against methionine synthase (IC50: 20 µM, 18 µM, 9 µM, respectively). Kinetic analysis of these compounds using Lineweaver-Burk plots revealed characteristics of mixed inhibition for 3g and 5c; and uncompetitive inhibition for 3j. Docking study into a homology model of the rat methionine synthase gave insights into the molecular determinants of the activity of this class of compounds. The identification of these drug-like inhibitors could lead the design of the next generation modulators of methionine synthase.


Assuntos
5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/química , Benzimidazóis/síntese química , Proteínas Fúngicas/química , Quinoxalinas/síntese química , 5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/genética , 5-Metiltetra-Hidrofolato-Homocisteína S-Metiltransferase/metabolismo , Animais , Benzimidazóis/química , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Metionina/metabolismo , Modelos Moleculares , Quinoxalinas/química
15.
Arch Pharm Res ; 36(6): 671-83, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23543653

RESUMO

Novel 4-(4-bromophenyl)phthalazine derivatives connected via an alkyl spacer to amine or N-substituted piperazine were designed and synthesized as promising α-adrenoceptor antagonists. The structures of the phthalazine derivatives were established using elemental and spectral analyses. Twelve of the tested compounds displayed significant α-blocking activity. Molecular modeling studies were performed to rationalize the biological results. Among the tested compounds, 7j displayed the best-fitting score and the highest in vitro activity.


Assuntos
Antagonistas Adrenérgicos alfa/farmacologia , Modelos Moleculares , Ftalazinas/farmacologia , Antagonistas Adrenérgicos alfa/síntese química , Antagonistas Adrenérgicos alfa/química , Animais , Humanos , Ftalazinas/síntese química , Ftalazinas/química , Coelhos , Relação Estrutura-Atividade
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