Carmen Terán

Synthesis and study of a series of 3-arylcoumarins as potent and selective monoamine oxidase B inhibitors.

New series of 6-substituted-3-arylcoumarins displaying several alkyl, hydroxyl, halogen, and alkoxy groups in the two benzene rings have been designed, synthesized, and evaluated in vitro as human monoamine oxidase A and B (hMAO-A and hMAO-B) inhibitors. Most of the studied compounds showed a high affinity and selectivity to the hMAO-B isoenzyme, with IC(50) values on nanomolar and picomolar range. Ten of the 22 described compounds displayed higher MAO-B inhibitory activity and selectivity than selegiline. Coumarin 7 is the most active compound of this series, being 64 times more active than selegiline and also showing the highest hMAO-B specificity. In addition, docking experiments were carried out on hMAO-A and h-MAO-B structures. This study provided new information about the enzyme-inhibitor interaction and the potential therapeutic application of this 3-arylcoumarin scaffold.

Variable Selection Methods in QSAR: An Overview

Variable selection is a procedure used to select the most important features to obtain as much information as possible from a reduced amount of features. The selection stage is crucial. The subsequent design of a quantitative structure-activity relationship (QSAR) model (regression or discriminant) would lead to poor performance if little significant features are selected. In drug design modern era, by the means of combinatorial chemistry and high throughput screening, an unprecedented amount of experimental information has been generated. In addition, many molecular descriptors have been defined in the last two decays. All this information can be analyzed by QSAR techniques using adequate statistical procedures. These techniques and procedures should be fast, automated, and applicable to large data sets of structurally diverse compounds. For that reason, the identification of the best one seems to be a very difficult task in view of the large variable selection techniques existing nowadays. The intention of this review is to summarize some of the present knowledge concerning to variable selection methods applied to some well-known statistical techniques such as linear regression, PLS, kNN, Artificial Neural Networks, etc, with the aim to disseminate the advances of this important stage of the QSAR building model.

AM1 theoretical study, synthesis and biological evaluation of some benzofuran analogues of anti-inflammatory arylalkanoic acids

Using the semi-empirical quantum-mechanical method AM1, the molecular geometries of the arylalkanoic acids, indomethacin, naproxen and ibuprofen, were optimized and their frontier orbital charge distributions evaluated. Then, these molecular parameters were compared in order to identify structure-activity relationships and, on the basis of these, four benzofuran-3-acetic acids were designed as potential non-steroidal anti-inflammatory agents, and rapidly synthesized by a novel and easily generalized route. Notwithstanding the structural similarities between the synthesized compounds and the anti-inflammatory arylalkanoic acids, these compounds did not appreciably inhibit human platelet cyclooxygenase in vitro.

New pyridazinone derivatives with vasorelaxant and platelet antiaggregatory activities

New 6-substituted and 2,6-disubstituted pyridazinone derivatives were obtained starting from easily accessible alkyl furans by using oxidation with singlet oxygen to give 4-methoxy or 4-hydroxybutenolides, key intermediates of this synthetic strategy. The new pyridazinone derivatives have been studied as vasorelaxant and antiplatelet agents. Analysis of biological data revealed the silyl ethers (4a-i) and N,O-dibenzyl derivatives (6g-i) as the most active compounds.

Phenylpiperazine derivatives with strong affinity for 5HT1A, D2A and D3 receptors

Four 7-[3-(4-phenyl-1-piperazinyl)propoxy]coumarins were synthesized. The affinities of these compounds for DA (D2A, D3) and 5HT1A receptors were evaluated for their ability to displace [3H]-raclopride and [3H]-8-OH-DPAT respectively from their specific binding sites. The affinities of the target compounds were all in the nanomolar range and followed the order 5-HT1A > D2 > D3.

Synthesis and structure–activity relationships of new arylpiperazines: para substitution with electron-withdrawing groups decrease binding to 5-HT1A and D2A receptors

Abstract Compounds in which N -phenylpiperazines were linked by a propyloxy chain to position 6 or 7 of a coumarin ring were designed and synthesised, and their affinities for 5-HT 1A and D 2A receptors were determined by radioligand binding assays. The influence of para substitution in the phenyl ring, substitution at position 4 of the coumarin system, and the coumarin position at which the piperazinylalkyl chain is linked was explored. Electron-withdrawing phenyl ring substituents para to the piperazine strongly reduced activity at both receptors. Binding at 5HT 1A was influenced by the bulk of substituents at position 4 of the coumarin system, and binding at D 2A by their electronic properties. Neither binding affinity was significantly affected by whether the piperazinylalkyl chain was inserted at position 6 or 7 of the coumarin system.

Pyridazine derivatives. IX, Synthesis of 2H-pyridazin-3-ones with aroylpiperazinyl groups

6-Phenyl-5-(N 4 -aroyl-N 1 -piperazinyl)-2H-pyridazin-3-ones were obtained by nucleophilic substitution of the chlorine atom of 6-phenyl-5-chloro-2H-pyridazin-3-one or alternatively, by aroylation of N 1 -piperazinyl-2H-pyridazin-3-one. Also, 6-phenyl-5-(N 4 -aroyl-N 1 -piperazinylmethyl)-2H-pyridazin-3-ones were prepared by displacement of the bromine in 6-phenyl-5-bromomethyl-2H-pyridazin-3-one.

Phthalazin-1(2H)-one as a remarkable scaffold in drug discovery

Phthalazinones are an important kind of nitrogen atom containing heterocyclic compounds due to their synthetic and pharmacological versatility. This fused heterocycle system represents a common structural feature for many bioactive compounds showing a variety of pharmacological activities such as anticancer, anti-diabetic, anti-asthmatic, antihistaminic, antihypertensive, antithrombotic, anti-inflammatory, analgesic, antidepressant or antimicrobial agents, which makes it an attractive scaffold for the design and development of new drugs. This review summarizes detailed and updated information, described in recent non-patent literature, about the most relevant pharmacological properties of phthalazinone derivatives, highlighting the application of this potent pharmacophore in drug discovery.

Quantitative structure activity relationships as useful tools for the design of new adenosine receptor ligands. 1. Agonist

In order to minimize expensive drug failures it is essential to determine the potential biological activity of new candidates as early as possible. In view of the large libraries of nucleoside analogues that are now being handled in organic synthesis, the identification of a drugs biological activity is advisable even before synthesis and this can be achieved using predictive biological activity methods. In this sense, computer aided rational drug design strategies like Quantitative Structure Activity Relationships (QSAR) or docking approaches have emerged as promising tools. Although a large number of in silico approaches have been described in the literature for the prediction of different biological activities, the use of traditional QSAR applications in the development of new agonist molecules with affinity toward adenosine receptors is scarce. This review attempts to summarize the current level of knowledge concerning computational affinity predictions for adenosine receptors using QSAR models based on knowledge of the agonist ligands. Several computational protocols and different 2D and 3D descriptors have been described in the literature for these targets, but more effort is still required in this area.

Synthesis and biological evaluation of 1,2-disubstituted carbonucleosides of 6-substituted purine and 8-azapurine.

A series of new one two substituted carbonucleoside analogues (OTC), with the purine and 8-azapurine base linked through a methylene group at the cyclopentane ring, were synthesized and evaluated for their activity against a number of viruses and tumor cells in vitro.