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1.
Eur J Med Chem ; 80: 439-46, 2014 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-24796884

RESUMO

The amino acid-conjugates (1a-k) with eleven amino acids attached to primary amine of (S)-1-[1-(4-aminobenzoyl)-2,3-dihydro-1H-indol-6-sulfonyl]-4-phenyl-imidazolidin-2-one (DW2282, 1) were prepared and studied for their prodrug characteristics and anti-cancer activity against SW620 cell line. All the amino acid derivatives showed not only improved water solubility but also displayed potent anti-cancer activity in vitro. Among these amino acid-conjugates the compounds, DW2282-L-Ala (1b), DW2282-L-Phe (1e), DW2282-L-Leu (1g) and DW2282-L-Met (1h) showed good reconversion within 8 h (104.76%, 84.03%, 95.02% and 78.34%, respectively) to the parent drug in human plasma. In addition, the compounds 1e, 1g and 1j also showed good bioavailability profile along with potent in vivo anticancer activity.


Assuntos
Aminoácidos/química , Imidazóis/química , Imidazóis/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Sulfonas/química , Sulfonas/farmacologia , Água/química , Aminas/química , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Estabilidade de Medicamentos , Humanos , Imidazóis/metabolismo , Imidazóis/farmacocinética , Camundongos , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacocinética , Solubilidade , Sulfonas/metabolismo , Sulfonas/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Bioorg Med Chem ; 21(9): 2543-50, 2013 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-23523388

RESUMO

A novel series of chromenone analogs were synthesized and evaluated for their inhibitory activity against interleukin-5. Among them 5-(cyclohexylmethoxy)-3-[3-hydroxy-3-(4-hydroxyphenyl)propyl]-4H-chromen-4-one (9b, 94% inhibition at 30 µM, IC(50) = 4.0 µM) and 5-(cyclohexylmethoxy)-3-[3-hydroxy-3-(4-methoxyphenyl)propyl]-4H-chromen-4-one (9c, 94% inhibition at 30 µM, IC(50) = 6.5 µM) showed the most potent activity. According to the SAR studies introduction of propanone unit in between chromenone and ring B as in 5-(cyclohexylmethoxy)-3-[3-(4-phenyl)-3-oxopropyl]-4H-chromen-4-ones (8) moderately increased the activity. However, the reduction of these propanones 8 to propanols 9 remarkably enhanced the activity. A small substituent at position 4 of ring B in 9, especially with hydrogen bonding capability, provides favorable contribution. Disappearance of IL-5 inhibitory activity upon saturation of chroman-4-one of 9 to chroman-4-ones 10 proves the critical importance of planar chromen-4-one unit of this scaffold in the IL-5 inhibition.


Assuntos
Cromonas/farmacologia , Desenho de Fármacos , Interleucina-5/antagonistas & inibidores , Cromonas/síntese química , Cromonas/química , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
3.
Eur J Med Chem ; 59: 31-8, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23202848

RESUMO

A series of (E)-5-alkoxy-3-(3-phenyl-3-oxoprop-1-enyl)-4H-chromen-4-ones (4) and (E)-5-alkoxy-3-(3-hydroxy-3-phenylprop-1-enyl)-4H-chromen-4-ones (5) were synthesized and evaluated for their IL-5 inhibitory activity. Propenone analogs 4 possess some of the structurally important characteristics of isoflavone 2 and chalcone 3 previously known as potent IL-5 inhibitor. However, the inhibitory activity of 4 was weak and therefore this structural hybridization appears to be ineffective for the design of IL-5 inhibitor. Meanwhile the potent activity profile of compounds 5 was discovered. This enhanced activity of 5 compared to 4 could be due to the effective location of hydroxyl group of allylic alcohol moiety of 5 in the 3D structure. The electron withdrawing substituents at position 4 of phenyl ring of 5 enhances the activity possibly due to an increase in the strength of hydrogen bonding property of hydroxyl group of allylic alcohol moiety.


Assuntos
Benzopiranos/síntese química , Interleucina-5/antagonistas & inibidores , Benzopiranos/química , Benzopiranos/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cumarínicos/síntese química , Cumarínicos/química , Cumarínicos/farmacologia , Humanos , Concentração Inibidora 50 , Ligação Proteica/efeitos dos fármacos , Relação Estrutura-Atividade
4.
Bioorg Med Chem ; 20(19): 5757-62, 2012 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-22954899

RESUMO

Hydroxyethylaminomethyl-4H-chromenones were previously discovered as fairly strong IL-5 inhibitor. For determination of detail structure activity relationship, N-substituted hydroxyethylaminomethylchromenones 4a-n were prepared and evaluated for their IL-5 inhibitory activity. Shifting the hydrophobic group to nitrogen from 1-position of hydroxyethylamino moiety of hydroxyethylaminomethyl-4H-chromenones enhances the activity. The increment in bulkiness or hydrophobicity of alkyl side chain at amino group increases the activity. The same level of activity of 5-(cyclohexylmethoxy)-3-(N-benzyl-2-hydroxyethylaminomethyl)-4H-chromenone analogs regardless of hydrophobic or hydrophilic substituents at 4th position of phenyl ring might infer the existence of tunnel structure in the putative receptor for accepting these side chains.


Assuntos
Benzopiranos/química , Benzopiranos/farmacologia , Interleucina-5/antagonistas & inibidores , Asma/tratamento farmacológico , Humanos , Modelos Moleculares , Relação Estrutura-Atividade
5.
Bioorg Med Chem Lett ; 22(14): 4523-7, 2012 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-22738641

RESUMO

To investigate the anti-proliferative effect of a newly discovered NF-kB inhibitor, 6,6-dimethyl-2-(phenylimino)-6,7-dihydrobenzo[d][1,3]oxathiol-4(5H)-one (1a), a series of its analogs (1b-n) were prepared and evaluated for their NF-κB inhibition and anti-proliferative activity against various human cancer cell lines. Slight variation of hydrophobicity by replacement of dimethyl group of 1a at 6-position with bulky isopropyl group and introduction of para-fluoro substitution on 2-phenyl group showed good NF-κB inhibitory activity and anti-proliferative activity. However, excessive increase in hydrophobicity with 2,4,6-trichloro substituents on phenyl group resulted in the loss of both the activities. From the SAR results, 2-phenylimino-6,7-dihydrobenzo[d][1,3]oxathiol-4(5H)-one was identified as the lead scaffold for investigating new anticancer agent through inactivation of NF-κB.


Assuntos
Derivados de Benzeno/síntese química , Proliferação de Células/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Compostos de Sulfidrila/química , Derivados de Benzeno/farmacologia , Linhagem Celular Tumoral , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Compostos de Sulfidrila/farmacologia
6.
Eur J Med Chem ; 54: 379-86, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22677029

RESUMO

To define the structural features responsible for the activity of 2,4-dihydroxy-6-isopentyloxychalcone, a newly established inhibitor of LPS induced NF-κB activation (IC(50) = 10 µM), a series of its analogues was prepared and studied for their in vitro activities against LPS induced NF-κB inhibition in RAW 264.7 cells. Among the synthesized derivatives, (E)-1-(2-(decyloxy)-6-hydroxyphenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one (IC(50) = 2.7 µM) and (E)-1-(2-hydroxy-6-(tetradecyloxy)phenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one (IC(50) = 4.2 µM) showed the most potent inhibition. The SAR studies confirmed that the length (C(8)-C(14)) and C-6 position of linear alkyl chain of ring A is an important factor for the inhibitory activity. Hydroxyl group and its location at 4-position on ring B is also important for the inhibition. The α,ß-unsaturated ketone moiety appears as a crucial motif of chalcones for the activity.


Assuntos
Chalcona/química , Chalcona/farmacologia , Interações Hidrofóbicas e Hidrofílicas , NF-kappa B/antagonistas & inibidores , Fosfatase Alcalina/metabolismo , Animais , Linhagem Celular , Chalcona/síntese química , Chalcona/toxicidade , Desenho de Fármacos , Concentração Inibidora 50 , Lipopolissacarídeos/farmacologia , Camundongos , Relação Estrutura-Atividade
7.
J Pharm Biomed Anal ; 70: 567-73, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22703836

RESUMO

We investigated the pharmacokinetic profile of (R)- and (S)-zaltoprofen (ZPF) in rats using rapid and selective liquid chromatography with solid-phase extraction (SPE). The ZPF enantiomers were extracted from a small volume of plasma (0.2 mL) by means of SPE using cartridges and were analyzed on a Chiralcel OJ-H (4.6 mm × 150 mm, 5 µm) column with ultraviolet detection at 244 nm. The lower limit of quantification of the ZPF enantiomers in plasma was 0.1µg/mL. The validated method was successfully applied to chiral pharmacokinetic studies of oral administration of racemic ZPF to rats. (S)-ZPF showed significantly higher AUC, T(max), and C(max) and a longer half-life than (R)-ZPF, indicating higher bioavailability of the (S)-isomer. A total of 8 samples (about 12% of the total number of samples) were selected for incurred sample reanalysis (ISR). The % difference between the re-assay concentrations and the original concentrations were all less than 15% of their mean values and met the acceptance criteria for ISR.


Assuntos
Benzopiranos/farmacocinética , Cromatografia Líquida de Alta Pressão , Propionatos/farmacocinética , Extração em Fase Sólida , Administração Oral , Animais , Área Sob a Curva , Benzopiranos/administração & dosagem , Benzopiranos/sangue , Benzopiranos/química , Disponibilidade Biológica , Calibragem , Celulose/análogos & derivados , Celulose/química , Cromatografia Líquida de Alta Pressão/normas , Estabilidade de Medicamentos , Meia-Vida , Isomerismo , Limite de Detecção , Modelos Lineares , Taxa de Depuração Metabólica , Propionatos/administração & dosagem , Propionatos/sangue , Propionatos/química , Ratos , Ratos Sprague-Dawley , Padrões de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Extração em Fase Sólida/normas , Espectrofotometria Ultravioleta
8.
Bioorg Med Chem Lett ; 22(2): 886-9, 2012 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-22217872

RESUMO

2-(Naphthalen-1-ylmethylene)hydrazinecarbothioamide (14, IC(50)=1.1µM) was discovered as a highly potent inhibitor of melanogenesis. To define the role of hydrogens (at N1 and N3) and sulfur in 14, a series of analogs 15a-p were synthesized and evaluated for anti-melanogenic activity using melanoma B16 cells under the stimulus of α-MSH. It was observed that replacement of either of these hydrogens at N1 or N3 by substituents increases the activity significantly. Conversely, concomitant substitutions decrease the inhibitory potency. In addition, the presence of sulfur in thiosemicarbazone is essential for the activity.


Assuntos
Melaninas/biossíntese , Semicarbazidas/farmacologia , alfa-MSH/antagonistas & inibidores , Linhagem Celular Tumoral , Humanos , Estrutura Molecular , Semicarbazidas/síntese química , Semicarbazidas/química , Estereoisomerismo , Relação Estrutura-Atividade , alfa-MSH/metabolismo
9.
Chem Pharm Bull (Tokyo) ; 59(10): 1285-8, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21963640

RESUMO

Based on the hits, 3,4-dihydroquinazoline-2-thione (1) and benzimidazole-2-thione (2), a series of indole-2-thione (3) and indole-2-thiol inhibitors (4) of melanogenesis were designed, synthesized and evaluated in melanoma B16 cells under the stimulant of α-melanocyte stimulating hormone (α-MSH). The indole-2-thione compounds (3a-g) exhibited an effective inhibitory activity on melanin synthesis. The Structure-Activity Relationship (SAR) studies of 2 have revealed that in potent inhibitor 3a (>100% inhibition at 30 µM, IC50=1.40 µM) the role of nitrogen (3-N) at 3-position is insignificance. In addition, the hydrophobic substituents of 3 were better than the hydrophilic one. However, conversion of thione (-C=S, 3) to thiol (-C-SH, 4) led to decrease in the potency.


Assuntos
Descoberta de Drogas , Melaninas/fisiologia , alfa-MSH/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Indóis/química , Concentração Inibidora 50 , Melanoma Experimental/metabolismo , Terapia de Alvo Molecular , Relação Estrutura-Atividade , Tionas/química
10.
Bioorg Med Chem Lett ; 21(22): 6829-32, 2011 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-21983438

RESUMO

In an effort to find novel N-arylsulfonylimidazolidinones as highly potent anticancer agent, the structure-activity relationship of ethyl 2-methyl-4-(2-oxo-4-phenylimidazolidin-1-ylsulfonyl)phenylcarbamate was explored through synthesis and evaluation of in vitro cytotoxicity of its analogs against HCT116, A549 and NCL-H460 cancer cell lines. Among the synthesized derivatives, the carbamate analogs (4a-f and 4k-p) exhibited superior cytotoxicity to doxorubicin for all cancer cell lines. The SAR studies of these derivatives confirm that the intact 4-phenyl-l-benzenesulfonylimidazolidinone has a pivotal role as a basic pharmacophore and hydrophobic substitutions only at 2-position of 1-aminobenzenesulfonyl moiety are beneficial for the enhancement of the activity.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Imidazóis/química , Imidazóis/farmacologia , Sulfonas/química , Sulfonas/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Citotoxinas/síntese química , Citotoxinas/química , Citotoxinas/farmacologia , Humanos , Imidazóis/síntese química , Neoplasias/tratamento farmacológico , Relação Estrutura-Atividade , Sulfonas/síntese química
11.
Bioorg Med Chem Lett ; 21(22): 6824-8, 2011 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-21978680

RESUMO

Effect of a series of 1-phenylthioureas 1a-k and 1,3-disubstituted thioureas 2a-k were evaluated against melanin formation in melanoma B16 cell line and mushroom tyrosinase. Inhibitory activity of tyrosinase of 1-phenylthioureas 1a-k is parallel to their melanogenic inhibition. Thus, the melanogenic inhibition in melanoma B16 cells of 1-phenylthioureas could be the result of inhibition of tyrosinase. However, 1,3-diaryl or 1-phenyl-3-alkylthioureas, 2a-k, appears as melanogenic inhibitor without inhibition of tyrosinase. The molecular docking study of 1e and 2b to binding pocket of tyrosinase provided convincing explanation regarding the necessity of direct connection of planar phenyl to thiourea unit without N'-substitution of phenylthioureas 1 as tyrosinase inhibitor and 2 as non-tyrosinase inhibitor.


Assuntos
Melaninas/antagonistas & inibidores , Melaninas/metabolismo , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/metabolismo , Feniltioureia/análogos & derivados , Feniltioureia/farmacologia , Agaricales/enzimologia , Animais , Domínio Catalítico , Linhagem Celular Tumoral , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Melanoma Experimental/metabolismo , Modelos Moleculares , Monofenol Mono-Oxigenase/química
12.
Bioorg Med Chem Lett ; 21(12): 3527-30, 2011 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-21601449

RESUMO

A series of 2-(1-phenylalkylidene)hydrazinecarbothioamides 2, 2-(1-phenylalkyl)hydrazinecarbothioamides 3, 2-(3,4-dihydronaphthalen-1(2H)-ylidene)hydrazinecarbothioamide (4), and 2-(1-(thiophen-2-yl)ethylidene)hydrazinecarbothioamide (5) were synthesized for their melanogenesis inhibition in melanoma B16 cells. The SAR of these ketonethiosemicarbazones revealed that the benzylidene hydrogen in aldehydethiosemicarbazones 1 can be replaced by hydrophobic moiety and substitutions with alkyl group for the terminal amino hydrogen of ketonethiosemicarbazones improved the activity appreciably. In addition, the double bond in thiosemicarbazones is an important factor for the increment of hydrophobicity. Thus hydrophobic ketonethiosemicarbazones are excellent inhibitors of melanogenesis like aldehydethiosemicarbazones.


Assuntos
Melaninas/antagonistas & inibidores , Pigmentação/efeitos dos fármacos , Tiossemicarbazonas/química , Tiossemicarbazonas/farmacologia , Animais , Linhagem Celular Tumoral , Interações Hidrofóbicas e Hidrofílicas , Concentração Inibidora 50 , Cetonas/síntese química , Cetonas/química , Cetonas/farmacologia , Melaninas/biossíntese , Melanoma Experimental , Estrutura Molecular , Relação Estrutura-Atividade , Tiossemicarbazonas/síntese química
13.
Eur J Med Chem ; 46(8): 3258-64, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21570750

RESUMO

To define the SAR, a series of novel N-arylsulfonylimidazolidinone derivatives were evaluated for their in vitro anticancer activity against five human tumor cell lines, including A549, COLO205, KATO III, K562, SK-OV-3 and murine leukemia (P288D1) cell line. Among them, N-(2-chloroacetyl)-6-(2-oxo-4-phenylimidazolidin-1-ylsulfonyl)-3,4-dihydroquinoline-1(2H)-carboxamide (4m) and N-cyclohexyl-6-(2-oxo-4-phenylimidazolidin-1-ylsulfonyl)-3,4-dihydroquinoline-1(2H)-carboxamide (4n) exhibited comparable in vitro anticancer activity to doxorubicin against A549, KATO III and K562 cell lines and gave superior xenographic results against NCI-H23 and SW620 cancer cell lines. Regarding the structure-activity relationship, two critical points were discovered; the steric congestion at 4-position of N-arylsulfonylimidazolidinone scaffold abolishes the activity and the bulkiness or hydrophobicity of acyl groups at 3,4-dihydroquinoline of 4, especially with carbamoyl moiety, enormously enhances the activity.


Assuntos
Antineoplásicos/farmacologia , Sulfonatos de Arila/farmacologia , Neoplasias do Colo/tratamento farmacológico , Imidazolidinas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Sulfonatos de Arila/síntese química , Sulfonatos de Arila/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/patologia , Doxorrubicina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Imidazolidinas/síntese química , Imidazolidinas/química , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Conformação Molecular , Transplante de Neoplasias , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Relação Estrutura-Atividade
14.
Bioorg Med Chem Lett ; 21(7): 1922-5, 2011 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-21388810

RESUMO

Chalcone type compound 1a ((E)-6'-benzylidene-4a'-methyl-4',4a',7',8'-tetrahydro-3'H-spiro[[1,3]dithiolane-2,2'-naphthalen]-5'(6'H)-one) was discovered as an potent inhibitor in melanogenesis. To define its structure-activity relationship, a series of analogs 1b-n, dithiolane truncated 2a-b and ring A removed 3a-e were prepared and evaluated. The electron donating substitution on the phenyl ring (ring C) rather than an electron withdrawing group and dithiolane motif of 1 are needed for the activity enhancement. The scaffold containing both rings A and B associated with α,ß-unsaturated system connected to phenyl of 1 was essential for antimelanogenesis.


Assuntos
Melaninas/antagonistas & inibidores , Naftalenos/química , Naftalenos/farmacologia , Melaninas/biossíntese , Estrutura Molecular
15.
Bioorg Med Chem Lett ; 20(22): 6794-6, 2010 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-20863702

RESUMO

A series of thiosemicarbazones 2(e-s) have been synthesized and studied their structure-activity relationship as melanogenesis inhibitor. Among them, (Z)-2-(naphthalen-1-ylmethylene)hydrazinecarbothioamide (2q, >100% inhibition at 10 µM, IC(50)=1.1 µM, ClogP=3.039) showed the strongest inhibitory activity. Regarding their structure-activity relationship, the hydrophobic substituents regardless the position on phenyl ring of benzaldehyde thiosemicarbazones enhance the inhibitory activity. Furthermore, the aromatic group of benzaldehydethiosemicarbazones can be replaced with sterically bulky cyclohexyl. Thus, hydrophobicity of the aryl or alkyl group on hydrazine of thiosemicarbazones is determinant factor for their inhibitory activity in melanogenesis rather than planarity.


Assuntos
Melaninas/antagonistas & inibidores , Tiossemicarbazonas/química , Tiossemicarbazonas/farmacologia , Animais , Melaninas/biossíntese , Melanoma Experimental/patologia , Camundongos , Relação Estrutura-Atividade
16.
Bioorg Med Chem Lett ; 20(16): 4771-3, 2010 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-20638280

RESUMO

In order to define the structural requirements of quinazoline-2(1H)-thiones 1 for their inhibitory activity on melanogenesis, a novel series of 3,4-dihydroquinazoline-2(1H)-thiones (3a-h) were prepared and screened for their melanogenesis inhibition on melanoma B16 cell line under the stimulant of alpha-MSH. The anti-melanogenesis activity of 3 is mainly mediated by the hydrogen bonding ability of thioamide unit in addition to complexation ability of thione and the hydrophobic binding power of side chain substitutions at 3-position. Thus, the pharmacophore of 3,4-dihydroquinazoline-2(1H)-thiones for their anti-melanogenesis activity could be refined as 3-hydrophobic substituted quinazolinethione.


Assuntos
Melaninas/biossíntese , Tionas/química , Animais , Linhagem Celular Tumoral , Camundongos , Relação Estrutura-Atividade , Tionas/síntese química , Tionas/uso terapêutico , alfa-MSH/antagonistas & inibidores , alfa-MSH/metabolismo
17.
Bioorg Med Chem ; 18(13): 4625-9, 2010 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-20627591

RESUMO

A series of hydroxyalkylaminomethylchromone analogs 3 were prepared and evaluated as inhibitors of interleukin-5. The most active analog 3d inhibited interleukin-5 activity with an IC50 of 17.5 µM. The structural requirements of chromone analogs possessing the inhibitory activity against IL-5 could be summarized as: (i) the cyclohexylmethoxy group at 5th position of the A ring, (ii) the planarity of chromone ring, (iii) hydrophobic unit around the B ring with hydroxyl functional group, (iv) the hydrophobic unit which does not have to be a planar and (v) the length of carbon units between amino and hydroxyl group is limited to two.


Assuntos
Anti-Inflamatórios/síntese química , Cromonas/química , Interleucina-5/antagonistas & inibidores , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Linhagem Celular , Cromonas/síntese química , Cromonas/farmacologia , Desenho de Fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Interleucina-5/metabolismo , Relação Estrutura-Atividade
18.
Chem Pharm Bull (Tokyo) ; 58(7): 918-21, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20606337

RESUMO

In order to determine the optimum size of heterocycle of lead compound 1 (6-methyl-3-phenethyl-3,4-dihydro-1H-quinoline-2-thione; IC(50)=0.8 microM) for inhibition of melanogenesis, we have synthesized and evaluated some benzimdazole-2(3H)-thiones 5a-e. The preliminary bioassay has shown that the benzimdazole-2(3H)-thione motif of 5 is essential structural unit for their inhibitory activity. Among all thiones 5a-e, the compound 5d strongly inhibited the formation of melanin with IC(50) value of 1.3 microM.


Assuntos
Antineoplásicos/química , Benzimidazóis/química , Melaninas/antagonistas & inibidores , Melanoma Experimental/tratamento farmacológico , Tionas/química , alfa-MSH/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Benzimidazóis/síntese química , Benzimidazóis/uso terapêutico , Linhagem Celular , AMP Cíclico/metabolismo , Humanos , Melaninas/biossíntese , Camundongos , Tionas/síntese química , Tionas/uso terapêutico , alfa-MSH/metabolismo
19.
Bioorg Med Chem Lett ; 20(9): 2991-3, 2010 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-20359890

RESUMO

In order to define the structural requirements of phenylthiourea (PTU), a series of thiourea and thiosemicarbazone analogs were prepared and evaluated as inhibitors of melanogenesis in melanoma B16 cells. The most potent analog was 2-(4-tert-butylbenzylidene)hydrazinecarbothioamide (1u) with an IC(50) value of 2.7 microM in inhibition of melanogenesis. The structure for potent inhibitory activity of these derivatives are required with the direct connection of pi-planar structure to thiourea without steric hinderance in PTU derivatives and the hydrophobic substituent at para position in case of semicarbazones.


Assuntos
Benzaldeídos/química , Melanoma Experimental/tratamento farmacológico , Peptídeos/química , Feniltioureia/química , Tiossemicarbazonas/química , Animais , Camundongos , Monofenol Mono-Oxigenase/antagonistas & inibidores , Monofenol Mono-Oxigenase/metabolismo , Peptídeos/síntese química , Peptídeos/uso terapêutico , Feniltioureia/síntese química , Feniltioureia/uso terapêutico , Relação Estrutura-Atividade , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/uso terapêutico
20.
Eur J Med Chem ; 45(6): 2531-6, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20226573

RESUMO

A novel series of chromone analogs were synthesized and evaluated for their inhibitory activity against interleukin-5. Among them compounds 5-Cyclohexylmethoxy-3-(4-hydroxybenzyl)-4H-chromen-4-one (6a, 98% inhibition at 30 microM, IC50<3.0 microM) and 5-Cyclohyxylmethoxy-3-(hydroxymethyl)-4H-chromen-4-one (8a, 84% inhibition at 30 microM, IC50=7.6 microM) showed most potent activity. The structural requirement of chromone analogs possessing the inhibitory activity against IL-5 could be summarized as: (i) importance of hydrophobic group such as cyclohexylmethoxy at 5th position of ring A, (ii) requirement of ring B with small size of hydrogen bonding group with electron donating property such as phenolic hydroxyl group at 4th position and (iii) planarity of the chromen-4-one ring.


Assuntos
Cromonas/síntese química , Cromonas/farmacologia , Interleucina-5/antagonistas & inibidores , Linhagem Celular , Cromonas/química , Cromonas/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Concentração Inibidora 50 , Permeabilidade , Relação Estrutura-Atividade
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