RESUMO
A priority of modern agriculture is to use novel and environmentally friendly plant-growth promoter compounds to increase crop yields and avoid the indiscriminate use of synthetic fertilizers. Brassinosteroids are directly involved in the growth and development of plants and are considered attractive candidates to solve this problem. Obtaining these metabolites from their natural sources is expensive and cumbersome since they occur in extremely low concentrations in plants. For this reason, much effort has been dedicated in the last decades to synthesize brassinosteroids analogs. In this manuscript, we present the synthesis and characterization of seven steroidal carbamates starting from stigmasterol, ß-sitosterol, diosgenin and several oxygenated derivatives of it. The synthesis route for functionalization of diosgenin included epoxidation and epoxy opening reactions, reduction of carbonyl groups, selective oxidation of hydroxyl groups, among others. All the obtained compounds were characterized by 1H and 13C NMR, HRMS, and their melting points are also reported. Rice lamina inclination test performed at different concentrations established that all reported steroidal carbamates show plant-growth-promoting activity. A molecular docking study evaluated the affinity of the synthesized compounds towards the BRI1-BAK1 receptor from Arabidopsis thaliana and three of the docked compounds displayed a binding energy lower than brassinolide.
Assuntos
Arabidopsis/crescimento & desenvolvimento , Carbamatos , Simulação de Acoplamento Molecular , Oryza/crescimento & desenvolvimento , Reguladores de Crescimento de Plantas , Brassinosteroides/química , Carbamatos/síntese química , Carbamatos/química , Carbamatos/farmacologia , Reguladores de Crescimento de Plantas/síntese química , Reguladores de Crescimento de Plantas/química , Reguladores de Crescimento de Plantas/farmacologia , Esteroides Heterocíclicos/químicaRESUMO
A novel series of arylcarbamate-N-acylhydrazones derivatives have been designed and synthesized as potential anti-cholinesterase agents. In vitro studies revealed that these compounds demonstrated selective for butyrylcholinesterase (BuChE) with potent inhibitory activity. The compounds 10a-d, 12b and 12d were the most potent BuChE inhibitors with IC50 values of 0.07-2.07 µM, highlighting the compound 10c (IC50 = 0.07 µM) which showed inhibitory activity 50 times greater than the reference drug donepezil (IC50 = 3.54 µM). The activity data indicates that the position of the carbamate group in the aromatic ring has a greater influence on the inhibitory activity of the derivatives. The enzyme kinetics studies indicate that the compound 10c has a non-competitive inhibition against BuChE with Ki value of 0.097 mM. Molecular modeling studies corroborated the in vitro inhibitory mode of interaction and show that compound 10c is stabilized into hBuChE by strong hydrogen bond interaction with Tyr128, π-π stacking interaction with Trp82 and CHâ¯O interactions with His438, Gly121 and Glu197. Based on these data, compound10cwas identified as low-cost promising candidate for a drug prototype for AD treatment.
Assuntos
Carbamatos/farmacologia , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Hidrazonas/farmacologia , Acetilcolinesterase/metabolismo , Animais , Butirilcolinesterase/metabolismo , Carbamatos/síntese química , Carbamatos/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Electrophorus , Cavalos , Hidrazonas/síntese química , Hidrazonas/química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Phialophora verrucosa causes several fungal human diseases, mainly chromoblastomycosis, which is extremely difficult to treat. Several studies have shown that human immunodeficiency virus peptidase inhibitors (HIV-PIs) are attractive candidates for antifungal therapies. This work focused on studying the action of HIV-PIs on peptidase activity secreted by P. verrucosa and their effects on fungal proliferation and macrophage interaction. We detected a peptidase activity from P. verrucosa able to cleave albumin, sensitive to pepstatin A and HIV-PIs, especially lopinavir, ritonavir and amprenavir, showing for the first time that this fungus secretes aspartic-type peptidase. Furthermore, lopinavir, ritonavir and nelfinavir reduced the fungal growth, causing remarkable ultrastructural alterations. Lopinavir and ritonavir also affected the conidia-macrophage adhesion and macrophage killing. Interestingly, P. verrucosa had its growth inhibited by ritonavir combined with either itraconazole or ketoconazole. Collectively, our results support the antifungal action of HIV-PIs and their relevance as a possible alternative therapy for fungal infections.
Assuntos
Antifúngicos/farmacologia , Ácido Aspártico Proteases/antagonistas & inibidores , Inibidores da Protease de HIV/farmacologia , Macrófagos/efeitos dos fármacos , Phialophora/efeitos dos fármacos , Antifúngicos/síntese química , Antifúngicos/química , Ácido Aspártico Proteases/metabolismo , Carbamatos/síntese química , Carbamatos/química , Carbamatos/farmacologia , Relação Dose-Resposta a Droga , Furanos , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/química , Humanos , Lopinavir/síntese química , Lopinavir/química , Lopinavir/farmacologia , Macrófagos/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Phialophora/enzimologia , Phialophora/crescimento & desenvolvimento , Ritonavir/síntese química , Ritonavir/química , Ritonavir/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
With the aim to develop new potential (99m)Tc-radiopharmaceuticals for imaging hypoxia based on the formation of Tc-nitrido complexes, two novel dithiocarbamate containing metronidazole derivatives (L1 and L2) have been prepared and characterised. The synthesis of L1 and L2 was achieved in excellent yield and high purity. Labelling with (99m)Tc was successfully performed using a low ligand concentration (approximately 2-3mg) and the desired products were obtained with high radiochemical purity (>90%). Lipophilicity, plasma protein binding, and biodistribution in normal- and tumour-bearing-CD1 mice studies were performed to asses the potentiality for nuclear medicine oncology. According to the physicochemical and biological behaviour both in healthy animals and in animals bearing solid tumours complex dtcTc1 could be considered as a starting point for the development of new radiopharmaceuticals for imaging hypoxia.
Assuntos
Carbamatos/química , Neoplasias/diagnóstico por imagem , Nitroimidazóis/química , Compostos de Organotecnécio/química , Compostos Radiofarmacêuticos/síntese química , Animais , Carbamatos/síntese química , Hipóxia Celular , Metronidazol/química , Camundongos , Compostos de Organotecnécio/síntese química , Cintilografia , Compostos Radiofarmacêuticos/químicaRESUMO
An efficient method for the synthesis of enol ethers and enecarbamates has been developed based on catalytic hydrosilane reduction of alpha-phosphonoxy enol ethers and alpha-phosphonoxy enecarbamates. This method has been applied to the total syntheses of two isoindolobenzazepine alkaloids, lennoxamine and chilenine.