Cristóbal de los Ríos

Bio: Cristóbal de los Ríos is an academic researcher from Autonomous University of Madrid. The author has contributed to research in topics: Neuroprotection & Tacrine. The author has an hindex of 26, co-authored 76 publications receiving 1921 citations. Previous affiliations of Cristóbal de los Ríos include University of Alcalá & University of Bologna.

Synthesis, Biological Evaluation, and Molecular Modeling of Donepezil and N-[(5-(Benzyloxy)-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine Hybrids as New Multipotent Cholinesterase/Monoamine Oxidase Inhibitors for the Treatment of Alzheimer’s Disease

Abstract: A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel compounds (3–9) have been designed using a conjunctive approach that combines the benzylpiperidine moiety of the AChE inhibitor donepezil (1) and the indolyl propargylamino moiety of the MAO inhibitor N-[(5-benzyloxy-1-methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine (2), connected through an oligomethylene linker. The most promising hybrid (5) is a potent inhibitor of both MAO-A (IC50 = 5.2 ± 1.1 nM) and MAO-B (IC50 = 43 ± 8.0 nM) and is a moderately potent inhibitor of AChE (IC50 = 0.35 ± 0.01 μM) and BuChE (IC50 = 0.46 ± 0.06 μM). Moreover, molecular modeling and kinetic studies support the dual binding site to AChE, which explains the inhibitory effect exerted on Aβ aggregation. Overall, the results suggest that the new compounds are promising multitarget drug candidates with potential impact for Al...

A review of metal-catalyzed molecular damage: protection by melatonin.

Abstract: Metal exposure is associated with several toxic effects; herein, we review the toxicity mechanisms of cadmium, mercury, arsenic, lead, aluminum, chromium, iron, copper, nickel, cobalt, vanadium, and molybdenum as these processes relate to free radical generation. Free radicals can be generated in cells due to a wide variety of exogenous and endogenous processes, causing modifications in DNA bases, enhancing lipid peroxidation, and altering calcium and sulfhydryl homeostasis. Melatonin, an ubiquitous and pleiotropic molecule, exerts efficient protection against oxidative stress and ameliorates oxidative/nitrosative damage by a variety of mechanisms. Also, melatonin has a chelating property which may contribute in reducing metal-induced toxicity as we postulate here. The aim of this review was to highlight the protective role of melatonin in counteracting metal-induced free radical generation. Understanding the physicochemical insights of melatonin related to the free radical scavenging activity and the stimulation of antioxidative enzymes is of critical importance for the development of novel therapeutic strategies against the toxic action of these metals.

Tacripyrines, the first tacrine-dihydropyridine hybrids, as multitarget-directed ligands for the treatment of Alzheimer's disease.

Abstract: Tacripyrines (1−14) have been designed by combining an AChE inhibitor (tacrine) with a calcium antagonist such as nimodipine and are targeted to develop a multitarget therapeutic strategy to confront AD. Tacripyrines are selective and potent AChE inhibitors in the nanomolar range. The mixed type inhibition of hAChE activity of compound 11 (IC50 105 ± 15 nM) is associated to a 30.7 ± 8.6% inhibition of the proaggregating action of AChE on the Aβ and a moderate inhibition of Aβ self-aggregation (34.9 ± 5.4%). Molecular modeling indicates that binding of compound 11 to the AChE PAS mainly involves the (R)-11 enantiomer, which also agrees with the noncompetitive inhibition mechanism exhibited by p-methoxytacripyrine 11. Tacripyrines are neuroprotective agents, show moderate Ca2+ channel blocking effect, and cross the blood−brain barrier, emerging as lead candidates for treating AD.

Novel multipotent tacrine-dihydropyridine hybrids with improved acetylcholinesterase inhibitory and neuroprotective activities as potential drugs for the treatment of Alzheimer's disease.

Abstract: In this work we describe the synthesis and biological evaluation of the tacrine-1,4-dihydropyridine (DHP) hybrids (3-11). These multipotent molecules are the result of the juxtaposition of an acetylcholinesterase inhibitor (AChEI) such as tacrine (1) and a 1,4-DHP such as nimodipine (2). Compounds 3-11 are very selective and potent AChEIs and show an excellent neuroprotective profile and a moderate Ca2+ channel blockade effect. Consequently, these molecules are new potential drugs for the treatment of Alzheimer's disease.

Melatonin as an antioxidant: under promises but over delivers.

Abstract: Melatonin is uncommonly effective in reducing oxidative stress under a remarkably large number of circumstances. It achieves this action via a variety of means: direct detoxification of reactive oxygen and reactive nitrogen species and indirectly by stimulating antioxidant enzymes while suppressing the activity of pro-oxidant enzymes. In addition to these well-described actions, melatonin also reportedly chelates transition metals, which are involved in the Fenton/Haber-Weiss reactions; in doing so, melatonin reduces the formation of the devastatingly toxic hydroxyl radical resulting in the reduction of oxidative stress. Melatonin's ubiquitous but unequal intracellular distribution, including its high concentrations in mitochondria, likely aid in its capacity to resist oxidative stress and cellular apoptosis. There is credible evidence to suggest that melatonin should be classified as a mitochondria-targeted antioxidant. Melatonin's capacity to prevent oxidative damage and the associated physiological debilitation is well documented in numerous experimental ischemia/reperfusion (hypoxia/reoxygenation) studies especially in the brain (stroke) and in the heart (heart attack). Melatonin, via its antiradical mechanisms, also reduces the toxicity of noxious prescription drugs and of methamphetamine, a drug of abuse. Experimental findings also indicate that melatonin renders treatment-resistant cancers sensitive to various therapeutic agents and may be useful, due to its multiple antioxidant actions, in especially delaying and perhaps treating a variety of age-related diseases and dehumanizing conditions. Melatonin has been effectively used to combat oxidative stress, inflammation and cellular apoptosis and to restore tissue function in a number of human trials; its efficacy supports its more extensive use in a wider variety of human studies. The uncommonly high-safety profile of melatonin also bolsters this conclusion. It is the current feeling of the authors that, in view of the widely diverse beneficial functions that have been reported for melatonin, these may be merely epiphenomena of the more fundamental, yet-to-be identified basic action(s) of this ancient molecule.

Multi-Target-Directed Ligands To Combat Neurodegenerative Diseases

Abstract: Our understanding of the pathogenesis of diseases has advanced enormously in recent decades. As a consequence, drug discovery has gradually shifted from an entirely humanphenotype-based endeavor to today’s reductionist approach centered on single molecular targets. The focus has shifted from the early animal models to isolated proteins via cellular models. This change has led to a decrease in complexity but also to a decrease in relevance to the human condition. In this context, drug research has become (and still is) aimed mainly at the discovery of small molecules able to modulate the biological function of a single protein target thought to be fully responsible for a certain disease. Much effort has been devoted to achieving selectivity for that given target, and indeed, nowadays, many ligands endowed with outstanding in vitro selectivity are available. This one-molecule, one-target paradigm has led to the discovery of many successful drugs, and it will probably remain a milestone for years to come. However, it should be noted that a highly selective ligand for a given target does not always result in a clinically efficacious drug. This may be because (a) the ligand does not recognize the target in vivo, (b) the ligand does not reach the site of action, or (c) the interaction with the respective target does not have enough impact on the diseased system to restore it effectively. Reasons for the latter might lie in both the multifactorial nature of many diseases and the fact that cells can often find ways to compensate for a protein whose activity is affected by a drug, by taking advantage of the redundancy of the system, i.e., of the existence of parallel pathways. Medicinal chemists are often faced with these frustrating aspects of drug research. Drawbacks a and b can be addressed through the well-established rational ligand modification approaches. But issue c is more problematic and needs to be carefully discussed. This is one of the aims of the present article.

Polypharmacology: Challenges and Opportunities in Drug Discovery

Abstract: At present, the legendary magic bullet, i.e., a drug with high potency and selectivity toward a specific biological target, shares the spotlight with an emerging and alternative polypharmacology approach. Polypharmacology suggests that more effective drugs can be developed by specifically modulating multiple targets. It is generally thought that complex diseases such as cancer and central nervous system diseases may require complex therapeutic approaches. In this respect, a drug that "hits" multiple sensitive nodes belonging to a network of interacting targets offers the potential for higher efficacy and may limit drawbacks generally arising from the use of a single-target drug or a combination of multiple drugs. In this review, we will compare advantages and disadvantages of multitarget versus combination therapies, discuss potential drug promiscuity arising from off-target effects, comment on drug repurposing, and introduce approaches to the computational design of multitarget drugs.

Melatonin: an ancient molecule that makes oxygen metabolically tolerable.

Abstract: Melatonin is remarkably functionally diverse with actions as a free radical scavenger and antioxidant, circadian rhythm regulator, anti-inflammatory and immunoregulating molecule, and as an oncostatic agent. We hypothesize that the initial and primary function of melatonin in photosynthetic cyanobacteria, which appeared on Earth 3.5-3.2 billion years ago, was as an antioxidant. The evolution of melatonin as an antioxidant by this organism was necessary as photosynthesis is associated with the generation of toxic-free radicals. The other secondary functions of melatonin came about much later in evolution. We also surmise that mitochondria and chloroplasts may be primary sites of melatonin synthesis in all eukaryotic cells that possess these organelles. This prediction is made on the basis that mitochondria and chloroplasts of eukaryotes developed from purple nonsulfur bacteria (which also produce melatonin) and cyanobacteria when they were engulfed by early eukaryotes. Thus, we speculate that the melatonin-synthesizing actions of the engulfed bacteria were retained when these organelles became mitochondria and chloroplasts, respectively. That mitochondria are likely sites of melatonin formation is supported by the observation that this organelle contains high levels of melatonin that are not impacted by blood melatonin concentrations. Melatonin has a remarkable array of means by which it thwarts oxidative damage. It, as well as its metabolites, is differentially effective in scavenging a variety of reactive oxygen and reactive nitrogen species. Moreover, melatonin and its metabolites modulate a large number of antioxidative and pro-oxidative enzymes, leading to a reduction in oxidative damage. The actions of melatonin on radical metabolizing/producing enzymes may be mediated by the Keap1-Nrf2-ARE pathway. Beyond its direct free radical scavenging and indirect antioxidant effects, melatonin has a variety of physiological and metabolic advantages that may enhance its ability to limit oxidative stress.

Synthesis and Pharmacological Activities of Pyrazole Derivatives: A Review

Abstract: Pyrazole and its derivatives are considered a pharmacologically important active scaffold that possesses almost all types of pharmacological activities. The presence of this nucleus in pharmacological agents of diverse therapeutic categories such as celecoxib, a potent anti-inflammatory, the antipsychotic CDPPB, the anti-obesity drug rimonabant, difenamizole, an analgesic, betazole, a H2-receptor agonist and the antidepressant agent fezolamide have proved the pharmacological potential of the pyrazole moiety. Owing to this diversity in the biological field, this nucleus has attracted the attention of many researchers to study its skeleton chemically and biologically. This review highlights the different synthesis methods and the pharmacological properties of pyrazole derivatives. Studies on the synthesis and biological activity of pyrazole derivatives developed by many scientists around the globe are reported.