Increasing the polarity of ß-lapachone does not affect its binding capacity with bovine plasma protein.

Despite ortho-quinones showing several biological and pharmacological activities, there is still a lack of biophysical characterization of their interaction with albumin - the main carrier of different endogenous and exogenous compounds in the bloodstream. Thus, the interactive profile between bovine serum albumin (BSA) with ß-lapachone (1) and its corresponding synthetic 3-sulfonic acid (2, under physiological pH in the sulphonate form) was performed. There is one main binding site of albumin for both ß-lapachones (n ≈ 1) and a static fluorescence quenching mechanism was proposed. The Stern-Volmer constant (KSV) values are 104 M-1, indicating a moderate binding affinity. The enthalpy (-3.41 ± 0.45 and - 8.47 ± 0.37 kJ mol-1, for BSA:1 and BSA:2, respectively) and the corresponding entropy (0.0707 ± 0.0015 and 0.0542 ± 0.0012 kJ mol-1 K-1) values indicate an enthalpically and entropically binding driven. Hydrophobic interactions and hydrogen bonding are the main binding forces. The differences in the polarity of 1 and 2 did not change significantly the affinity to albumin. In addition, the 1,2-naphthoquinones showed a similar binding trend compared with 1,4-naphthoquinones.

Novel N,N-di-alkylnaphthoimidazolium derivative of ß-lapachone impaired Trypanosoma cruzi mitochondrial electron transport system.

Trypanosoma cruzi is a protozoan parasite that causes Chagas disease, a neglected tropical disease that is endemic in Latin America and spreading worldwide due to globalization. The current treatments are based on benznidazole and nifurtimox; however, these drugs have important limitations and limited efficacy during the chronic phase, reinforcing the necessity of an alternative chemotherapy. For the last 30 years, our group has been evaluating the biological activity of naphthoquinones and derivatives on T. cruzi, and of the compounds tested, N1, N2 and N3 were found to be the most active in vitro. Here, we show the synthesis of a novel ß-lapachone-derived naphthoimidazolium named N4 and assess its activity on T. cruzi stages and the mechanism of action. The new compound was very active on all parasite stages (IC50/24 h in the range of 0.8-7.9 µM) and had a selectivity index of 5.4. Mechanistic analyses reveal that mitochondrial ROS production begins after short treatment starts and primarily affects the activity of complexes II-III. After 24 h treatment, a partial restoration of mitochondrial physiology (normal complexes II-III and IV activities and controlled H2O2 release) was observed; however, an extensive injury in its morphology was still detected. During treatment with N4, we also observed that trypanothione reductase activity increased in a time-dependent manner and concomitant with increased oxidative stress. Molecular docking calculations indicated the ubiquinone binding site of succinate dehydrogenase as an important interaction point with N4, as with the FMN binding site of dihydroorotate dehydrogenase. The results presented here may be a good starting point for the development of alternative treatments for Chagas disease and for understanding the mechanism of naphthoimidazoles in T. cruzi.

Fluorescence and Docking Studies of the Interaction between Human Serum Albumin and Pheophytin.

In the North of Brazil (Pará and Amazonas states) the leaves of the plant Talinum triangulare (popular: cariru) replace spinach as food. From a phytochemical point of view, they are rich in compounds of the group of pheophytins. These substances, related to chlorophyll, have photophysical properties that give them potential application in photodynamic therapy. Human serum albumin (HSA) is one of the main endogenous vehicles for biodistribution of molecules by blood plasma. Association constants and thermodynamic parameters for the interaction of HSA with pheophytin from Talinum triangulare were studied by UV-Vis absorption, fluorescence techniques, and molecular modeling (docking). Fluorescence quenching of the HSA's internal fluorophore (tryptophan) at temperatures 296 K, 303 K, and 310 K, resulted in values for the association constants of the order of 104 L∙mol(-1), indicating a moderate interaction between the compound and the albumin. The negative values of ΔG° indicate a spontaneous process; ΔH° = 15.5 kJ∙mol(-1) indicates an endothermic process of association and ΔS° = 0.145 kJ∙mol(-1)∙K(-1) shows that the interaction between HSA and pheophytin occurs mainly by hydrophobic factors. The observed Trp fluorescence quenching is static: there is initial non-fluorescent association, in the ground state, HSA:Pheophytin. Possible solution obtained by a molecular docking study suggests that pheophytin is able to interact with HSA by means of hydrogen bonds with three lysine and one arginine residues, whereas the phytyl group is inserted in a hydrophobic pocket, close to Trp-214.

Crystal structure and hydrogen bonding study of (10E)-2,2-dimethyl-3,4-dihydro-2H-benzo[g]chromene-5,10-dione 10-oxime derived from α-lapachone.

The compound (10E)-2,2-dimethyl-3,4-dihydro-2H-benzo[g]chromene-5,10-dione-10-oxime (1) was synthesized from a-lapachone and hydroxylamine chloride in alkaline medium. Single-crystals suitable for X-ray diffraction measurements were grown from an ethanol solution, and the crystal structure of the title molecule is reported for the first time. The title molecule was also characterized by ¹H- and ¹³C-NMR in CDCl3 solution, FTIR and MS. The crystal structure of 1 shows an E stereochemistry and dimers formed through classical hydrogen bonds.

The (alpha-1,6) glycosidic bond of isomaltose: a tricky system for theoretical conformational studies.

Stable conformations of beta-isomaltose (alpha-D-glucopyranosyl-(1-->6)-beta-D-glucose) in gas-phase and aqueous solution are investigated in this study using quantum mechanical calculations. Conformational maps are calculated at HF/6-31G(d,p) level and lower energy structures are sampled in the most stable regions. Entropic and thermal corrections are considered and the Boltzmann population is obtained for conformers that are representative of the 18 most stable regions found on the potential energy surface. B3LYP/6-31+G(d,p) and B3LYP/6-311+G(2d,2p) calculations are used in conformational samplings. Solvation effects are considered through the polarizable continuum model approach. Hydroxymethyl group orientations are investigated for the most stable conformers. The influence of electronic correlation and solvation on the glycosidic linkage preference (TG, GT, and GG) and hydroxymethyl group orientation (tg, gt, and gg) are discussed. Heteronuclear spin coupling constants ((3)J(C,H)) along the glycosidic linkage are calculated and comparison with other theoretical results and experiments is used to validate the obtained structures.