RESUMEN
A novel series of polyhalobenzonitrile quinazolin-4(3H)-one derivatives were synthesized and characterized by NMR, IR, MS, and HRMS spectra. All of the newly prepared compounds were screened for antimicrobial activities against four strains of bacteria (Gram-positive bacterial: Staphylococcus aureus and Bacillus cereus; Gram-negative bacterial: Escherichia coli and Pseudomonas aeruginosa) and one strain of fungi (Candida albicans). Among the synthesized compounds, 5-(dimethylamino)-8-(2,4,5-trichloro-isophthalonitrile) quinazolin-4(3H)-one (7k) exhibited significant activity towards Gram-positive bacterial, Gram-negative bacterial, and the fungi strains. The MIC (0.8-3.3µg/mL) and MBC (2.6-7.8µg/mL) for this compound were close to those of nofloxacin, chlorothalonil, and fluconazole, making it the most potent antimicrobial agents in the series.
Asunto(s)
Antiinfecciosos/química , Antiinfecciosos/farmacología , Bacterias/efectos de los fármacos , Candida albicans/efectos de los fármacos , Quinazolinas/química , Quinazolinas/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Antiinfecciosos/síntesis química , Antifúngicos/síntesis química , Antifúngicos/química , Antifúngicos/farmacología , Infecciones Bacterianas/tratamiento farmacológico , Candidiasis/tratamiento farmacológico , Humanos , Pruebas de Sensibilidad Microbiana , Quinazolinas/síntesis químicaRESUMEN
Previously it was found that 4-hydroxybenzaldehyde is a competitive inhibitor of GABA transaminase. Here 3-chloro-1-(4-hydroxyphenyl)propan-1-one (9), a 4-hydroxybenzaldehyde analogue, was found to inactivate potently the enzyme in a time-dependent manner. alpha-Ketoglutarate prevented the enzyme from inactivation, suggesting that the inactivation occurs in its active site. Several experiments indicated that the inactivation is irreversible. This study provides a novel strategy for the design of more effective inhibitors.
Asunto(s)
4-Aminobutirato Transaminasa/antagonistas & inhibidores , 4-Aminobutirato Transaminasa/química , Química Farmacéutica/métodos , Inhibidores Enzimáticos/farmacología , Ácidos Cetoglutáricos/química , Propiofenonas/química , Dominio Catalítico , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Activación Enzimática , Inhibidores Enzimáticos/síntesis química , Humanos , Cinética , Modelos Químicos , Propiofenonas/síntesis químicaRESUMEN
In the present review, English literature on the pharmacological effects of Gastrodia elata was summarized. The literature mainly reported the effects of G. elata on central nervous system, including anticonvulsant, neuroprotection, improvement on learning and memory, and so on. These pharmacological effects were closely associated with its phenolic components.
Asunto(s)
Medicamentos Herbarios Chinos/farmacología , Gastrodia/química , Animales , Sistema Nervioso Central/efectos de los fármacos , Humanos , Memoria/efectos de los fármacosRESUMEN
Previous study showed that 4-hydroxybenzaldehyde is a competitive inhibitor of GABA transaminase. As a result, 4-acryloylphenol was synthesized as a 4-hydroxybenzaldehyde analogue, and shown to inactivate potently the enzyme in a time-dependent manner. The inactivation was protected by alpha-ketoglutarate, indicating that it occurs at the active site of the enzyme. Beta-mercaptoethanol also prevented the enzyme from inactivation. The possible mechanism involving a Michael addition was proposed to rationalize the inactivation.
Asunto(s)
4-Aminobutirato Transaminasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Fenoles/síntesis química , Fenoles/farmacología , Benzaldehídos/química , Sitios de Unión , Ácidos Cetoglutáricos/farmacología , Mercaptoetanol/farmacología , Relación Estructura-Actividad , Factores de TiempoRESUMEN
4-Hydroxybenzaldehyde (HBA) derivatives were examined as inhibitors for GABA transaminase (GABA-T) and succinic semialdehyde dehydrogenase (SSADH). Investigation of structure-activity relation revealed that a carbonyl group or an amino group as well as a hydroxy group at the para position of the benzene ring are important for both enzymes' inhibition. HBA was shown to give competitive inhibition of GABA-T with respect to alpha-ketoglutarate and competitive inhibition of SSADH. 4-Hydroxybenzylamine (HBM) also showed the competitive inhibition on GABA-T with respect to GABA. In conclusion, the inhibitory effects of HBA and HBM on both enzymes could result from the similarity between both molecules and the two enzymes' substrates in structure, as well as the conjugative effect of the benzene ring. This suggested that the presence of the benzene ring may be accepted by the active site of both enzymes, HBA and HBM may be considered as lead compounds to design novel GABA-T inhibitors.