Subject(s)
Congenital Abnormalities/virology , Fetus/abnormalities , Milk, Human/virology , Nervous System Diseases/virology , Zika Virus/isolation & purification , Adult , Body Fluids/virology , Brazil , Congenital Abnormalities/diagnostic imaging , Female , Fetus/diagnostic imaging , Fetus/virology , Genotype , Humans , Infant, Newborn , Mothers , Nervous System Diseases/diagnostic imaging , Phylogeny , Pregnancy , RNA, Viral/analysis , RNA, Viral/urine , Ultrasonography , Zika Virus/geneticsABSTRACT
The discovery of new drugs is generally considered a long and expensive process, which often leads to molecules with low efficacy and high toxicity, which in many cases can be related to metabolism. In an attempt to reduce these failures and the production costs of a new drug, in silico studies have been used to obtain important information about the behavior of these compounds in the metabolism phases: absorption, distribution, metabolism (or biotransformation) and elimination (or excretion). Quantum Mechanical (QM) calculations are based on Schrödinger's equation that can be used to develop models and theoretical parameters able to explain properties observed experimentally. In recent years, there has been an increase in the development of studies involving the application of QM methods to describe properties related to ADMET profile of new compounds. Amongst these, the most commonly used methods are ab initio (Hartree-Fock), Semiempirical (AM1 and PM3) and Density Functional Theory (DFT). The application of these methods allows the modeling of the predicted profile of absorption and elimination of chalcone-chloroquinoline hybrids; the ability of drugs to cross the blood-brain barrier (distribution); proposal of the route for oxidation of several compounds, via CYP450; and to predict the toxicity of pyrethroid analogs. Finally, QM methods can be considered as a valuable tool in the prediction of metabolism when applied to drug discovery.
Subject(s)
Models, Biological , Pharmaceutical Preparations/metabolism , Quantum Theory , SoftwareABSTRACT
In this study, we designed and synthesized a series of thiophen-2-iminothiazolidine derivatives from thiophen-2-thioureic with good anti-Trypanosoma cruzi activity. Several of the final compounds displayed remarkable trypanocidal activity. The ability of the new compounds to inhibit the activity of the enzyme cruzain, the major cysteine protease of T. cruzi, was also explored. The compounds 3b, 4b, 8b and 8c were the most active derivatives against amastigote form, with significant IC50 values between 9.7 and 6.03µM. The 8c derivative showed the highest potency against cruzain (IC50=2.4µM). Molecular docking study showed that this compound can interact with subsites S1 and S2 simultaneously, and the negative values for the theoretical energy binding (Eb=-7.39kcal·mol(-1)) indicates interaction (via dipole-dipole) between the hybridized sulfur sp(3) atom at the thiazolidine ring and Gly66. Finally, the results suggest that the thiophen-2-iminothiazolidines synthesized are important lead compounds for the continuing battle against Chagas disease.
Subject(s)
Thiazolidines/pharmacology , Thiophenes/pharmacology , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/drug effects , Animals , Cell Line , Cysteine Endopeptidases , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/pharmacology , Cysteine Proteinase Inhibitors/toxicity , Glycine/chemistry , Mice , Molecular Docking Simulation , Octoxynol , Protozoan Proteins/antagonists & inhibitors , Thiazolidines/chemical synthesis , Thiazolidines/toxicity , Thiophenes/chemical synthesis , Thiophenes/toxicity , Thiourea/analogs & derivatives , Thiourea/chemical synthesis , Thiourea/pharmacology , Thiourea/toxicity , Trypanocidal Agents/chemical synthesis , Trypanocidal Agents/toxicityABSTRACT
RESUMO O presente estudo teve como objetivo avaliar a atividade antibacteriana, antioxidante e citotóxica da espécie Opuntia cochenillifera (L.) Mill. Foi realizada a prospecção fitoquímica e espectroscopia de absorção de infravermelho (IV) dos extratos etanólicos brutos e frações dos cladódios grande e pequeno. A atividade antioxidante foi avaliada pelo método da capacidade sequestradora de radicais livres utilizando o radical sintético 2,2-difenil-1-picrilhidrazila (DPPH). A atividade citotóxica foi obtida através do método colorimétrico do Metiltetrazolium (MTT). Já a atividade antibacteriana foi avaliada pelo método de microdiluição em caldo para determinar a concentração inibitória mínima (CIM) frente às estirpes bacterianas Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa e Escherichia coli. A prospecção fitoquímica revelou principalmente a presença de fenóis, esteroides livres, alcaloides, alcanos, além de outras classes químicas. O IV apresentou grupos funcionais como alcanos, carbonilas, grupos de metila, duplas ligações de carbono, grupamentos alquilamina, entre outros. Sobre a citotoxicidade na concentração de 100 μg/mL, os dois extratos brutos, todas as frações do cladódio grande e as frações de clorofórmio e metanol do cladódio pequeno não apresentaram toxicidade. Os extratos brutos e frações do cladódio grande e pequeno, não demonstraram atividade antibacteriana e nem antioxidante. Esses resultados podem fornecer suporte para pesquisas futuras, visando outras atividades biológicas da presente espécie vegetal.
ABSTRACT The purpose of this study was to evaluate the antibacterial, antioxidant, and cytotoxic activity of Opuntia cochenillifera (L.) Mill. A phytochemical screening and infrared (IR) absorption spectroscopy were performed in the crude ethanolic extracts and fractions of large and small cladodes. The antioxidant activity was evaluated through the qualitative method of free-radical scavenging capacity using the synthetic radical 2,2-diphenyl-1-picrylhydrazyl (DPPH). The cytotoxic activity was obtained by the cell viability assay using methyl thiazolyl tetrazolium (MTT). Antibacterial activity was evaluated by broth microdilution method to determine the minimum inhibitory concentration (MIC) against the bacterial strains Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, and Escherichia coli. The phytochemical screening mainly revealed the presence of phenols, flavonoids, free steroids, alkaloids, alkanes, and other chemical classes. The IR spectroscopy presented functional groups such as alkanes, carbonyls, methyl groups, carbon double bonds, and alkylamino groups, among others. Regarding cytotoxicity in the concentration of 100 μg/mL, neither the crude extracts, the fractions of the large cladode, nor the chloroform and methanol fractions of small cladode presented toxicity. The crude ethanolic extracts and fractions of large and small cladode showed no antibacterial or antioxidant activity. These results may provide support for future research aimed at other biological activities of this plant species.
