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1.
Arch Pharm (Weinheim) ; 356(6): e2200653, 2023 Jun.
Article in English | MEDLINE | ID: mdl-36922908

ABSTRACT

Vanillin is the main component of natural vanilla extract and is responsible for its flavoring properties. Besides its well-known applications as an additive in food and cosmetics, it has also been reported that vanillin can inhibit fungi of clinical interest, such as Candida spp., Cryptococcus spp., Aspergillus spp., as well as dermatophytes. Thus, the present work approaches the synthesis of a series of vanillin derivatives with 1,2,3-triazole fragments and the evaluation of their antifungal activities against Candida albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans, Cryptococcus gattii, Trichophyton rubrum, and Trichophyton interdigitale strains. Twenty-two vanillin derivatives were obtained, with yields in the range of 60%-91%, from copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) click reaction between two terminal alkynes prepared from vanillin and different benzyl azides. In general, the evaluated compounds showed moderate activity against the microorganisms tested, with minimum inhibitory concentration (MIC) values ranging from 32 to >512 µg mL-1 . Except for compound 3b against the C. gattii R265 strain, all vanillin derivatives showed fungicidal activity for the yeasts tested. The predicted physicochemical and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties for the compounds indicated favorable profiles for drug development. In addition, a four-dimensional structure-activity relationship (4D-SAR) analysis was carried out and provided useful insights concerning the structures of the compounds and their biological profile. Finally, molecular docking calculations showed that all compounds bind favorably at the lanosterol 14α-demethylase enzyme active site with binding energies ranging from -9.1 to -12.2 kcal/mol.


Subject(s)
Fungicides, Industrial , Fungicides, Industrial/pharmacology , Molecular Docking Simulation , Structure-Activity Relationship , Antifungal Agents/chemistry , Triazoles/pharmacology , Microbial Sensitivity Tests
2.
J Pept Sci ; 28(5): e3382, 2022 May.
Article in English | MEDLINE | ID: mdl-34859535

ABSTRACT

Disintegrins comprise a family of small proteins that bind to and alter the physiological function of integrins, especially integrins that mediate platelet aggregation in blood. Here, we report a lysine-glycine-aspartic acid (KGD) disintegrin-like motif present in a 15-amino acid residue peptide identified in a cDNA library of the amphibian Hypsiboas punctatus skin. The original peptide sequence was used as a template from which five new analogs were designed, chemically synthesized by solid phase, and tested for disintegrin activity and tridimensional structural studies using NMR spectroscopy. The original amphibian peptide had no effect on integrin-mediated responses. Nevertheless, derived peptide analogs inhibited integrin-mediated platelet function, including platelet spreading on fibrinogen.


Subject(s)
Disintegrins , Peptides , Amphibians/genetics , Amphibians/metabolism , Animals , DNA, Complementary/genetics , Disintegrins/chemistry , Disintegrins/genetics , Disintegrins/pharmacology , Peptides/chemistry , Peptides/genetics , Peptides/pharmacology , Platelet Aggregation/physiology
3.
J Enzyme Inhib Med Chem ; 37(1): 287-298, 2022 Dec.
Article in English | MEDLINE | ID: mdl-34894959

ABSTRACT

We synthesised and screened 18 aromatic derivatives of guanylhydrazones and oximes aromatic for their capacity to bind to dengue virus capsid protein (DENVC). The intended therapeutic target was the hydrophobic cleft of DENVC, which is a region responsible for its anchoring in lipid droplets in the infected cells. The inhibition of this process completely suppresses virus infectivity. Using NMR, we describe five compounds able to bind to the α1-α2 interface in the hydrophobic cleft. Saturation transfer difference experiments showed that the aromatic protons of the ligands are important for the interaction with DENVC. Fluorescence binding isotherms indicated that the selected compounds bind at micromolar affinities, possibly leading to binding-induced conformational changes. NMR-derived docking calculations of ligands showed that they position similarly in the hydrophobic cleft. Cytotoxicity experiments and calculations of in silico drug properties suggest that these compounds may be promising candidates in the search for antivirals targeting DENVC.


Subject(s)
Antiviral Agents/pharmacology , Capsid Proteins/antagonists & inhibitors , Dengue Virus/drug effects , Hydrazones/pharmacology , Oximes/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Capsid Proteins/metabolism , Dengue Virus/metabolism , Dose-Response Relationship, Drug , Hydrazones/chemical synthesis , Hydrazones/chemistry , Hydrophobic and Hydrophilic Interactions , Microbial Sensitivity Tests , Molecular Structure , Oximes/chemical synthesis , Oximes/chemistry , Structure-Activity Relationship
4.
Biochim Biophys Acta Proteins Proteom ; 1869(2): 140580, 2021 02.
Article in English | MEDLINE | ID: mdl-33278593

ABSTRACT

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.


Subject(s)
Benzofurans/chemistry , Copper/chemistry , Enzyme Inhibitors/chemistry , Monophenol Monooxygenase/chemistry , Structure-Activity Relationship , Catalytic Domain/drug effects , Enzyme Inhibitors/pharmacology , Ligands , Molecular Docking Simulation , Molecular Structure , Monophenol Monooxygenase/antagonists & inhibitors , Nuclear Magnetic Resonance, Biomolecular
5.
Peptides ; 106: 37-44, 2018 08.
Article in English | MEDLINE | ID: mdl-29933027

ABSTRACT

A previously undescribed six residues long peptide His-Arg-Phe-Leu-Arg-His was identified and purified from the skin secretion of the amphibian Phyllomedusa centralis. A synthetic analogue carboxyamidated HRFLRH-NH2 showed structural changes induced by CO2 and metal ions in aqueous solution when analyzed by NMR. The present work reports NMR structures for the carboxyamidated hexapeptide in the presence CO2, Zn2+ and Cd2+, suggesting possible affinity regions on the polypeptide chain for each ligand. The NMR structures were optimized by DFT to identify probable biding sites of these species in the polypeptide structure. To our best knowledge, this is the first time that a putative CO2 binding site is described on a peptide structure obtained in aqueous conditions, at room temperature.


Subject(s)
Amphibian Proteins/chemistry , Anura/physiology , Carbon Dioxide/chemistry , Cations, Divalent/chemistry , Oligopeptides/chemistry , Skin/metabolism , Amphibian Proteins/isolation & purification , Animals , Binding Sites , Cadmium/chemistry , Ligands , Oligopeptides/isolation & purification , Protein Conformation , Zinc/chemistry
6.
Magn Reson Chem ; 46(11): 1051-4, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18780308

ABSTRACT

Three different calibration curves based on (1)H-NMR spectroscopy (300 MHz) were used for quantifying the reaction yield during biodiesel synthesis by esterification of fatty acids mixtures and methanol. For this purpose, the integrated intensities of the hydrogens of the ester methoxy group (3.67 ppm) were correlated with the areas related to the various protons of the alkyl chain (olefinic hydrogens: 5.30-5.46 ppm; aliphatic: 2.67-2.78 ppm, 2.30 ppm, 1.96-2.12 ppm, 1.56-1.68 ppm, 1.22-1.42 ppm, 0.98 ppm, and 0.84-0.92 ppm). The first curve was obtained using the peaks relating the olefinic hydrogens, a second with the parafinic protons and the third curve using the integrated intensities of all the hydrogens. A total of 35 samples were examined: 25 samples to build the three different calibration curves and ten samples to serve as external validation samples. The results showed no statistical differences among the three methods, and all presented prediction errors less than 2.45% with a co-efficient of variation (CV) of 4.66%.


Subject(s)
Energy-Generating Resources , Fatty Acids/analysis , Gasoline , Magnetic Resonance Spectroscopy/standards , Plant Oils , Calibration , Esterification , Magnetic Resonance Spectroscopy/methods , Protons
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