Publications

Abstract The discovery of potent and selective monoamine oxidase-B inhibitors for the management of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases is still a challenging endeavor. Herein, we report the discovery of two new classes of potent and selective MAO-B inhibitors based on chromane-2,4-dione and chromone-3-carboxamide scaffolds.

Abstract Reactive species are continuously produced in vivo by all body tissues. However, when an imbalance between the reactive species production and the endogenous pool of antioxidants occurs, the resulting oxidative stress can somehow intensify the pathophysiological mechanisms of several diseases, such as neurodegenerative diseases. Although the aetiology of Parkinson's and Alzheimer's diseases is not yet completely understood, it is accepted by the scientific community that the oxidative stress can act as a trigger or can be involved in the course of both diseases. Therefore, the development of an antioxidant-based therapy could be a helpful approach to ameliorate the deleterious effects of oxidative stress in neurodegenerative diseases. Coumarins and chromones are natural or synthetic chemical entities described as privileged structures with diverse biological activities that have been used to design new drugs with potential anti-Alzheimer and anti-Parkinson profiles. Since some of these compounds also displayed potent antioxidant activity, the rationale approach to developing new drugs based on the benzopyran scaffold, as therapeutic alternatives for neurodegenerative diseases, is a valid and compelling topic. This review provides a medicinal chemistry overview on the discovery and development of benzopyran-based compounds endowed with antioxidant, neuroprotective and anti-Alzheimer or anti-Parkinson activities.

Abstract One of the major hurdles in the development of safe and effective drugs targeting G-protein coupled receptors (GPCRs) is finding ligands that are highly selective for a specific receptor subtype. The search for novel compounds with therapeutic value by targeting the A(3) adenosine receptor (A(3)AR) is still in its early stages. The increasing knowledge about the biological, physiological and pathological role of the A(3)AR subtype was accompanied by the design and development of the A(3)AR ligands, but the particular role of A(3)AR agonists and antagonists is still an open issue. Among the large variety of chemical classes screened towards ARs flavonoids have been indicated as remarkable A(3)AR antagonists. However, the search of A(3)AR ligands based on this framework seems to be discontinued. In this context, our research group focused its investigation into the discovery and development of novel, potent and selective AR ligands based on the chemical core of flavonoids, the chromone scaffold. The ongoing research has shown that chromone-2-phenylcarboxamide derivatives display a remarkable preference for hA(3)AR. In this work we report stimulating results, supported by A(2A)/A(3) molecular docking simulations and structure-affinity-relationship (SAR) studies by which N-(4,5-methylthiazol-2-yl)-4-oxo-4H-chromene-2-carboxamide (compound 31) emerged as the most potent and selective compound, displaying an hA(3) K-i of 167 nM and a selectivity ratio of 590 vs. the hA(1) and 480 vs. the hA(2A)AR subtypes. The chromone-based ligand was obtained by a simple synthetic approach and will enter in a lead optimization program to enhance its potency and drug-like properties.

Abstract The crystal structures of the 3-substituted tertiary chromone carboxamide derivative, C17H13NO3, N-methyl-4-oxo-N-phenyl-4H-chromene-3-carboxamide (1), and the chromone carbonyl pyrrolidine derivatives, C14H13NO3, 3-(pyrrolidine-1-carbonyl)-4H-chromen-4-one (3) and 2-(pyrrolidine-1-carbonyl)-4H-chromen-4-one (4) have been determined. Their structural features are discussed and compared with similar compounds namely with respect to their MAO-B inhibitory activities. The chromone carboxamide presents a -syn conformation with the aromatic rings twisted with respect to each other [the dihedral angle between the mean planes of the chromone system and the exocyclic phenyl ring is 58.48 (8)degrees]. The pyrrolidine derivatives also display a significant twist: the dihedral angles between the chromone system and the best plane formed by the pyrrolidine atoms are 48.9 (2) and 23.97 (12)degrees in (3) and (4), respectively. Compound (3) shows a short C-H center dot center dot center dot O intramolecular contact forming an S(7) ring. The supramolecular structures for each compound are defined by weak C-H center dot center dot center dot O hydrogen bonds, which link the molecules into chains and sheets. The Cambridge Structural Database gave 45 hits for compounds with a pyrrolidinecarbonyl group. A simple statistical analysis of their geometric parameters is made in order to compare them with those of the molecules determined in the present work.

Abstract The development and application of a polyaniline/carbon nanotube (CNT) cyclodextrin matrix (PANI-beta-CD/MWCNT)-based electrochemical sensor for the quantitative determination of the herbicide 4-chloro-2-methylphenoxyacetic acid (MCPA) and its main transformation product 4-chloro-2-methylphenol in natural waters are described. A simple cyclic voltammetry-based electrochemical methodology, in phosphate buffer solution at pH 6.0, was used to develop a method to determine both MCPA and 4-chloro-2-methylphenol, without any previous extraction or derivatization steps. A linear concentration range (10 to 50 mu mol L-1) and detection limits of 1.1 and 1.9 mu mol L-1, respectively, were achieved using optimized cyclic voltammetric parameters. The proposed method was successfully applied to the determination of MCPA and 4-chloro-2-methylphenol in natural water samples with satisfactory recoveries (94 to 107 %) and in good agreement with the results obtained by an established high-performance liquid chromatography technique, no significant differences being found between the methods. Interferences from ionic species and other herbicides used for broad-leaf weed control were shown to be small. The newly developed methodology was also successfully applied to MCPA photodegradation environmental studies.

Abstract A detailed investigation of the dilute solutions of several imidazolium-based ([BMIM][Br], [EMIM][BF4], [BMIM][BF4], [HexMIM][BF4], [BMIM][Tf]) and pyridinium-based ([BMP][BF4]) ionic liquids, and two tetraalkylammonium salts (Bu4NBr and Bu4NBPh4) in methanol was carried out between 278.15 and 328.15 K. The limiting molar and ionic association constants were derived using the Lee-Wheaton equation. The limiting molar conductivity for room-temperature ionic liquids with common anion ([BF4]-) is found to obey the Stokes' law: Λ0 increases as the cation size decreases. Ionic association in all studied systems does not show definite correlation with cation structure, while it strongly depends on anion size and structure. Ion association constants are discussed and the role of non-Coulombic forces is demonstrated with the help of short-range square-mound potential. Performed data analysis indicates the formation of contact ion pair of similar structure in studied solutions of ionic liquids, with anion coordinated by imidazole or pyridine ring. The formation of H-bonding between bromide-anion and hydroxy-group of methanol was observed.

Abstract With the aim of finding new adenosine receptor (AR) ligands presenting the 3-amidocoumarin scaffold, a study focusing on the discovery of new chemical entities was carried out. The synthesized compounds 1-8 were evaluated in radioligand binding (A(1), A(2A) and A(3)) and adenylyl cyclase activity (A(2B)) assays in order to determine their affinity for human AR subtypes. The 3-benzamide derivative 4 showed the highest affinity of the whole series and was more than 30-fold selective for the A(3) AR (K-i = 3.24 mu M). The current study supported that small structural changes in this scaffold allowed modulating the affinity resulting in novel promising classes of A(1), A(2A), and/or A(3) AR ligands. We also performed docking calculations in hA(2A) and hA(3) to identify the hypothetical binding mode for the most active compounds. In addition, some ADME properties were calculated in order to better understand the potential of these compounds as drug candidates.