Eduardo Hernández-Vázquez

Synthesis, hypoglycemic activity and molecular modeling studies of pyrazole-3-carbohydrazides designed by a CoMFA model.

Diabetes and obesity are two universal health problems that constitute a research objective of several groups due to the lack of efficient and safe drug treatment. In this sense, cannabinoid receptor 1 (CB1) has attracted interest because of its role in food intake and metabolic balance, two targets in the control of metabolic syndrome. In this work, novel 1,5-diaryl pyrazole derivatives were synthesized in accordance with the pKi prediction of a previously reported CoMFA model by our group. To further investigate the biological activity of these compounds in metabolic disorders, their hypoglycemic activity in an in vivo model was tested. Interestingly, a high degree of correlation was observed between the predicted pKi and hypoglycemic effect 7 h after administration. Compounds 4, 9 and 13 showed the most significant plasma glucose reduction with decreases of 60%, 64% and 60% respectively. This result not only surpasses the activity of the lead rimonabant, but also that of the reference drug glibenclamide. Moreover, PASS prediction and molecular docking in an excellent validated homology model of CB1 suggest that these compounds would probably act as CB1 antagonists/inverse agonists and therefore, anti-obesity agents. The ligand-receptor complexes demonstrate that 1,5-diaryl pyrazole derivatives bind to the proposed binding site where a hydrophobic moiety interacts with the phenyl rings in the pyrazole nucleus and Lys192 forms a hydrogen bond with the oxygen of the carbonyl group. Dynamics simulations were also carried out to study the stability of the ligand-receptor complexes where the most active compounds showed smaller ΔG values and more hydrogen bonds throughout the simulation. These compounds are considered useful leads for further optimization in the treatment of such metabolic illnesses.

Multicomponent/Palladium-Catalyzed Cascade Entry to Benzopyrrolizidine Derivatives: Synthesis and Antioxidant Evaluation.

A versatile and efficient protocol for the synthesis of highly substituted benzopyrrolizidines (tetrahydro-3H-pyrrolo[2,1-a]isoindol-3-ones) is reported. The strategy consisted of an Ugi four-component reaction/elimination methodology to afford dehydroalanines containing trans-cinnamic acid derivatives and different substituted 2-bromobenzylamines, followed by a palladium-catalyzed 5-exo-trig/5-exo-trig cascade carbocyclization process. Gratifyingly, benzopyrrolizidines were obtained in moderate to good yields (42-77%) with a Z geometry due to the structural requirements for syn-β-hydride elimination. The prepared heterocyclic scaffolds are decorated with several substituents and incorporate a benzopyrrolizidine-fused system, along with an embedded cinnamic acid derivative, two privileged medicinal chemistry scaffolds. Additionally, since some of the compounds are derived from the well-known antioxidants ferulic and sinapinic acids, they were tested for their in vitro antioxidant capacity. The data suggested that compounds having a p-hydroxyl group showed moderate 2,2-diphenyl-1-picrylhydrazyl-radical-scavenging activity and were effective antioxidants in preventing lipoperoxidation in a thiobarbituric acid reactive substances assay.

1,5-Diarylpyrazole and vanillin hybrids: Synthesis, biological activity and DFT studies.

Herein, we report the design and synthesis of 13 diarylpyrazole hybrids with vanillin constructed as dual compounds against oxidative stress and diabetes. Compounds were tested in two different antioxidant assays. It was found that all compounds showed an important antioxidant activity in both DPPH and ORAC models and the activity was even more remarkable than vanillin. In addition, the hypoglycemic effect of compounds 1, 2, 4 and 12 was evaluated. Interestingly, compound 1 had the most potent hypoglycemic effect with a glycemia reduction of 71%, which was higher than rimonabant. Finally, a DFT study to propose a reasonable antioxidant mechanism is detailed. Both thermodynamic and kinetic studies indicated that the most feasible mechanism consists in the HAT abstraction of the phenolic hydrogen due to the formation of an stable transition state through the most rapid and exergonic path, while the SPLET mechanism is the most significant at higher pH values.

Activity landscape analysis, CoMFA and CoMSIA studies of pyrazole CB1 antagonists

Obesity and the metabolic syndrome are pandemic diseases with high morbidity and mortality. With the aim of discovering novel therapies for those diseases, the cannabinoid receptor 1 (CB1), which has been validated as a target for treating appetitive disorders, is now considered a novel target for the design of anti-obesity compounds. Our main goal was to determine the activity landscape of pyrazole derivatives and to develop reliable three-dimensional quantitative structure–activity relationship (3D-QSAR) models. Structure–activity similarity (SAS) maps of pyrazole analogs acting as antagonists of CB1 were constructed in order to identify activity cliffs, compounds that have high structural similarity with the rest of the compound set, but low activity similarity. According to the SAS maps, one molecule was identified as an outlier and before comparative molecular field analysis (COMFA) and comparative molecular similarity analysis (CoMSIA) 3D-QSAR models were derived. The best models resulted in an r2 value of 0.992 and a q2 of 0.766 for CoMFA and an r2 of 0.983 and a q2 of 0.681 for CoMSIA. Contour plots identified that the R3 position at the pyrazole moiety is an important feature for the optimization of the binding affinity to the CB1 receptor. According to our results, these models can be a useful tool for the design and prediction of novel CB1 antagonists.

Antidiabetic, antidyslipidemic and toxicity profile of ENV-2: A potent pyrazole derivative against diabetes and related diseases

Abstract Diabetes is a major health problem and a predisposition factor for further degenerative complications and, therefore, novel therapies are urgently needed. Currently, cannabinoid receptor 1 (CB1 receptor) antagonists have been considered as promissory entities for metabolic disorders treatment. Accordingly, the purpose of this work was the evaluation of the sub‐acute antidiabetic, anti‐hyperglycemic, antidyslipidemic and toxicological profile of ENV‐2, a potent hypoglycemic and antioxidant CB1 receptor antagonist. In this study, ENV‐2 showed a pronounced anti‐hyperglycemic effect even at a dose of 5 mg/kg (P<0.05) in a glucose tolerance test on normoglycemic rats. Moreover, after administration of ENV‐2 (16 mg/kg) to diabetic rats, a prominent antidiabetic activity was observed (P<0.05), which was higher than glibenclamide. Sub‐acute treatment (10 days) of ENV‐2 resulted in a significant reduction of plasma glucose (P<0.05). Also, the levels of peripheral lipids were improved; blood triacylglycerols (TG) and cholesterol (CHOL) were diminished (P<0.05). In addition, it was found that ENV‐2 reduced IL‐1&bgr; and IL‐18 mRNA expression in adipose tissue (P<0.05). Due to the satisfactory outcomes, we were interested in evaluating the toxicity of ENV‐2 in both acute and sub‐chronic approaches. Regarding the acute administration, the compound resulted to be non‐toxic and was grouped in category 5 according to OECD. It was also found that sub‐chronic administration did not increase the size of the studied organs, while no structural damage was observed in heart, lung, liver and kidney tissues. Finally, neither AST nor ALT damage hepatic markers were augmented. Graphical abstract Figure. No caption available.

ENP11, a potential CB1R antagonist, induces anorexia in rats

Over the past decade, pharmacological manipulation of cannabinoid 1 receptor (CB1R) has become an interesting approach for the management of food ingestion disorders, among other physiological functions. Searching for new substances with similar desirable effects, but fewer side-effects we have synthesized a SR141716A (a cannabinoid receptor inverse agonist also called Rimonabant) analog, 1-(2,4-Difluorophenyl)-4-methyl-N-(1-piperidinyl)-5-[4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide, ENP11, that so far, as we have previously shown, has induced changes in glucose availability, i.e. hypoglycemia, in rats. In this study we tested the effects, if any, of ENP11 (0.5, 1.0, and 3.0mg/kg) in food ingestion, core temperature, pain perception and motor control in adult Wistar rats. Results showed that ENP11 reduced food ingestion during the first hour immediately after administration. Likewise, ENP11 (1.0mg/kg) blocked anandamide (AEA)-induced hyperphagia during the first 4h of the dark phase of the light-dark cycle, and it also blocked AEA-induced hypothermia. However, none of the ENP11 doses used affected pain perception or motor control. We believe that ENP11 is a potential useful CB1R antagonist that reduces food ingestion and regulates core temperature.

Potential utility of adenosine 5′-ester prodrugs to enhance its plasma half-life: synthesis and molecular docking studies

Adenosine, the adenine nucleoside, has demonstrated various pharmacological properties related to the treatment of relevant clinical diseases. With respect to this, one of the most fascinating biological activities of adenosine is its capacity for reversing hepatic fibrosis, which has been established in several in vitro and in vivo studies. Although adenosine seems to be a privileged compound, it lacks of metabolic stability to be considered as a drug candidate. For this reason, in this preliminary study, six prodrugs were developed in order to enhance the plasma half-life of adenosine, in which the esterification at 5′ position of adenosine was considered. According to previous works, the increase in steric hindrance at this position could develop unfavorable interactions inside adenosine deaminase (ADA) catalytic domain, which is reported as the main enzyme implicated in adenosine metabolism. Besides, molecular docking was employed to verify if the hindrance at carbinol group in the prodrugs is enough to diminish its oxidation and also to predict if compounds would be metabolized by a promiscuous esterase. Finally, the in vitro assays corroborated the theoretical findings and also indicated that the compounds are less metabolized than adenosine by ADA; in the case of compounds containing proline and thioproline progroups (4d and 4e, respectively), the reduction was more than three-fold of decrease.

Acute and subacute antidiabetic studies of ENP‐9, a new 1,5‐diarylpyrazole derivative

To explore the antihyperglycaemic and antidiabetic effects and to determine the acute toxicity of 5‐(4‐chlorophenyl)‐1‐(2,4‐dichloro‐phenyl)‐4‐methyl‐N‐(piperidin‐1‐yl)‐1H‐pyrazole‐3‐carboxamide (ENP‐9).

Cytotoxic Activity and Structure-Activity Relationship of Triazole-Containing Bis(Aryl Ether) Macrocycles

Cancer continues to be a worldwide health problem. Certain macrocyclic molecules have become attractive therapeutic alternatives for this disease because of their efficacy and, frequently, their novel mechanisms of action. Herein, we report the synthesis of a series of 20‐, 21‐, and 22‐membered macrocycles containing triazole and bis(aryl ether) moieties. The compounds were prepared by a multicomponent approach from readily available commercial substrates. Notably, some of the compounds displayed interesting cytotoxicity against cancer (PC‐3) and breast (MCF‐7) cell lines, especially those bearing an aliphatic or a trifluoromethyl substituent on the N‐phenyl moiety (IC50<13 μm). Additionally, some of the compounds were able to induce apoptosis relative to the solvent control; in particular, (Z)‐N‐cyclohexyl‐7‐oxo‐6‐[4‐(trifluoromethyl)phenyl]‐11H‐3,10‐dioxa‐6‐aza‐1(4,1)‐triazola‐4(1,3),9(1,4)‐dibenzenacyclotridecaphane‐5‐carboxamide (12 f) was the most potent in this regard (22.7 % of apoptosis).