Miguel A. Vázquez

Densely substituted unnatural L- and D-prolines as catalysts for highly enantioselective stereodivergent (3 + 2) cycloadditions and aldol reactions

(3 + 2) Cycloaddition reaction between azomethine ylides and π-deficient alkenes leads to densely substituted L- and D-unnatural prolines. These (3 + 2) cycloadducts in turn catalyse the preparation of an offspring of unnatural endo- and exo-L-proline derivatives. These latter compounds are also efficient catalysts of aldol reactions and yield aldol adducts with the opposite stereochemistry obtained under natural L-Pro organocatalysis.

Highly Regio- and Stereoselective Diels-Alder Cycloadditions via Two-Step and Multicomponent Reactions Promoted by Infrared Irradiation under Solvent-Free Conditions

Infrared irradiation promoted the Diels-Alder cycloadditions of exo-2-oxazolidinone dienes 1–3 with the Knoevenagel adducts 4–6, as dienophiles, leading to the synthesis of new 3,5-diphenyltetrahydrobenzo[d]oxazol-2-one derivatives (7, 9, 11 and 13–17), under solvent-free conditions. These cycloadditions were performed with good regio- and stereoselectivity, favoring the para-endo cycloadducts. We also evaluated the one-pot three-component reaction of active methylene compounds 20, benzaldehydes 21 and exo-2-oxazolidinone diene 2 under the same reaction conditions. A cascade Knoevenagel condensation/Diels-Alder cycloaddition reaction was observed, resulting in the final adducts 13–16 in similar yields. These procedures are environmentally benign, because no solvent and no catalyst were employed in these processes. The regioselectivity of these reactions was rationalized by Frontier Molecular Orbital (FMO) calculations.

Synthesis, ex vivo and in silico studies of 3-cyano-2-pyridone derivatives with vasorelaxant activity

An efficient and simple synthesis of 3-cyano-2-pyridone derivatives (6a-f) through 3,4-dihydropyridin-2-one oxidation process is described. A greener method to synthesize 3,4-dihydropyridin-2-one has also been developed by rearranging 4H-pyran (4a-f) derivatives in aqueous medium applying H₂SO₄ as the catalyst source and microwave irradiation. The vasorelaxant activity of 3-cyano-2-pyridone derivatives (6a-f) was proved on isolated thoracic aorta rat rings with and without endothelium (+E and -E, respectively) pre-contracted with noradrenaline (0.1 μM). All compounds exhibited significant concentration-dependent and endothelium-independent vasorelaxant effects being the nitro derivatives (6a and f) and compound 6d the most potent with EC₅₀ of 7, 4.4 and 5 μM, respectively. Finally, a previously described 3D model of the central pore of human L-type calcium channel (LCC), modified to be on agreement with NCBI sequence NP_005174.2 for subunit alpha-1F isoform 1, was used to dock most active compounds. 6a, d and f lowest affinity energy structures were found docked in the same cavity conformed by IS6, IS5, IP and IIS6 helices. Nifedipine lowest energy structure was found in the cavity formed by IIS6, IIS5, IIP and IIIS6. Although nifedipine docked in a different cavity, the superposition of both, allowed us to observe that they were almost the same cavities, indicating that there exist subtle steric differences that lead to a different docking for nifedipine. All compounds docked with similar free energy of binding.

Molecular docking-based screening of newly designed coumarin derivatives with potential antifungal activity against lanosterol 14 α-demethylase

A number of new coumarin derivatives (CD) have been proposed at our research laboratory, from a molecular docking study, and we determine the ones that potentially would show antifungal activity. This is done by comparing the binding modes of the new CD with the active site of protein CYP51, which is experimentally known to be the biological target of one very important group of commercial antifungal agents currently employed (azolic antifungal drugs), such as Fluconazole (FLU). In this way, we could establish which of the new CD would bind in a similar way to the FLU binding mode to the active site of CYP51 and compare the relative interaction energies. Our computational study suggests that two of the proposed CD show ligand efficiencies and binding modes comparable to those of FLU, and thus that they would be suitable antifungal agents.

A simple method for the synthesis of 1,3-diaminopropan-2-ols derivatives and their ex vivo relaxant activity on isolated rat tracheal rings

A mild and eco-friendly method has been developed for the synthesis of a series of 1,3-diaminopropan-2-ols 8a–n. The epoxide of epichlorohydrin undergoes ring-opening with amines using MgSO4 or mixed metal oxides catalysts under mild and neutral conditions to afford the corresponding β-amino alcohols in excellent yields. Preliminary evaluation of relaxant activity of 8b–n was carried out on rat tracheal rings contracted by carbachol 1 μM. Most of the tested compounds exhibited significantly relaxant effects in a concentration-dependent manner. Compound 8n was found to be the most active, being twofolds more potent than theophylline (positive control). This compound has the potential for development as an anti-asthma drug.Graphical Abstract

Mechanism of Relaxant Action of Ethyl 6-amino-5-cyano-2-methyl-4-(pyridin-4-yl)-4H-pyran-3-carboxylate Mainly Through Calcium Channel Blockade in Isolated Rat Trachea

This study aims to investigate the mechanism of relaxant action of Ethyl 6-amino-5-cyano-2-methyl-4-(pyridin-4-yl)-4H-pyran-3-carboxylate (1) in in silico study and ex vivo tracheal rat rings pre-contracted with carbachol (1 µM). Compound 1 was more active than theophylline a phosphodiesterases (PDE’s) inhibitor used as positive control. Moreover, pretreatment with 1 significantly shifted to the right the carbachol-induced contraction and did not allow to reach the maximum effect (p

CCDC 830011: Experimental Crystal Structure Determination

Related Article: E.Conde, D.Bello, A.de Cozar, M.Sanchez, M.A.Vazquez, F.P.Cossio|2012|Chemical Science|3|1486|doi:10.1039/c2sc20199b