One-Pot Multicomponent Synthesis of Methoxybenzo[h]quinoline-3-carbonitrile Derivatives; Anti-Chagas,X-ray,and In Silico ADME/Tox Profiling Studies

Several methoxybenzo[h]quinoline-3-carbonitrile analogs were designed and synthesized in a repositioning approach to developing compounds with anti-prostate cancer and anti-Chagas disease properties. The compounds were synthesized through a sequential multicomponent reaction of aromatic aldehydes, malononitrile, and 1-tetralone in the presence of ammonium acetate and acetic acid (catalytic). The effect of the one-pot method on the generation of the target product has been studied. The compounds were in vitro screened against bloodstream trypomastigotes of T. cruzi (NINOA and INC-5 strains) and were most effective at showing a better activity profile than nifurtimox and benznidazole (reference drugs). A study in silico on absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) profiling to help describe the molecular properties related to the pharmacokinetic aspects in the human body of these compounds was reported. In addition, X-ray data for the compound 2-Amino-5,6-dihydro-4-(3-hydroxy-4-methoxy-phenyl)-8-methoxybenzo[h]quinoline-3-carbonitrile 6 was being reported. Spectral (IR, NMR, and elemental analyses) data on all final compounds were consistent with the proposed structures.     

Synthesis and Fungicidal Activity of Hydrated Geranylated Phenols against Botrytis cinerea

Botrytis cinerea is a ubiquitous fungus that affects hundreds of plants, resulting in economic losses to the horticulture and fruit industry. The search for new antifungal agents is a matter of current interest. Thus, in this work a series of geranylated phenols in which the side alkyl chain has been hydrated have been synthesized, and their activity against B. cinerea has been evaluated. The coupling of phenol and geraniol has been accomplished under microwave irradiation obtaining the highest reaction yields in the shortest reaction times. Hydration of the side chain was carried out in dioxane with p-toluenesulfonic acid polymer-bound as the catalyst. All synthesized compounds were tested against B. cinerea using the growth inhibition assay and EC₅₀ values were determined. The results show that activity depends on the number and nature of functional groups in the phenol ring and hydration degree of the geranyl chain. The most active compound is 1,4-dihydroquinone with one hydroxyl group attached at the end of the alkyl chain. Results from a molecular docking study suggest that hydroxyl groups in the phenol ring and alkyl chain are important in the binding of compounds to the active site, and that the experimental antifungal activity correlates with the number of H-bond that can be formed in the binding site.     

Entropy Method for Decision-Making: Uncertainty Cycles in Tourism Demand

A new methodology is presented for measuring, classifying and predicting the cycles of uncertainty that occur in temporary decision-making in the tourist accommodation market (apartments and hotels). Special attention is paid to the role of entropy and cycles in the process under the Adaptive Markets Hypothesis. The work scheme analyses random cycles from time to time, and in the frequency domain, the linear and nonlinear causality relationships between variables are studied. The period analysed is from January 2005 to December 2018; the following empirical results stand out: (1) On longer scales, the periodicity of the uncertainty of decision-making is between 6 and 12 months, respectively, for all the nationalities described. (2) The elasticity of demand for tourist apartments is approximately 1% due to changes in demand for tourist hotels. (3) The elasticity of the uncertainty factor is highly correlated with the country of origin of tourists visiting Spain. For example, it has been empirically shown that increases of 1% in uncertainty cause increases in the demand for apartments of 2.12% (worldwide), 3.05% (UK), 1.91% (Germany), 1.78% (France), 7.21% (Ireland), 3.61% (The Netherlands) respectively. This modelling has an explanatory capacity of 99% in all the models analysed.     

Hydrothermal CO2 Reduction by Glucose as Reducing Agent and Metals and Metal Oxides as Catalysts

High-temperature water reactions to reduce carbon dioxide were carried out by using an organic reductant and a series of metals and metal oxides as catalysts, as well as activated carbon (C). As CO₂ source, sodium bicarbonate and ammonium carbamate were used. Glucose was the reductant. Cu, Ni, Pd/C 5%, Ru/C 5%, C, Fe₂O₃ and Fe₃O₄ were the catalysts tested. The products of CO₂ reduction were formic acid and other subproducts from sugar hydrolysis such as acetic acid and lactic acid. Reactions with sodium bicarbonate reached higher yields of formic acid in comparison to ammonium carbamate reactions. Higher yields of formic acid (53% and 52%) were obtained by using C and Fe₃O₄ as catalysts and sodium bicarbonate as carbon source. Reactions with ammonium carbamate achieved a yield of formic acid up to 25% by using Fe₃O₄ as catalyst. The origin of the carbon that forms formic acid was investigated by using NaH¹³CO₃ as carbon source. Depending on the catalyst, the fraction of formic acid coming from the reduction of the isotope of sodium bicarbonate varied from 32 to 81%. This fraction decreased in the following order: Pd/C 5% > Ru/C 5% > Ni > Cu > C ≈ Fe₂O₃ > Fe₃O₄.     

Hetero‐Diels‐Alder and Cheletropic Additions of Sulfur Dioxide to 1,2‐Dimethylidenecycloalkanes. Determination of Thermochemical and Kinetics Parameters for Reactions in Solution and Comparison with Estimates From Quantum Calculations

Below −60° and without catalyst, 1,2‐dimethylidenecyclopentane ( 16 ), 1,2‐dimethylidenecyclohexane ( 13 ), 1,2‐dimethylidenecycloheptane ( 17 ), and 1,2‐dimethylidenecyclooctane ( 18 ) add to sulfur dioxide in the hetero‐Diels‐Alder mode, giving the corresponding sultines 4,5,6,7‐tetrahydro‐1H‐cyclopent[d][1,2]oxathiin 3‐oxide ( 19 ), 1,4,5,6,7,8‐hexahydro‐2,3‐benzoxathiin 3‐oxide ( 14 ), 4,5,6,7,8,9‐hexahydro‐1H‐cyclohept[d][1,2]oxathiin 3‐oxide ( 20 ), and 1,4,5,6,7,8,9,10‐octahydrocyclooct[d][1,2]oxathiin 3‐oxide ( 21 ), respectively. Above −40°, the sultines are isomerized into the corresponding sulfolenes 3,4,5,6‐tetrahydro‐1H‐cyclopenta[c]thiophene 2,2‐dioxide ( 22 ), 1,3,4,5,6,7‐hexahydrobenzo[c]thiophene 2,2‐dioxide ( 15 ), 3,4,5,6,7,8‐hexahydro‐1H‐cyclohepta[c]thiophene 2,2‐dioxide ( 23 ), and 1,3,4,5,6,7,8,9‐octahydrocycloocta[c]thiophene 2,2‐dioxide ( 24 ). Kinetics and thermodynamics data were collected for these reactions. The sultines are ca. 10 kcal/mol Diels‐Alder additions (ΔH^≠( 16 −36±3 cal mol⁻¹ K⁻¹) in agreement with third‐order rate laws that imply that two molecules of SO₂ intervene in the transition states of these cycloadditions. Similar observations were made for the cheletropic additions of SO₂. Attempts to simulate the thermodynamics and kinetics parameters of the reactions of SO₂ with dienes 16 and 13 by density‐functional theory (DFT) suggest that the calculations require an appropriate number of polarization functions in the basis set employed. A satisfactory recipe to compute the SO₂ additions to large dienes can be: B3LYP/6‐31G(d) geometry optimizations followed by B3LYP/6‐31+G(2df,p) single‐point calculations or G2(MP2,SVP) estimates on the B3LYP/6‐31G(d) geometries.     

Entropy Dissipation Methods for Degenerate ParabolicProblems and Generalized Sobolev Inequalities

We analyse the large-time asymptotics of quasilinear (possibly) degenerate parabolic systems in three cases: 1) scalar problems with confinement by a uniformly convex potential, 2) unconfined scalar equations and 3) unconfined systems. In particular we are interested in the rate of decay to equilibrium or self-similar solutions. The main analytical tool is based on the analysis of the entropy dissipation. In the scalar case this is done by proving decay of the entropy dissipation rate and bootstrapping back to show convergence of the relative entropy to zero. As by-product, this approach gives generalized Sobolev-inequalities, which interpolate between the Gross logarithmic Sobolev inequality and the classical Sobolev inequality. The time decay of the solutions of the degenerate systems is analyzed by means of a generalisation of the Nash inequality. Porous media, fast diffusion, p-Laplace and energy transport systems are included in the considered class of problems. A generalized Csiszár–Kullback inequality allows for an estimation of the decay to equilibrium in terms of the relative entropy.     

Unstable manifold computations for the two-dimensional plane Poiseuille flow

We follow the unstable manifold of periodic and quasi-periodic solutions in time for the Poiseuille problem, using two formulations: holding a constant flux or mean pressure gradient. By means of a numerical integrator of the Navier–Stokes equations, we let the fluid evolve from an initially perturbed unstable solution until the fluid reaches an attracting state. Thus, we detect several connections among different configurations of the flow such as laminar, periodic, quasi-periodic with two or three basic frequencies, and more complex sets that we have not been able to classify. These connections make possible the location of new families of solutions, usually hard to find by means of numerical continuation of curves, and show the richness of the dynamics of the Poiseuille flow. PACS 05.45.-a, 47.11.+j, 47.20.-k, 47.20.Ft     

Specific polyclonal-based immunoassays for sulfathiazole

A highly sensitive and specific enzyme-linked immunosorbent assay has been developed for detection of sulfathiazole (STZ, 4-amino-N-thiazol-2-yl-benzenesulfonamide). A set of haptens was synthesized in order to produce polyclonal antibodies against sulfonamides. Two ELISA formats (antibody-coated and conjugate-coated) were also investigated using all the serum/coating conjugate combinations that showed specific recognition. The developed ELISA succeeded in detection of STZ at concentrations as low as 0.03 ng mL^–1 over a measurable range of 0.12–6.71 ng mL^–1. Selectivity studies have demonstrated that other sulfonamides do not interfere significantly (<10%) with analysis of STZ by this immunochemical technique. Analysis of spiked bee honey samples by the developed ELISA method showed recoveries were good. The selectivity and sensitivity (IC₅₀=1.6 ng mL^–1) make it a suitable screening method for determination of low levels of STZ in food samples.     

Sandwich immunoassay for determination of vitellogenin in golden grey mullet (<Emphasis Type="Italic">Liza aurata</Emphasis>) serum as a field exposure biomarker

Vitellogenin (VTG) is a protein produced in the liver of oviparous animals in response to oestrogens. Abnormal production of VTG by males, therefore, is used as a biological indicator of exposure to xeno-oestrogens. In this study, a sandwich-ELISA for measuring VTG in Liza aurata (golden grey mullet) was developed and validated. Plasma VTG was purified from 17-oestradiol-injected immature individuals of mullet, by size-exclusion and ion-exchange chromatography. Polyclonal antibodies against VTG were raised in rabbits. A sensitive immunoassay was developed for measurement of vitellogenin in L. aurata serum, reaching a quantification limit of 0.01 g mL^–1 and a dynamic range from 0.02 to 2 g mL^–1. The assay is specific, because high levels (>100 g mL^–1) of carp (Cyprinus carpio), goldfish (Carassius auratus), tilapia (Oreochromis niloticus), tench (Tinca tinca), rainbow trout (Oncorhynchus mykiss), European eel (Anguilla anguilla) and frog (Rana perezi) purified VTG, give negligible responses. The assay was used to analyse plasma samples from wild mullet.     

Regioselective Diels-Alder reactions of 3-indolylquinones

6-(3-Indolyl)quinolinequinone derivatives gave regioselective Diels-Alder reactions with a variety of dienophiles, yielding polycyclic carbazole derivatives. One-pot reactions, proceeding through a cascade of reactions including regioselective Michael and Diels-Alder steps, gave heptacyclic derivatives starting from indoles and 2,5,8(1H)-quinolinetriones. Double Diels-Alder reactions of 6-(3-indolyl)quinolinequinones and dihalobenzoquinones gave eleven-cycle products in one step.