RESUMO
In this work we aimed to perform an in silico predictive screening, docking and molecular dynamic study to identify 1,2,3-triazole-phthalimide derivatives as drug candidates against SARS-CoV-2. The in silico prediction of pharmacokinetic and toxicological properties of hundred one 1,2,3-triazole-phtalimide derivatives, obtained from SciFinder® library, were investigated. Compounds that did not show good gastrointestinal absorption, violated the Lipinski's rules, proved to be positive for the AMES test, and showed to be hepatotoxic or immunotoxic in our ADMET analysis, were filtered out of our study. The hit compounds were further subjected to molecular docking on SARS-CoV-2 target proteins. The ADMET analysis revealed that 43 derivatives violated the Lipinski's rules and 51 other compounds showed to be positive for the toxicity test. Seven 1,2,3-triazole-phthalimide derivatives (A7, A8, B05, E35, E38, E39, and E40) were selected for molecular docking and MFCC-ab initio analysis. The results of molecular docking pointed the derivative E40 as a promising compound interacting with multiple target proteins of SARS-CoV-2. The complex E40-Mpro was found to have minimum binding energy of -10.26 kcal/mol and a general energy balance, calculated by the quantum mechanical analysis, of -8.63 eV. MD simulation and MMGBSA calculations confirmed that the derivatives E38 and E40 have high binding energies of -63.47 ± 3 and -63.31 ± 7 kcal/mol against SARS-CoV-2 main protease. In addition, the derivative E40 exhibited excellent interaction values and inhibitory potential against SAR-Cov-2 main protease and viral nucleocapsid proteins, suggesting this derivative as a potent antiviral for the treatment and/or prophylaxis of COVID-19.Communicated by Ramaswamy H. Sarma.
Assuntos
Tratamento Farmacológico da COVID-19 , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ftalimidas/farmacologia , Inibidores de Proteases/química , SARS-CoV-2 , Triazóis/farmacologiaRESUMO
Organic compounds obtained by click chemistry reactions have demonstrated a broad spectrum of biological activities being widely applied for the development of molecules against pathogens of medical and veterinary importance. Cutaneous leishmaniasis (CL), caused by intracellular protozoa parasite of genus Leishmania, comprises a complex of clinical manifestations that affect the skin and mucous membranes. The available drugs for the treatment are toxic and costly, with long periods of treatment, and the emergence of resistant strains has been reported. In this study we investigated the in vitro effects of a phthalimide-1,2,3-triazole derivative, the 4-Phenyl-1-[2-(phthalimido-2-yl)ethyl]-1H-1,2,3-triazole (PT4) obtained by click chemistry, on mammalian cells and on L. amazonensis and L. braziliensis, the causative agents of CL in Brazil. In silico ADMET evaluation of PT4 showed that this molecule has good pharmacokinetic properties with no violation of Lipinski's rules. The in vitro assays showed that PT4 was more selective for both Leishmania species than to mammalian cells. This compound also presented low cytotoxicity to mammalian cells with CC50 > 500 µM. Treatment of promastigote forms with different concentrations of PT4 resulted in ultrastructural alterations, such as plasma membrane wrinkling, shortening of cell body, increased cell volume and cell rupture. The molecular dynamic simulations showed that PT4 interacts with Lanosterol 14 α-demethylase from Leishmania, an essential enzyme of lipid synthesis pathway in this parasite. Our results demonstrated PT4 was effective against both species of Leishmania. PT4 caused a decrease of mitochondrial membrane potential and increased production of reactive oxygen species, which may lead to parasite death. Taken together, our results pointed PT4 as promissing therapeutic agent against CL.
Assuntos
Antiprotozoários/farmacologia , Leishmania/efeitos dos fármacos , Triazóis/farmacologia , Animais , Antiprotozoários/síntese química , Antiprotozoários/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Macrófagos/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Testes de Sensibilidade Parasitária , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/químicaRESUMO
CONTEXT: Buchenavia tetraphylla (Aubl.) RA Howard (Combretaceae: Combretoideae) is an ethnomedicinal plant with reported antifungal action. OBJECTIVE: This study evaluates the antimicrobial activity of B. tetraphylla leaf extracts against clinical isolates of Candida albicans. The morphological alterations, combinatory effects with fluconazole and the cytotoxicity of the active extract were analyzed. MATERIALS AND METHODS: Extracts were obtained using different solvents (hexane: BTHE; chloroform: BTCE; ethyl acetate: BTEE; and methanol: BTME). Antimicrobial activity was determined by the broth microdilution method using nine strains of C. albicans isolated from vaginal secretions and one standard strain (UFPEDA 1007). RESULTS: All extracts showed anti-C. albicans activity, including against the azole-resistant strains. The MIC values ranged from 156 to 2500 µg/mL for the BTHE; 156 to 1250 µg/mL for the BTCE; 625 to 1250 µg/mL for the BTME and 625 µg/mL to 2500 µg/mL for the BTEE. BTME showed the best anti-C. albicans activity. This extract demonstrated additive/synergistic interactions with fluconazole. Scanning electron microscopy analysis suggested that the BTME interferes with the cell division and development of C. albicans. BTME showed IC50 values of 981 and 3935 µg/mL, against J774 macrophages and human erythrocytes, respectively. This extract also enhanced the production of nitric oxide by J774 macrophages. DISCUSSION AND CONCLUSION: Buchenavia tetraphylla methanolic extract (BTME) is a great source of antimicrobial compounds that are able to enhance the action of fluconazole against different C. albicans strains; this action seems related to inhibition of cell division.
Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Combretaceae/química , Extratos Vegetais/farmacologia , Vagina/microbiologia , Animais , Antifúngicos/isolamento & purificação , Antifúngicos/toxicidade , Candida albicans/crescimento & desenvolvimento , Candida albicans/isolamento & purificação , Candida albicans/ultraestrutura , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Farmacorresistência Fúngica , Quimioterapia Combinada , Feminino , Fluconazol/farmacologia , Hemólise/efeitos dos fármacos , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Testes de Sensibilidade Microbiana , Óxido Nítrico/metabolismo , Fitoterapia , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/toxicidade , Plantas Medicinais , Solventes/química , Vagina/metabolismoRESUMO
This study aimed to evaluate the antibacterial activities of the essential oils from Origanum vulgare L. (OV) and Rosmarinus officinalis L. (RO), both singly and in combination at sub-inhibitory concentrations (» MIC + » MIC), against Aeromonas hydrophila and to investigate the possible mechanisms underlying these activities. Used singly (OV: 2.5 µL/mL; RO: 20 µL/mL) or in a mixture (OV: 0.625 µL/mL + RO: 5 µL/L), these essential oils led to a significant decrease (p<0.01) in bacterial viability after 24 h of exposure. A decrease in glucose consumption by A. hydrophila and release of cellular material were observed immediately after the addition of the essential oils, both singly and as a mixture, and continued for up to 6 h. Electron microscopy of cells exposed to the essential oils revealed severe changes in the plasma membrane, cytoplasmic appearance, and cell shape during the 6-h exposure period. OV and RO essential oils combined at sub-inhibitory concentrations could be rationally applied to inhibit the growth of A. hydrophila in food products, particularly minimally processed vegetables.