RESUMO
The modulation of melatonin signaling in peripheral tissues holds promise for treating metabolic diseases like obesity, diabetes, and nonalcoholic steatohepatitis. Here, several benzimidazole derivatives have been identified as novel agonists of the melatonin receptors MT1 and MT2. The lead compounds 10b, 15a, and 19a demonstrated subnanomolar potency at MT1/MT2 receptors, high oral bioavailability in rodents, peripherally preferred exposure, and excellent selectivity in a broad panel of targets. Two-month oral administration of 10b in high-fat diet rats led to a reduction in body weight gain similar to dapagliflozin with superior results on hepatic steatosis and triglyceride levels. An early toxicological assessment indicated that 10b (also codified as ACH-000143) was devoid of hERG binding, genotoxicity, and behavioral alterations at doses up to 100 mg/kg p.o., supporting further investigation of this compound as a drug candidate.
Assuntos
Acetamidas/uso terapêutico , Fármacos Antiobesidade/uso terapêutico , Benzimidazóis/uso terapêutico , Fígado Gorduroso/tratamento farmacológico , Receptor MT1 de Melatonina/agonistas , Receptor MT2 de Melatonina/agonistas , Acetamidas/síntese química , Acetamidas/farmacocinética , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacocinética , Compostos Benzidrílicos/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/farmacocinética , Dieta Hiperlipídica , Desenho de Fármacos , Fígado Gorduroso/patologia , Glucosídeos/farmacologia , Fígado/patologia , Masculino , Camundongos , Estrutura Molecular , Obesidade/tratamento farmacológico , Ratos Sprague-Dawley , Ratos Wistar , Relação Estrutura-Atividade , Triglicerídeos/metabolismoRESUMO
An efficient synthetic route to prepare O-(2-O-benzyl-3,4-di-O-acetyl-α/ß-l-fucopyranosyl)-trichloroacetimidate from l-fucose was developed by introducing the thiophenyl group at the anomeric center and the benzylidene functional group to protect the 3 and 4 positions. Although three approaches were considered, the best result was obtained when, after the 2-hydroxyl benzylation, both protective groups were simultaneously removed by using acetic anhydride and perchloric acid supported on silica as catalyst. Selective deacetylation of the obtained tri-O-acetate followed by the reaction of the resultant hemiacetal with trichloroacetonitrile and DBU afforded the trichloroacetimidate with an overall yield of 56% from the l-fucose.
Assuntos
Acetamidas/síntese química , Cloroacetatos/síntese química , Fucose/síntese química , Acetamidas/química , Configuração de Carboidratos , Cloroacetatos/química , Fucose/análogos & derivados , Fucose/químicaRESUMO
Klebsiella pneumoniae causes a wide range of community and nosocomial infections. The high capacity of this pathogen to acquire resistance drugs makes it necessary to develop therapeutic alternatives, discovering new antibacterial molecules. Acetamides are molecules that have several biological activities. However, there are no reports on the activity of 2-chloro-N-(4-fluoro-3-nitrophenyl)acetamide. Based on this, this study aimed to investigate the in vitro antibacterial activity of this molecule on K. pneumoniae, evaluating whether the presence of the chloro atom improves this effect. Then, analyzing its antibacterial action more thoroughly, as well as its cytotoxic and pharmacokinetic profile, in order to contribute to future studies for the viability of a new antibacterial drug. It was shown that the substance has good potential against K. pneumoniae and the chloro atom is responsible for improving this activity, stabilizing the molecule in the target enzyme at the site. The substance possibly acts on penicillin-binding protein, promoting cell lysis. The analysis of cytotoxicity and mutagenicity shows favorable results for future in vivo toxicological tests to be carried out, with the aim of investigating the potential of this molecule. In addition, the substance showed an excellent pharmacokinetic profile, indicating good parameters for oral use.
Assuntos
Acetamidas/farmacologia , Antibacterianos/farmacologia , Acetamidas/síntese química , Acetamidas/química , Acetamidas/toxicidade , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/toxicidade , Técnicas de Química Sintética , Hemólise/efeitos dos fármacos , Humanos , Infecções por Klebsiella/tratamento farmacológico , Infecções por Klebsiella/microbiologia , Klebsiella pneumoniae/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A series of 18 novel 2-hydrazolyl-4-thiazolidinones-5-carboxylic acids, amides and 5,6-α,ß-unsaturated esters were synthesized, and their in vitro activity on cruzipain and T. cruzi epimastigotes was determined. Some agents show activity at 37 µm concentration in the enzyme assay. Computational tools and docking were used to correlate the biological response with the physicochemical parameters of the compounds and their cruzipain inhibitory effects.
Assuntos
Antiprotozoários/síntese química , Tiazolidinas/química , Trypanosoma cruzi/efeitos dos fármacos , Acetamidas/síntese química , Acetamidas/química , Acetamidas/toxicidade , Animais , Antiprotozoários/química , Antiprotozoários/toxicidade , Sítios de Ligação , Domínio Catalítico , Chlorocebus aethiops , Simulação por Computador , Cisteína Endopeptidases/química , Cisteína Endopeptidases/metabolismo , Proteínas de Protozoários , Relação Quantitativa Estrutura-Atividade , Trypanosoma cruzi/enzimologia , Células VeroRESUMO
The present article describes a series of 21 N-(aryl)-2-thiophen-2-ylacetamides, which were synthesized and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis, and the activity expressed as the minimum inhibitory concentration (MIC) in mug/mL. The compounds 2, 3, 7, 8, 11, 12, 15, 16, and 20 exhibited activity between 25 and 100 microg/mL and could be a good start point to find new lead compounds in the fight against multidrug resistant tuberculosis.
Assuntos
Acetamidas/síntese química , Acetamidas/farmacologia , Antituberculosos/síntese química , Antituberculosos/farmacologia , Tiofenos/química , Acetamidas/química , Acetamidas/classificação , Animais , Antituberculosos/química , Antituberculosos/classificação , Linhagem Celular , Macrófagos/efeitos dos fármacos , Camundongos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The main molecular features which determine the selectivity of a set of 80 N-hydroxy-alpha-phenylsulfonylacetamide derivatives (HPSAs) in the inhibition of three matrix metalloproteinases (MMP-1, MMP-9, and MMP-13) have been identified by using linear and nonlinear predictive models. The molecular information has been encoded in 2D autocorrelation descriptors, obtained from different weighting schemes. The linear models were built by multiple linear regression (MLR) combined with genetic algorithm (GA), and a robust QSAR mapping paradigm. The Bayesian-regularized genetic neural network (BRGNN) was employed for nonlinear modeling. In such approaches each model could have its own set of input variables. All models were predictive according to internal and external validation experiments; but the best results correspond to nonlinear ones. The 2D autocorrelation space brings different descriptors for each MMP inhibition, and suggests the atomic properties relevant for the inhibitors to interact with each MMP active site. On the basis of the current results, the reported models have the potential to discover new potent and selective inhibitors and bring useful molecular information about the ligand specificity for MMP S(1)(') and S(2)(') subsites.
Assuntos
Acetamidas/farmacologia , Modelos Lineares , Inibidores de Metaloproteinases de Matriz , Modelos Moleculares , Inibidores de Proteases/farmacologia , Relação Quantitativa Estrutura-Atividade , Acetamidas/síntese química , Acetamidas/química , Algoritmos , Teorema de Bayes , Simulação por Computador , Ligantes , Modelos Biológicos , Estrutura Molecular , Redes Neurais de Computação , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Ésteres do Ácido Sulfúrico/químicaRESUMO
The inhibitory activity (IC50) toward matrix metalloproteinases (MMP-1, MMP-2, MMP-3, MMP-9, and MMP-13) of N-hydroxy-2-[(phenylsulfonyl)amino]acetamide derivatives (HPSAAs) has been successfully modeled using 2D autocorrelation descriptors. The relevant molecular descriptors were selected by linear and nonlinear genetic algorithm (GA) feature selection using multiple linear regression (MLR) and Bayesian-regularized neural network (BRANN) approaches, respectively. The quality of the models was evaluated by means of cross-validation experiments and the best results correspond to nonlinear ones (Q2>0.7 for all models). Despite the high correlation between the studied compound IC50 values, the 2D autocorrelation space brings different descriptors for each MMP inhibition. On the basis of these results, these models contain useful molecular information about the ligand specificity for MMP S'1, S1, and S'2 pockets.
Assuntos
Acetamidas/farmacologia , Inibidores Enzimáticos/farmacologia , Modelos Lineares , Inibidores de Metaloproteinases de Matriz , Relação Quantitativa Estrutura-Atividade , Sulfonamidas/farmacologia , Acetamidas/síntese química , Acetamidas/química , Algoritmos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Modelos Genéticos , Estrutura Molecular , Redes Neurais de Computação , Análise de Regressão , Estereoisomerismo , Sulfonamidas/síntese química , Sulfonamidas/químicaRESUMO
Iridium complexes of DMA-imine [2,6-dimethylphenyl-1'-methyl-2'-methoxyethylimine, 1 a) and (R)-DMA-amine [(1'R)-2,6-dimethylphenyl-1'-methyl-2'-methoxyethylamine, 2 a] that are relevant to the catalytic imine hydrogenation step of the Syngenta (S)-Metolachlor process were synthesized: metathetical exchange of [Ir2Cl2(cod)2] (cod=1,5-cyclooctadiene) with [Ag(1 a)2]BF4 and [Ag((R)-2 a)2]BF4 afforded [Ir(cod)(kappa2- -1 a)]BF4 (11) and [Ir(cod)(kappa2-(R)-2 a)]BF4 ((R)-19)), respectively. These complexes were then used in stopped-flow experiments to study the displacement of amine 2 a from complex 19 by imine 1 a to form the imine complex 11, thus modeling the product/substrate exchange step in the catalytic cycle. The data suggest a two-step associative mechanism characterized by k1=(2.6+/-0.3) x 10(2) M(-1) s(-1) and k2=(4.3+/-0.6) x 10(-2) s(-1) with the respective activation energies EA1=(7.5+/-0.6) kJ mol(-1) and EA2=(37+/-3) kJ mol(-1). Furthermore, complex 11 reacted with H2O to afford the hydrolysis product [Ir(cod)(eta(6-)-2,6-dimethylaniline)]BF4 (12), and with I2 to liberate quantitatively the DMA-iminium salt 14. On the other hand, the chiral amine complex (R)-19 formed the optically inactive eta6-bound compound [Ir(cod)(eta6-rac-2 a)]BF4 (rac-18) upon dissolution in THF at room temperature, presumably via intramolecular C-H activation. This racemization was found to be a two-step event with k'1=9.0 x 10(-4) s(-1) and k2=2.89 x 10(-5) s(-1), featuring an optically active intermediate prior to sp3 C-H activation. Compounds 11, 12, rac-18, and (R)-19 were structurally characterized by single-crystal X-ray analyses.