Copper-Catalyzed Huisgen 1,3-Dipolar Cycloaddition under Oxidative Conditions: Polymer-Assisted Assembly of 4‑Acyl-1-Substituted-1,2,3-Triazoles

We herein document the first example of a reliable copper-catalyzed Huisgen 1,3-dipolar cycloaddition under oxidative conditions. The combined use of two polymer-supported reagents (polystyrene-1,5,7-triaza­bicyclo­[4,4,0]­dec-5-ene/Cu and polystyrene-2-iodoxy­benzamide) overcomes the thermodynamic instability of copper­(I) species toward oxidation, enabling the reliable Cu-catalyzed Huisgen 1,3-dipolar cycloadditions in the presence of an oxidant agent. This polymer-assisted pathway, not feasible under conventional homogeneous conditions, provides a direct assembly of 4-acyl-1-substituted-1,2,3-triazoles, contributing to expand the reliability and scope of Cu­(I)-catalyzed alkyne–azide cycloaddition

Model for High-Throughput Screening of Multitarget Drugs in Chemical Neurosciences: Synthesis, Assay, and Theoretic Study of Rasagiline Carbamates

The disappointing results obtained in recent clinical trials renew the interest in experimental/computational techniques for the discovery of neuroprotective drugs. In this context, multitarget or multiplexing QSAR models (mt-QSAR/mx-QSAR) may help to predict neurotoxicity/neuroprotective effects of drugs in multiple assays, on drug targets, and in model organisms. In this work, we study a data set downloaded from CHEMBL; each data point (>8000) contains the values of one out of 37 possible measures of activity, 493 assays, 169 molecular or cellular targets, and 11 different organisms (including human) for a given compound. In this work, we introduce the first mx-QSAR model for neurotoxicity/neuroprotective effects of drugs based on the MARCH-INSIDE (MI) method. First, we used MI to calculate the stochastic spectral moments (structural descriptors) of all compounds. Next, we found a model that classified correctly 2955 out of 3548 total cases in the training and validation series with Accuracy, Sensitivity, and Specificity values > 80%. The model also showed excellent results in Computational-Chemistry simulations of High-Throughput Screening (CCHTS) experiments, with accuracy = 90.6% for 4671 positive cases. Next, we reported the synthesis, characterization, and experimental assays of new rasagiline derivatives. We carried out three different experimental tests: assay (1) in the absence of neurotoxic agents, assay (2) in the presence of glutamate, and assay (3) in the presence of H₂O₂. Compounds <b>11</b> with 27.4%, <b>8</b> with 11.6%, and <b>9</b> with 15.4% showed the highest neuroprotective effects in assays (1), (2), and (3), respectively. After that, we used the mx-QSAR model to carry out a CCHTS of the new compounds in >400 unique pharmacological tests not carried out experimentally. Consequently, this model may become a promising auxiliary tool for the discovery of new drugs for the treatment of neurodegenerative diseases

Effect of Nitrogen Atom Substitution in A₃ Adenosine Receptor Binding: <i>N</i>‑(4,6-Diarylpyridin-2-yl)acetamides as Potent and Selective Antagonists

We report the first family of 2-acetamidopyridines as potent and selective A₃ adenosine receptor (AR) antagonists. The computer-assisted design was focused on the bioisosteric replacement of the N1 atom by a CH group in a previous series of diarylpyrimidines. Some of the generated 2-acetamidopyridines elicit an antagonistic effect with excellent affinity (<i>K</i>_i < 10 nM) and outstanding selectivity profiles, providing an alternative and simpler chemical scaffold to the parent series of diarylpyrimidines. In addition, using molecular dynamics and free energy perturbation simulations, we elucidate the effect of the second nitrogen of the parent diarylpyrimidines, which is revealed as a stabilizer of a water network in the binding site. The discovery of 2,6-diaryl-2-acetamidopyridines represents a step forward in the search of chemically simple, potent, and selective antagonists for the hA₃AR, and exemplifies the benefits of a joint theoretical–experimental approach to identify novel hA₃AR antagonists through succinct and efficient synthetic methodologies

Effect of Nitrogen Atom Substitution in A₃ Adenosine Receptor Binding: <i>N</i>‑(4,6-Diarylpyridin-2-yl)acetamides as Potent and Selective Antagonists

We report the first family of 2-acetamidopyridines as potent and selective A₃ adenosine receptor (AR) antagonists. The computer-assisted design was focused on the bioisosteric replacement of the N1 atom by a CH group in a previous series of diarylpyrimidines. Some of the generated 2-acetamidopyridines elicit an antagonistic effect with excellent affinity (<i>K</i>_i < 10 nM) and outstanding selectivity profiles, providing an alternative and simpler chemical scaffold to the parent series of diarylpyrimidines. In addition, using molecular dynamics and free energy perturbation simulations, we elucidate the effect of the second nitrogen of the parent diarylpyrimidines, which is revealed as a stabilizer of a water network in the binding site. The discovery of 2,6-diaryl-2-acetamidopyridines represents a step forward in the search of chemically simple, potent, and selective antagonists for the hA₃AR, and exemplifies the benefits of a joint theoretical–experimental approach to identify novel hA₃AR antagonists through succinct and efficient synthetic methodologies