Fernando Cagide

Combining QSAR classification models for predictive modeling of human monoamine oxidase inhibitors.

Due to their role in the metabolism of monoamine neurotransmitters, MAO-A and MAO-B present a significant pharmacological interest. For instance the inhibitors of human MAO-B are considered useful tools for the treatment of Parkinson Disease. Therefore, the rational design and synthesis of new MAOs inhibitors is considered of great importance for the development of new and more effective treatments of Parkinson Disease. In this work, Quantitative Structure Activity Relationships (QSAR) has been developed to predict the human MAO inhibitory activity and selectivity. The first step was the selection of a suitable dataset of heterocyclic compounds that include chromones, coumarins, chalcones, thiazolylhydrazones, etc. These compounds were previously synthesized in one of our laboratories, or elsewhere, and their activities measured by the same assays and for the same laboratory staff. Applying linear discriminant analysis to data derived from a variety of molecular representations and feature selection algorithms, reliable QSAR models were built which could be used to predict for test compounds the inhibitory activity and selectivity toward human MAO. This work also showed how several QSAR models can be combined to make better predictions. The final models exhibit significant statistics, interpretability, as well as displaying predictive power on an external validation set made up of chromone derivatives with unknown activity (that are being reported here for first time) synthesized by our group, and coumarins recently reported in the literature.

Host-guest complexes of phenoxy alkyl acid herbicides and cyclodextrins. MCPA and β-cyclodextrin

The chlorophenoxy herbicide MCPA (4-chloro-2-methylphenoxyacetic acid), widely used for the control of broad-leaf weeds primarily in cereal and grass seed crops, still remains one of the most often used herbicides in Portugal. As the formation of inclusion complexes with cyclodextrins can improve its solubility properties, the interaction between the herbicide MCPA and β-cyclodextrin was investigated. The stability constants describing the extent of formation of the complexes have been determined by phase-solubility studies. Different analytical techniques [ultraviolet-visible spectroscopy (UV-Vis), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), proton nuclear magnetic resonance spectroscopy (1H NMR)] were employed for a thorough investigation of the structural characteristics of the obtained complexes, which exhibited distinct features and properties from both “guest” and “host” molecules. FTIR and 1H NMR data obtained for the MCPA/β-CD complexes gave information about the interaction between MCPA and the nonpolar cyclodextrin cavity. The dramatic change observed in band frequency and proton displacements of OCH2 group and H6 aromatic proton confirmed the inclusion of MCPA in β-CD. The formation of an inclusion complex between MCPA and β-CD increased the aqueous solubility of this herbicide which could be a particularly advantageous property for some specific applications, namely to improve commercial formulation and for environmental protection.

Development of hydroxybenzoic-based platforms as a solution to deliver dietary antioxidants to mitochondria

Oxidative stress and mitochondrial dysfunction have been associated with metabolic and age-related diseases. Thus, the prevention of mitochondrial oxidative damage is nowadays a recognized pharmacological strategy to delay disease progression. Epidemiological studies suggested an association between the consumption of polyphenol-rich diet and the prevention of different pathologies, including diseases with a mitochondrial etiology. The development of mitochondrial-targeted antioxidants based on dietary antioxidants may decrease mitochondrial oxidative damage. Herein, we report the design and synthesis of two new mitochondriotropic antioxidants based on hydroxybenzoic acids (AntiOxBENs). The results obtained showed that the novel antioxidants are accumulated inside rat liver mitochondria driven by the organelle transmembrane electric potential and prevented lipid peroxidation, exhibiting low toxicity. Some of the observed effects on mitochondrial bioenergetics resulted from an increase of proton leakage through the mitochondrial inner membrane. The new derivatives present a higher lipophilicity than the parent compounds (protocatechuic and gallic acids) and similar antioxidant and iron chelating properties. AntiOxBENs are valid mitochondriotropic antioxidant prototypes, which can be optimized and used in a next future as drug candidates to prevent or slow mitochondrial oxidative stress associated to several pathologies.

Development of a Mitochondriotropic Antioxidant Based on Caffeic Acid: Proof of Concept on Cellular and Mitochondrial Oxidative Stress Models

Targeting mitochondrial oxidative stress is an effective therapeutic strategy. In this context, a rational design of mitochondriotropic antioxidants (compounds 22-27) based on a dietary antioxidant (caffeic acid) was performed. Jointly named as AntiOxCINs, these molecules take advantage of the known ability of the triphenylphosphonium cation to target active molecules to mitochondria. The study was guided by structure-activity-toxicity-property relationships, and we demonstrate in this work that the novel AntiOxCINs act as mitochondriotropic antioxidants. In general, AntiOxCINs derivatives prevented lipid peroxidation and acted as inhibitors of the mitochondrial permeability transition pore. AntiOxCINs toxicity profile was found to be dependent on the structural modifications performed on the dietary antioxidant. On the basis of mitochondrial and cytotoxicity/antioxidant cellular data, compound 25 emerged as a potential candidate for the development of a drug candidate with therapeutic application in mitochondrial oxidative stress-related diseases. Compound 25 increased GSH intracellular levels and showed no toxicity on mitochondrial morphology and function.

Navigating in chromone chemical space: discovery of novel and distinct A3 adenosine receptor ligands

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 A3 adenosine receptor (A3AR) is still in its early stages. The increasing knowledge about the biological, physiological and pathological role of the A3AR subtype was accompanied by the design and development of the A3AR ligands, but the particular role of A3AR agonists and antagonists is still an open issue. Among the large variety of chemical classes screened towards ARs flavonoids have been indicated as remarkable A3AR antagonists. However, the search of A3AR 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 hA3AR. In this work we report stimulating results, supported by A2A/A3 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 hA3 Ki of 167 nM and a selectivity ratio of 590 vs. the hA1 and 480 vs. the hA2AAR 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.

The crystal structures of four N-(4-halophen­yl)-4-oxo-4H-chromene-3-carboxamides

In four N-(4-halophenyl)-4-oxo-4H-chromene-3-carboxamides, halo = -F, -Cl, -Br and -I, the molecules are essentially planar and exhibit anti conformations with respect to the C—N rotamer of the amide and with cis geometries with respect to the relative positions of the C3arom—C2arom bond of the chromone ring and the carbonyl group of the amide.

Ligand-Based Virtual Screening Using Tailored Ensembles: A Prioritization Tool for Dual A 2A Adenosine Receptor Antagonists / Monoamine Oxidase B Inhibitors

BACKGROUND Virtual Screening methodologies have emerged as efficient alternatives for the discovery of new drug candidates. At the same time, ensemble methods are nowadays frequently used to overcome the limitations of employing a single model in ligand-based drug design. However, many applications of ensemble methods to this area do not consider important aspects related to both virtual screening and the modeling process. During the application of ensemble methods to virtual screening the proper validation of the models in virtual screening conditions is often neglected. No analysis of the diversity of the ensemble members is performed frequently or no considerations regarding the applicability domain of the base models are being made. METHODS In this research, we review basic concepts and definitions related to virtual screening. We comment recent applications of ensemble methods to ligand-based virtual screening and highlight their advantages and limitations. RESULTS Next, we propose a method based on genetic algorithms optimization for the generation of virtual screening tailored ensembles which address the previously identified problems in the current applications of ensemble methods to virtual screening. CONCLUSION Finally, the proposed methodology is successfully applied to the generation of ensemble models for the ligand-based virtual screening of dual target A2A adenosine receptor antagonists and MAO-B inhibitors as potential Parkinsons disease therapeutics.

Synthesis and NMR studies of novel chromone‐2‐carboxamide derivatives

Chromones are heterocyclic compounds of natural or synthetic origin that possess relevant pharmacological activities. Versatile functionalization of the chromone nucleus allows attaining of a chemical diversity suitable to perform structure–activity relationships in drug discovery and development programs. Accordingly, the synthesis and identification of novel chromone carboxamide derivatives with electron‐donating and electron‐withdrawing substituents in different positions of the exocyclic ring are reported in this work. Their complete structural characterization was performed using one‐dimensional and two‐dimensional resonance techniques. The data acquired are useful for a prompt analysis of related compounds that encompass our integrated medicinal chemistry sketch. Copyright

NO and HNO donors, nitrones, and nitroxides: Past, present, and future

The biological effects attributed to nitric oxide (•NO) and nitroxyl (HNO) have been extensively studied, propelling their array of putative clinical applications beyond cardiovascular disorders toward other age‐related diseases, like cancer and neurodegenerative diseases. In this context, the unique properties and reactivity of the N‐O bond enabled the development of several classes of compounds with potential clinical interest, among which •NO and HNO donors, nitrones, and nitroxides are of particular importance. Although primarily studied for their application as cardioprotective agents and/or molecular probes for radical detection, continuous efforts have unveiled a wide range of pharmacological activities and, ultimately, therapeutic applications. These efforts are of particular significance for diseases in which oxidative stress plays a key pathogenic role, as shown by a growing volume of in vitro and in vivo preclinical data. Although in its early stages, these efforts may provide valuable guidelines for the development of new and effective N‐O‐based drugs for age‐related disorders. In this report, we review recent advances in the chemistry of NO and HNO donors, nitrones, and nitroxides and discuss its pharmacological significance and potential therapeutic application.

New insights in the discovery of novel h-MAO-B inhibitors: structural characterization of a series of N-phenyl-4-oxo-4H-chromene-3-carboxamide derivatives

N-(Substituted phenyl)-4-oxo-4H-chromene-3-carboxamides have very similar conformations but show different inhibition activities against h-MAO-B so it may be assumed that the electronic environment provided by the substituents on the phenyl ring is the primary condition for the pharmacological activities displayed by these molecules.