RESUMO
A novel series of N(1)-(3-fluoro-4-(6,7-disubstituted-quinolin-4-yloxy)phenyl)-N(4)-arylidenesemicarbazide derivatives were synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against A549, HT-29, MKN-45 and MDA-MB-231 cancer cell lines in vitro. Several potent compounds were further evaluated against three other cancer cell lines (U87MG, NCI-H460 and SMMC7721). Most of compounds tested exhibited moderate to excellent activity. The studies of SARs identified the most promising compound 28 (c-Met IC50=1.4nM) as a c-Met kinase inhibitor. In this study, a promising compound 28 was identified, which displayed 2.1-, 3.3-, 48.4- and 3.6-fold increase against A549, HT-29, U87MG and NCI-H460 cell lines, respectively, compared with that of Foretinib.
Assuntos
Antineoplásicos/química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Quinolinas/química , Semicarbazidas/síntese química , Semicarbazonas/química , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Células HT29 , Humanos , Simulação de Acoplamento Molecular , Fosforilação/efeitos dos fármacos , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/toxicidade , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas c-met/metabolismo , Quinolinas/síntese química , Quinolinas/toxicidade , Semicarbazidas/química , Semicarbazidas/toxicidade , Semicarbazonas/síntese química , Semicarbazonas/toxicidade , Relação Estrutura-AtividadeRESUMO
Monoamine oxidase B (MAO-B) is an important drug target for the treatment of neurological disorders. A series of 6-nitrobenzothiazole-derived semicarbazones were designed, synthesized, and evaluated as inhibitors of the rat brain MAO-B isoenzyme. Most of the compounds were found to be potent inhibitors of MAO-B, with IC(50) values in the nanomolar to micromolar range. Molecular docking studies were performed with AutoDock 4.2 to deduce the affinity and binding mode of these inhibitors toward the MAO-B active site. The free energies of binding (ΔG) and inhibition constants (K(i)) of the docked compounds were calculated by the Lamarckian genetic algorithm (LGA) of AutoDockâ 4.2. Good correlations between the calculated and experimental results were obtained. 1-[(4-Chlorophenyl)(phenyl)methylene]-4-(6-nitrobenzothiazol-2-yl)semicarbazide emerged as the lead MAO-B inhibitor, with top ranking in both the experimental MAO-B assay (IC(50): 0.004±0.001 µM) and in computational docking studies (K(i): 1.08 µM). Binding mode analysis of potent inhibitors suggests that these compounds are well accommodated by the MAO-B active site through stable hydrophobic and hydrogen bonding interactions. Interestingly, the 6-nitrobenzothiazole moiety is stabilized in the substrate cavity with the aryl or diaryl residues extending up into the entrance cavity of the active site. According to our results, docking experiments could be an interesting approach for predicting the activity and binding interactions of this class of semicarbazones against MAO-B. Thus, a binding site model consisting of three essential pharmacophoric features is proposed, and this can be used for the design of future MAO-B inhibitors.
Assuntos
Benzotiazóis/química , Benzotiazóis/síntese química , Desenho de Fármacos , Inibidores da Monoaminoxidase/síntese química , Monoaminoxidase/química , Semicarbazidas/síntese química , Semicarbazonas/química , Animais , Benzotiazóis/farmacologia , Sítios de Ligação , Encéfalo/enzimologia , Domínio Catalítico , Avaliação Pré-Clínica de Medicamentos , Simulação de Acoplamento Molecular , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , Ratos , Semicarbazidas/química , Semicarbazidas/farmacologia , Semicarbazonas/síntese química , Semicarbazonas/farmacologia , Software , Relação Estrutura-AtividadeRESUMO
A series of N-per-O-acetyl-glucosyl arylthiosemicarbazide and thiosemicarbazone derivatives have been synthesized and evaluated for their in vivo anti-dyslipidemic and in vitro antioxidant activities. Among 16 compounds tested, 3 compounds showed potent anti-dyslipidemic activity and 6 compounds showed potent antioxidant and scavenger of oxygen free radicals activity.
Assuntos
Antioxidantes/síntese química , Hipolipemiantes/síntese química , Semicarbazidas/síntese química , Tiossemicarbazonas/síntese química , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Avaliação Pré-Clínica de Medicamentos , Dislipidemias/tratamento farmacológico , Hipolipemiantes/farmacologia , Hipolipemiantes/uso terapêutico , Ratos , Semicarbazidas/farmacologia , Semicarbazidas/uso terapêutico , Tiossemicarbazonas/farmacologia , Tiossemicarbazonas/uso terapêuticoRESUMO
N-Hydroxythiosemicarbazide was prepared by two methods starting from 2,4-dimethoxy benzyl amine and hydroxylamine hydrochloride, which in turn was reacted with various aldehydes and ketones to obtain the titled compounds. Eighteen compounds were tested for their in vitro activity against Mycobacterium tuberculosis H37Rv using the agar dilution method. Compound 10p was found to be the most potent compound (MIC: 0.28 microM) and was 2.5 times more active than standard isoniazid.
Assuntos
Antituberculosos/síntese química , Química Farmacêutica/métodos , Mycobacterium tuberculosis/metabolismo , Semicarbazidas/química , Semicarbazidas/síntese química , Semicarbazonas/química , Semicarbazonas/síntese química , Ágar/química , Animais , Antituberculosos/farmacologia , Chlorocebus aethiops , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Concentração Inibidora 50 , Testes de Sensibilidade Microbiana , Modelos Químicos , Conformação Molecular , Semicarbazidas/farmacologia , Temperatura , Células VeroRESUMO
The synthesis of some aroylisothiosemicarbazides was accomplished and their biological activity against bacteria, fungi, and mycobacteria was investigated. Different synthetic pathways were followed according to the kind of substituents that were introduced on both the aroyl ring and the sulfur atom. Anti-bacterial activity was measured against Staphylococcus aureus, S. epidermidis, Streptococcus agalactiae and S. faecalis, Escherichia coli, and Salmonella typhi, while antifungal activity was evaluated against C. albicans. Two species, Mycobacterium tuberculosis H37RV and Mycobacterium avium ATCC19421, were employed to evaluate antimycobacterial activity.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Semicarbazidas/síntese química , Semicarbazidas/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Testes de Sensibilidade Microbiana/métodosRESUMO
The phenyl (thio) semicarbazide derivatives of phthalimido pharmacophore were synthesized and evaluated for their anticonvulsant and neurotoxic properties. Initial anticonvulsant screening was performed using intraperitoneal (i.p.), maximal electroshock-induced seizure (MES), subcutaneous pentylenetetrazole (scPTZ) and subcutaneous strychnine (sc STY)-induced seizure threshold tests in mice. Compound 2c afforded protection in all the three screens. Compounds except 1d, 2a and 2d showed no neurotoxicity up to 300 mg/kg. Compounds 1a, 1b, 2c, 2d, 2g and 2i were found to show oral MES activity. The compounds exhibited CNS depression and behavioral despair side effects, lesser than the conventional antiepileptic drugs.
Assuntos
Anticonvulsivantes/síntese química , Anticonvulsivantes/toxicidade , Semicarbazidas/síntese química , Semicarbazidas/toxicidade , Animais , Anticonvulsivantes/uso terapêutico , Avaliação Pré-Clínica de Medicamentos/métodos , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley , Convulsões/tratamento farmacológicoRESUMO
The cyclization of 4-(p-tolyl)-selenosemicarbazides of acetic, benzoic, isonicotinic, nicotinic and picolinic acids (Ia-e) with omega-bromoacetophenone was investigated in the medium of methanol (Method A) or in methanol in the presence of anhydrous sodium acetate (Method B). Acid hydrolysis of compounds IIf-i and IVa-c, e was studied. Results of UV and IR spectrometric measurements and of the in vitro microbiological studies are presented. In contradistinction to corresponding thiosemicarbazides, the change in N4 nitrogen atom basicity of the parent selenosemicarbazide I (pKa of p-toluidine = 5.1), in comparison to that of 4-phenyl-selenosemicarbazide (pKa of aniline = 4.63), proved to influence the equilibrium of the reaction with omega-bromoacetophenone only in the methanol medium without addition of anhydrous sodium acetate (Method A).