Isabel Dorronsoro

A mild and efficient method for the regioselective iodination of pyrazoles

Abstract The iodination of N-H or N-benzylpyrazoles using elemental iodine in the presence of CAN as the in situ oxidant is a mild and efficient method to prepare 4-iodopyrazoles containing even electron-withdrawing substituents. The reaction is regioselective since the iodine atom preferred pyrazole instead of the benzyl group, and the 4-pyrazolic position instead of other possible positions in the heterocycle.

Inhibitors of glycogen synthase kinase-3: future therapy for unmet medical needs?

Glycogen synthase kinase-3 (GSK-3) has recently emerged, in the field of medicinal chemistry, as one of the most attractive therapeutic targets for the development of selective inhibitors as promising new drugs for numerous serious pathologies, including Alzheimer’s disease, stroke, bipolar disorders, chronic inflammatory processes, cancer and Type II diabetes. The full potential of GSK-3 inhibitors is yet to be realised and the number of drug candidates being developed by both academic centres and pharmaceutical companies has increased exponentially in the last three years. This review discloses recent discoveries on peptides and small molecules targeting GSK-3. Antisense therapy for the modulation of GSK-3 expression is also discussed. Focusing attention on this exciting target could thus reap considerable clinical and economic rewards.

Dual binding site acetylcholinesterase inhibitors: potential new disease-modifying agents for AD.

The therapeutic potential of acetylcholinesterase (AChE) inhibitors has been strengthened recently by evidence showing that besides their role in cognitive function, they might contribute to slow down the neurodegeneration in Alzheimers disease (AD) patients. It is known that AChE exerts secondary noncholinergic functions, related to its peripheral anionic site, in cell adhesion and differentiation, and recent findings also support its role in mediating the processing and deposition of beta-amyloid (Abeta) peptide. AChE is one of the proteins that colocalizes with Abeta peptide deposits in the brain of AD patients and promotes Abeta fibrillogenesis by forming stable AChEA beta complexes. Additionally, it has also been postulated that AChE binds through its peripheral site to the Abeta nonamyloidogenic form and acts as a pathological chaperone inducing a conformational transition to the amyloidogenic form (Inestrosa et al., 1996; Bartolini et al., 2003). Anew series of dual binding site AChE inhibitors has been designed and synthesized as new potent AChE inhibitors, which might simultaneously alleviate cognitive deficits and behave as disease-modifying agents by inhibiting Abeta peptide aggregation through binding to both catalytic and peripheral sites of the enzyme.

Peripheral and dual binding site inhibitors of acetylcholinesterase as neurodegenerative disease modifying agents

Current treatment approaches in Alzheimer’s disease have been dominated by the use of acetylcholinesterase (AChE) inhibitors, which increase the acetylcholine concentration in the brain, thus alleviating the decline in cognitive and mental function associated with this neurodegenerative disorder. However, AChE itself has been implicated in the pathogenesis of Alzheimer’s disease and it appears that AChE may directly interact with β-amyloid, increasing the deposition of this peptide into insoluble plaques. This new role suggests that properly designed or biologically directed screened AChE inhibitors might be able to act as disease-modifying agents rather than as a mere palliative treatment. This review discloses recent discoveries of small molecules targeting the non-cholinergic actions of this well-known cholinergic enzyme.

Synthesis and muscarinic activities of O-[(Benzyl- or benzoyl-pyrazolyl)propynyl]-oximes of N-methylpiperidinone, 3-tropinone, and 3-quinuclidinone

The synthesis of O-propynyloximes of N-methylpiperidinone, 3-tropinone, and 3-quinuclidinone, containing several pyrazole frameworks is described, together with their muscarinic receptor affinities. Compounds derived from N-methylpiperidinone or 3-tropinone and N-(4-methoxybenzyl)- or N-(2,4,6-trimethylbenzoyl)pyrazole showed moderate activity for muscarinic receptors in the rat central nervous system. A semi-empirical AM1 calculation has shown that the O-[(benzoyl-pyrazolyl)propynyl]-oximes of tropinone fit a previously described muscarinic pharmacophoric model, revealing structural features useful for the development of new muscarinic agents.

Synthesis of New N-(4-Pyridyl)-1-aminopyrazoles and Their Muscarinic and Adrenergic Properties

The synthesis of new N‐(4‐pyridyl)‐1‐aminopyrazoles is described. Their binding properties were tested for muscarinic and other neurotransmitter receptors, together with their acetylcholinesterase inhibitory activity. The series derived from 3,5‐dimethyl‐1H‐ pyrazole showed moderate activities in both muscarinic and adrenergic receptor binding tests

Synthesis of new 1-(but-2-ynyl)pyrazoles: containing a pyrrolidine or diethylamine moiety and their muscarinic properties.

The synthesis of two series of 1‐(but‐2‐ynyl)pyrazole containing a pyrrolidine or a diethylamine moiety, respectively, is described, together with their muscarinic receptor affinities.

Regioselective lipase catalyzed synthesis of diester crowns. New asymmetric macrocycles containing a 1,3-bis(1H-pyrazol-1-yl)propane unit

Abstract Regioselective lipase catalyzed intramolecular transesterification of dipyrazolic tetraester 1 with di-, tri- and tetraethyleneglycol afforded symmetric and, in smaller amounts, asymmetric diester crowns including a 1,3-bis(1 H -pyrazol-1-yl)propane unit. Their structures have been unequivocally elucidated after their 1 H and 13 C NMR spectra and INEPT experiments.

Intermediates in the synthesis of dipyrazolic podands and ester crowns via regioselective lipase catalyzed hydrolysis of a tetraester

Abstract In this work we study the Mucor miehei lipase-catalyzed hidrolysis of 1,3-bis[3,5-bis(ethoxycarbonyl)-1 H -pyrazol-1-yl]propane and the potential usefulness of the resulting acids as intermediates in the synthesis of podand and crown esters.