Carlos A. L. Barros

Avaliação toxicológica do óleo essencial de Piper aduncum L.

Este trabalho teve como objetivo a avaliacao da toxidade aguda e subaguda do oleo essencial de Piper aduncum pela determinacao da DL50 em camundongos e a analise dos parâmetros bioquimicos e hematologicos em ratos. A planta e utilizada na medicina popular da regiao amazonica em diversas doencas e no seu oleo essencial o constituinte majoritario e o fenilpropanoide dilapiol, com propriedades inseticida, fungicida, bactericida, larvicida e moluscicida. A DL50 foi de 2,400 ± 191,7 mg/kg. O oleo essencial nao alterou de maneira significativa os parâmetros hematologicos e bioquimicos em relacao ao controle no tratamento subagudo, exceto a reducao da creatinina. O valor da DL50 e os resultados observados nos parâmetros hematologicos e bioquimicos sugerem que o oleo essencial apresenta toxidade baixa.

The tautomerism influence on the antioxidant prediction of oxederavone

A detailed theoretical prediction of oxedaravone (a hydro-soluble derivative of edaravone) as antioxidant was performed. The DFT method with B3LYP/6-31G(d) basis sets was used for the tautomerism study in gas phase and solvent medium (water and methanol) and the antioxidant capacity was predicted from HOMO, ionization energy (IE), and bond dissociation energies (BDE). All calculations showed that the keto–enol tautomerism of oxedaravone is thermodynamically more favored than the imine–enamine tautomerism and the solvent effect reduced the isomerization energy barriers for the O–H or N–H tautomers. HOMO and IE values showed that the N–H tautomer is a better antioxidant, while the BDE values showed that the O–H tautomer is the better antioxidant. Our results showed that the oxedaravone may be a good strategy for designing polar derivatives of edaravone.

Structure and toxicity of clozapine and olanzapine on agranulocytosis

The structure and toxicity relationship of the dibenzo-1,4-diazepine derivatives has been investigated using quantum chemical calculations at the density functional theory level/B3LYP with the 6-311G(d,p) basis sets by electron or hydrogen transfer calculations as model for the reaction prediction between the derivatives and the free radical species on agranulocytosis. Our results show that the abstraction of an electron or hydrogen from the amino group of the olanzapine is more favored than clozapine. The spin density calculations performed for the radicals formed clarify that olanzapine is more stable than clozapine. These results support that the highest toxicity of the 1,4-dibenzodiazepine compounds on agranulocytosis can be related with a high reactivity of diazepine ring in agreement to experimental results. The toxicity of dibenzo-1,4-diazepine derivatives is more related to hydrogen than electron transfers.

A computational study for the antioxidant capacity increases in hydroxy-derivatives of paracetamol and salicylic acid

Paracetamol is a more potent antioxidant than salicylic acid on the several oxidative stress-forced models. A possible mechanism of hydroxylation by the hydroxyl radicals and their antioxidant properties was performed by molecular modeling using quantum chemical calculations at the B3LYP level of theory. The calculation was made in gas phase and water using PCM method. The electron abstraction for hydroxylated paracetamol derivatives is more favored than hydroxylated salicylic acid derivatives. The increase in antioxidant capacity is more observed for hydroxylated derivatives of the paracetamol than salicylic acid. Some hydroxylated derivatives of paracetamol and salicylic acid were more reactive than trolox by hydrogen transfer. Their antioxidant capacity can be increased by number and position of the hydroxyl group.

Understanding the cytotoxicity or cytoprotective effects of biological and synthetic quinone derivatives by redox mechanism.

AbstractQuinones represent an important class of biological compounds, but are also involved with toxicological intermediates and among their hazardous effects include cytotoxicity, immunotoxicity, and carcinogenesis. The structure–toxicity relationship for quinone derivatives has been used to cytotoxicity or cytoprotective effects by redox mechanism is determined using quantum chemical calculations through the density functional theory (DFT). According to our DFT study, the electron acceptance is related with LUMO, electron affinity, and stabilization energy values. The highest spin density distribution in the heteroatoms is more favored for the more cytotoxic compounds. The electrophilic capacities of these compounds have been related with LUMO values. The cytotoxic properties of quinones are related to the stabilization energy after electron accepting by redox mechanism. Electron affinity is the most relevant parameter related to toxicity mechanism. Regioisomers has different electrophilic capacity. The electrophilicity increases on molecules containing electron-withdrawing groups (EWG) and reduces on molecules containing electron-donating groups (EDG). These results explain the toxic difference between natural and synthetic quinone derivatives and can be used in the design and study of new drugs. Graphical AbstractBiological and synthetic ortho and para quinone derivatives

Molecular dynamics simulation and binding free energy studies of novel leads belonging to the benzofuran class inhibitors of Mycobacterium tuberculosis Polyketide Synthase 13

In this work, the binding mechanism of new Polyketide Synthase 13 (Pks13) inhibitors has been studied through molecular dynamics simulation and free energy calculations. The drug Tam1 and its analogs, belonging to the benzofuran class, were submitted to 100 ns simulations, and according to the results obtained for root mean square deviation, all the simulations converged from approximately 30 ns. For the analysis of backbone flotation, the root mean square fluctuations were plotted for the Cα atoms; analysis revealed that the greatest fluctuation occurred in the residues that are part of the protein lid domain. The binding free energy value (ΔGbind) obtained for the Tam16 lead molecule was of −51.43 kcal/mol. When comparing this result with the ΔGbind values for the remaining analogs, the drug Tam16 was found to be the highest ranked: this result is in agreement with the experimental results obtained by Aggarwal and collaborators, where it was verified that the IC50 for Tam16 is the smallest necessary to inhibit the Pks13 (IC50 = 0.19 μM). The energy decomposition analysis suggested that the residues which most interact with inhibitors are: Ser1636, Tyr1637, Asn1640, Ala1667, Phe1670, and Tyr1674, from which the greatest energy contribution to Phe1670 was particularly notable. For the lead molecule Tam16, a hydrogen bond with the hydroxyl of the phenol not observed in the other analogs induced a more stable molecular structure. Aggarwal and colleagues reported this hydrogen bonding as being responsible for the stability of the molecule, optimizing its physic-chemical, toxicological, and pharmacokinetic properties.

Experimental and theoretical study between cefoxitin and Escherichia coli 5 protein on selection of bioactive molecules against resistant strain

The penicillin‐binding proteins (PBPs) are important biological target for new antibacterial drugs development. This study focused on molecular interaction between cefoxitin and the Escherichia coli PBP5 by molecular dynamics (MD) using hybrid quantum mechanics/molecular mechanics (QM/MM) simulations approach, searching to develop a computational simulations prototype method on antimicrobial susceptibility of gram‐negative bacteria against antibiotics. Escherichia coliATCC 8739 strain susceptibility for the drugs used in the antimicrobial susceptibility testing and selection of bioactive molecules against resistant strain. The protonation revealed a deprotonate state for His146, His151, His216, and His320 residues. The complex was stabilized after 0.6 ns of MD simulation. The global interaction means for inhibition zone diameters of E. coliATCC8739 strain and cefoxitin were 24.33 mm no showing significant difference between computational and experimental methods. Our computational simulation method can reliably be performed as a molecular modeling prototype for gram‐negative antimicrobial susceptibility testing bacteria.The Penicillin Binding Proteins (PBPs) are important biological target for new antibacterial drugs development. This study focused on molecular interaction between cefoxitin and the Escherichia coli PBP5 by molecular dynamics (MD) by using hybrid quantum mechanics/molecular mechanics (QM/MM) simulations approach, searching to develop a computational simulations prototype method on antimicrobial susceptibility of gram-negative bacteria against antibiotics. E. coli ATCC 8739 strain susceptibility for the drugs used in the antimicrobial susceptibility testing and selection of bioactive molecules against resistant strain. The protonation revealed a deprotonate state for His146, His151, His216 and His320 residues. The complex was stabilized after 0.6 ns of MD simulation. The global interaction means for inhibition zone diameters of E. coli ATCC8739 strain and cefoxitin was 24.33 mm no showing significant difference between computational and experimental methods. Our computational simulation method can reliably be performed as a molecular modeling prototype for gram-negative antimicrobial susceptibility testing bacteria. This article is protected by copyright. All rights reserved.