Isobenzofuran-1(3H)-ones as new tyrosinase inhibitors: Biological activity and interaction studies by molecular docking and NMR.

Tyrosinase is a multifunctional, glycosylated and copper-containing oxidase enzyme that can be found in animals, plants, and fungi. It is involved in several biological processes such as melanin biosynthesis. In this work, a series of isobenzofuran-1(3H)-ones was evaluated as tyrosinase inhibitors. It was found that compounds phthalaldehydic acid (1), 3-(2,6-dihydroxy-4-isopropylphenyl)isobenzofuran-1(3H)-one (7), and 2-(3-oxo-1,3-dihydroisobenzofuran-1-yl)-1,3-phenylene diacetate (9) were the most potent compounds inhibiting tyrosinase activity in a concentration dependent manner. Ligand-enzyme NMR studies and docking investigations allowed to map the atoms of the ligands involved in the interaction with the copper atoms present in the active site of the tyrosinase. This behaviour is similar to kojic acid, a well know tyrosinase inhibitor and used as positive control in the biological assays. The findings herein described pave the way for future rational design of new tyrosinase inhibitors.

Theoretical studies and NMR assay of coumarins and neoflavanones derivatives as potential inhibitors of acetylcholinesterase.

Currently Alzheimer's disease (AD) is a devastating neurological disorder that mainly affects the elderly. The treatment of AD has as main objective to increase the levels of ACh in the synaptic cleft by inhibiting the cholinesterase enzymes, which are responsible for the degradation of ACh. Twenty one synthesized coumarins and neoflavanones (4-arylcoumarins) and theoretical studies were used to select the most promising ligands for in vitro experimental studies by Nuclear Magnetic Resonance. The eight compounds selected for the experimental study only 12b (effectiveness 68.54 ±â€¯3.22%) was promising AChE inhibitor. This compound (12b) presents substituents at positions 4, 5, 6, 7 and 8 in a coumarin nucleus, being the most significant characteristic in comparison to the other studied compounds. These results can be used for the design and synthesis of other possible derivatives with inhibitory potential of AChE.

Synthesis of New Quinoline-Piperonal Hybrids as Potential Drugs against Alzheimer's Disease.

Six quinoline-piperonal hybrids were synthesized and evaluated as potential drugs against Alzheimer's disease (AD). Theoretical analysis of the pharmacokinetic and toxicological properties of the compounds suggest that they present good oral bio-availability and are also capable of penetrating the blood-brain barrier, qualifying as leads for new drugs against AD. Evaluation of their inhibitory capacity against acetyl- and butyrilcholinesterases (AChE and BChE) through Ellmann's test showed that three compounds present promising results with one of them being capable of inhibiting both enzymes. Further docking studies of the six compounds synthesized helped to elucidate the main interactions that may be responsible for the inhibitory activities observed.

Expression, purification and spectrophotometric analysis of nucleoside hydrolase from Leishmania chagasi (LcNH).

Leishmaniasis represents an important public health problem in several countries. The main target in this study is the nucleoside hydrolase Leishmania chagasi (LcNH) that is responsible for causing visceral leishmaniasis, principally in Brazil. Nucleoside hydrolase enzymes are members of this pathway, hydrolyzing the N-glycosidic bond of ribonucleosides for the synthesis of nucleic acids. We present here for the first time, the expression and purification protocols to obtain the enzymes LcNH1 and LcNH2 that can be employed to explore novel strategies to produce nucleoside hydrolase inhibitors for use in chemotherapy. Protein integrity was also confirmed by SDS-PAGE gel, mass spectrometry and enzymatic activity.

The importance of nucleoside hydrolase enzyme (NH) in studies to treatment of Leishmania: A review.

Leishmania is a genus of trypanosomes, which are responsible for leishmaniasis disease, a major trypanosome infection in humans. In recent years, published studies have shown that the search for new drugs for Leishmania treatments has intensified. Through technique modeling it has been possible to develop new compounds, which act as nucleoside hydrolase (NH) inhibitors. The effect of these enzymes is the hydrolysis of certain RNA nucleotides, which include uridine and inosine, necessary for the protozoa to transform certain nucleosides obtained from infected individuals into nucleobases for the preparation of their DNA. The obtention of NH inhibitors is very important to eliminate leishmaniasis disease in infected individuals. The aim of this study is to discuss the research and development of new agents for the treatment of Leishmania, and to stimulate the formulation of new NH inhibitors.

Coumarins as cholinesterase inhibitors: A review.

The first report in literature of the isolation of coumarin was in the year 1820. After this report, other papers were published demonstrating the isolation and synthesis of coumarin and analogues. These compounds have been studying along the years for several different pathologies. One of these pathologies was Alzheimer's disease (AD), being the main cause of dementia in the contemporary world. There are two hypotheses to explain the pathogenesis mechanism and disease symptoms, then having the "amyloid hypothesis" and the "cholinergic hypothesis". Some drugs for AD are based on the theory of "cholinergic hypothesis", which objective is to increase the concentration of ACh in the synaptic cleft by the inhibition of cholinesterases. Over the last twenty years, many studies with coumarins compounds were reported as cholinesterases inhibitors. The aim of the present review is to discuss the studies and development of new compounds for AD treatment.

Conformational analysis of 1-chloro- and 1-bromo-2-propanol.

The conformational isomerism of 1-chloro- (1) and 1-bromo-2-propanol (2) was theoretically and spectroscopically (NMR) analyzed. Conformers with the X-C-C-O (X = Cl and Br) fragment in the gauche orientation were found to be strongly prevalent both in the gas phase and solution, as analyzed by means of coupling constants in the diastereotopic methylene hydrogens. The gauche effect was calculated to be due to hyperconjugation rather than intramolecular X···HO hydrogen bond, indicating the rule of the stereochemical control in compounds with motifs (halohydrins) widely found in pharmaceutical and agrochemical products and intermediates.

Nucleophilic reactivation of sarin-inhibited acetylcholinesterase: a molecular modeling study.

Oximes have been used as reactivators for organophosphorus-inhibited acetylcholinesterase (AChE). However, it is still not clear why oximes are more efficient than other nucleophiles, since the reactivation consists of a simple nucleophilic substitution. In an attempt to answer this question, we have modeled the sarin-inhibited AChE reactivation by other nucleophiles (with and without the so-called alpha-effect) by applying the B3LYP/6-311G(d,p) level of theory. We have concluded that oximes reactivate AChE by a three-step mechanism in opposition to the four-step processes of the other modeled nucleophiles. In addition, our model suggests that oximes react with AChE in the deprotonated form (oximate). Our results also indicate that other nucleophiles may be used as AChE reactivators. We propose the use of hydrazones and hydrazonates for further evaluation as antidotes for intoxication by chemical warfare agents.

A three-dimensional structure of Plasmodium falciparum serine hydroxymethyltransferase in complex with glycine and 5-formyl-tetrahydrofolate. Homology modeling and molecular dynamics.

Cytosolic Plasmodium falciparum serine hydroxymethyltransferase (pfSHMT) is a potential target for antimalarial chemotherapy. Contrasting with the other enzymes involved in the parasite folate cycle, little information is available about this enzyme, and its crystallographic structure is unknown yet. In this paper, we propose a theoretical low-resolution 3D model for pfSHMT in complex with glycine and 5-formyl tetrahydrofolate (5-FTHF) based on homology modeling by multiple alignment followed by intensive optimization, validation and dynamics simulations in water. Comparison between the active sites of our model and that of crystallographic Human SHMT (hSHMT) revealed key differences that could be useful for the design of new selective inhibitors of pfSHMT.