For a new molecular entity (NME) to become a drug, it is not only essential to have the right biological activity also be safe and efficient, but it is also required to have a favorable pharmacokinetic profile including toxicity (ADMET). Consequently, there is a need to predict, during the early stages of development, the ADMET properties to increase the success rate of compounds reaching the lead optimization process. Since Lipinski’s rule of five, the prediction of pharmacokinetic parameters has evolved towards the current in silico tools based on empirical approaches or molecular modeling. The commercial specialized software for performing such predictions, which is usually costly, is, in many cases, not among the possibilities for research laboratories in academia or at small biotech companies. Nevertheless, in recent years, many free online tools have become available, allowing, more or less accurately, for the prediction of the most relevant pharmacokinetic parameters. This paper studies 18 free web servers capable of predicting ADMET properties and analyzed their advantages and disadvantages, their model-based calculations, and their degree of accuracy by considering the experimental data reported for a set of 24 FDA-approved tyrosine kinase inhibitors (TKIs) as a model of a research project.

Pyrazolo[3,4-b]pyridines are a group of heterocyclic compounds presenting two possible tautomeric forms: the 1H- and 2H-isomers. More than 300,000 1H-pyrazolo[3,4-b]pyridines have been described which are included in more than 5500 references (2400 patents) up to date. This review will cover the analysis of the diversity of the substituents present at positions N1, C3, C4, C5, and C6, the synthetic methods used for their synthesis, starting from both a preformed pyrazole or pyridine, and the biomedical applications of such compounds.

Insect damage to plants is known to up-regulate defense and down-regulate growth processes. While there are frequent reports about up-regulation of defense signaling and production of defense metabolites in response to herbivory, much less is understood about the mechanisms by which growth and carbon assimilation are down-regulated. Here we demonstrate that insect herbivory down-regulates the 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway in Arabidopsis (Arabidopsis thaliana), a pathway making primarily metabolites for use in photosynthesis. Simulated feeding by the generalist herbivore Spodoptera littoralis suppressed flux through the MEP pathway and decreased steady-state levels of the intermediate 1-deoxy-D-xylulose 5-phosphate (DXP). Simulated herbivory also increased reactive oxygen species content which caused the conversion of β-carotene to β-cyclocitral (βCC). This volatile oxidation product affected the MEP pathway by directly inhibiting DXP synthase (DXS), the rate-controlling enzyme of the MEP pathway in Arabidopsis and inducing plant resistance against S. littoralis. βCC inhibited both DXS transcript accumulation and DXS activity. Molecular models suggested that βCC binds to DXS at the binding site for the thymine pyrophosphate cofactor and blocks catalysis, which was confirmed by direct assays of βCC with the purified DXS protein in vitro. Another intermediate of the MEP pathway, 2-C-methyl-D-erythritol-2, 4-cyclodiphosphate, which is known to stimulate salicylate defense signaling, showed greater accumulation and enhanced export out of the plastid in response to simulated herbivory. Together, our work implicates βCC as a signal of herbivore damage in Arabidopsis that increases defense and decreases flux through the MEP pathway, a pathway involved in growth and carbon assimilation. Significance Plants are known to respond to insect herbivory in multiple ways. Under herbivore attack, plants increase their commitment to defense but decrease their commitment to growth and carbon assimilation. Unfortunately, this second aspect is less studied. Here we report the discovery of an herbivore-triggered signal (β-cyclocitral) that enhances plant resistance and down-regulates the methylerythritol-4-phosphate (MEP) pathway of terpenoid biosynthesis. The MEP pathway supplies the precursors for many metabolites important in photosynthesis such as chlorophylls, carotenoids, plastoquinones, phylloquinones, and tocopherols. We also elucidated the mechanism responsible for the reduction of MEP pathway flux under herbivory and found that β-cyclocitral inhibits the activity of the first step of the pathway, which was also shown to control flux under normal growth conditions.

Pyrido[2,3-d]pyrimidines (1) are a type of privileged heterocyclic scaffolds capable of providing ligands for several receptors in the body. Among such structures, our group and others have been particularly interested in pyrido[2,3-d]pyrimidine-7(8H)-ones (2) due to the similitude with nitrogen bases present in DNA and RNA. Currently there are more than 20,000 structures 2 described which correspond to around 2900 references (half of them being patents). Furthermore, the number of references containing compounds of general structure 2 have increased almost exponentially in the last 10 years. The present review covers the synthetic methods used for the synthesis of pyrido[2,3-d]pyrimidine-7(8H)-ones (2), both starting from a preformed pyrimidine ring or a pyridine ring, and the biomedical applications of such compounds.

Changes in the molecular structure of synthetic cathinones has led to an increase in the number of novel emerging drugs in the illicit drug market at an unprecedented rate. Unfortunately, little is known about the neuropsychopharmacology of recently emerged halogen-substituted α-PVP derivatives. Thus, the aim of this study was to investigate the role of para- and meta-halogen (F-, Cl-, and Br-) substitutions on the in vitro, in silico, and in vivo effects of α-pyrrolidinopentiophenone (α-PVP) derivatives. HEK293 cells expressing the human dopamine or serotonin transporter (hDAT and hSERT) were used for the uptake inhibition and transporter affinity assays. Molecular docking was used to model the interaction mechanism against DAT. Swiss CD-1 mice were used for the horizontal locomotor activity, open field test, and conditioned place preference paradigm. All compounds demonstrated potent DA uptake inhibition and higher DAT selectivity than cocaine. Meta-substituted cathinones showed higher DAT/SERT ratios than their para- analogs, which correlates with an increased psychostimulant effect in vivo and with different meta- and para-in silico interactions at DAT. Moreover, all compounds induced rewarding and acute anxiogenic effects in mice. In conclusion, the present study demonstrates the role of meta- and para-halogen substitutions in the mechanism of action and provides the first evidence of the rewarding and anxiety-like properties of halogenated α-PVP derivatives.

Chalcones are a type of molecule that can be considered as easily synthesizable through aldol condensation or that can be readily purchased from habitual commercial vendors. However, on reviewing the literature, one realizes that there are no standard procedures for such aldol condensations, that there exists a wide range of alternative methods for the aldol condensation (indicating that such a condensation is not always simple), and that, in many cases, low yields are obtained that involve purifications by recrystallization or column chromatography. To develop a robust standard protocol independent of the nature of the substituents present on the acetophenone or the benzaldehyde involved in the aldol condensation leading to the chalcone, we made a comparison between an aldol condensation in KOH/EtOH and a Wittig reaction between the corresponding ylide and benzaldehyde in water. We describe an improved procedure for the Wittig reaction and a protocol for the elimination of the Ph₃P=O byproduct (and the excess of ylide used) by filtration of the crude reaction product through a silica gel plug. We thus demonstrate that such an improved procedure can be a general method for the synthesis of chalcones in high yield and excellent purity and is clearly an improvement on the classical aldol condensation.