Daniel O. Bennardi

QSAR prediction of inhibition of aldose reductase for flavonoids

We performed a predictive analysis based on quantitative structure-activity relationships (QSAR) of an important property of flavonoids, which is the inhibition (IC(50)) of aldose reductase (AR). The importance of AR inhibition is that it prevents cataract formation in diabetic patients. The best linear model constructed from 55 molecular structures incorporated six molecular descriptors, selected from more than a thousand geometrical, topological, quantum-mechanical, and electronic types of descriptors. As a practical application, we used the obtained QSAR model to predict the AR inhibitory effect of newly synthesized flavonoids that present 2-, 7-substitutions in the benzopyrane backbone.

Efficient Microwave Solvent-Free Synthesis of Flavones, Chromones, Coumarins and Dihydrocoumarins

Simple, clean, environmentally friendly procedures for the solvent-free preparation of coumarins, dihydrocou- marins, flavones and chromones under microwave heating are described. Silica-supported Wells-Dawson heteropolyacid (H6P2W18O62·24 H2O) was employed as catalyst. High selectivity, very good yields and short reaction times were ob- tained. The results are compared with those of the reactions performed under conventional heating.

Sustainable synthesis of flavonoid derivatives, QSAR study and insecticidal activity against the fall armyworm, Spodoptera frugiperda (Lep.: Noctuidae).

A simple, clean, solvent-free preparation of flavones by the use of a silica-supported Preyssler heteropolyacid as reusable catalyst is described. High selectivity and very good yields (87-94%) were obtained in short reaction times (7-13 min). Bioassays for insecticidal activity against Spodoptera frugiperda were carried out with a set of flavones. Bioassays showed that some of the flavones had moderate insecticidal activity. Quantitative structure-activity relationships were established on the available data with the purpose of predicting the insecticidal activity of a number of structurally related flavones. A relationship between the molecular structure and biological activity is proposed.

QSAR analysis on Spodoptera litura antifeedant activities for flavone derivatives.

We establish useful models that relate experimentally measured biological activities of compounds to their molecular structure. The pED(50) feeding inhibition on Spodoptera litura species exhibited by aurones, chromones, 3-coumarones and flavones is analyzed in this work through the hypothesis encompassed in the Quantitative Structure-Activity Relationships (QSAR) Theory. This constitutes a first necessary computationally based step during the design of more bio-friendly repellents that could lead to insights for improving the insecticidal activities of the investigated compounds. After optimizing the molecular structure of each furane and pyrane benzoderivative with the semiempirical molecular orbitals method PM3, more than a thousand of constitutional, topological, geometrical and electronic descriptors are calculated and multiparametric linear regression models are established on the antifeedant potencies. The feature selection method employed in this study is the Replacement Method, which has proven to be successful in previous analyzes. We establish the QSAR both for the complete molecular set of compounds and also for each chemical class, so that acceptably describing the variation of the inhibitory activities from the knowledge of their structure and thus achieving useful predictive results. The main interest of developing trustful QSAR models is that these enable the prediction of compounds having no experimentally measured activities for any reason. Therefore, the structure-activity relationships are further employed for investigating the antifeedant activity on previously synthesized 2-,7-substituted benzopyranes, which do not pose any measured values on the biological expression. One of them, 2-(alpha-naphtyl)-4H-1-benzopyran-4-one, results in a promising structure to be experimentally analyzed as it has predicted pED(50)=1.162.

QSAR on antiproliferative naphthoquinones based on a conformation-independent approach

The antiproliferative activities of a series of 36 naphthoquinone derivatives were subjected to a Quantitative Structure-Activity Relationships (QSAR) study. For this purpose a panel of four human cancer cell lines was used, namely HBL-100 (breast), HeLa (cervix), SW-1573 (non-small cell lung) and WiDr (colon). A conformation-independent representation of the chemical structure was established in order to avoid leading with the scarce experimental information on X-ray crystal structure of the drug interaction. The 1179 theoretical descriptors derived with E-Dragon and Recon software were simultaneously analyzed through linear regression models based on the Replacement Method variable subset selection technique. The established models were validated and tested through the use of external test sets of compounds, the Leave-One-Out Cross Validation method, Y-Randomization and Applicability Domain analysis.

A simple and mild acylation of alcohols, phenols, amines, and thiols with a reusable heteropoly acid catalyst (H 6 P 2 W 18 O 62 ·24 H 2 O)

The acylation of alcohols, phenols, thiols, and amines with varied substitution using acid anhydrides is efficiently catalyzed by Wells- Dawson heteropoly acid (H6P2W18 O62 ·24 H 2O). Reactions proceed with very good to excellent yield in air at room temperature, using toluene as solvent (40 examples). The bulk catalyst was easily reused without appreciable loss of its activity.

SYNTHESIS OF SUBSTITUTED FLAVONES AND ARYLCHROMONES USING Ρ AND Si KEGGIN HETEROPOLYACIDS AS CATALYSTS

A simple and clean procedure for the preparation of functionalized flavones and chromones using commercial Keggin heteropolyacid in acetonitrile medium is described for the cyclization of l-(2hydroxyaiyl)-3-aryl-l,3-propanodiones. Sixteen examples are reported, yields ranging in 60-91%; five substituted 2-naphthyIchromones are prepared for the first time. Introduction Compounds containing the chromone skeleton (4//-benzopyran-4-one) are widely distributed in the plant kingdom; they constitute a group of compounds in the flavonoid family (1). These compounds have multiple biological properties, for example anti-inflammatory, antibacterial, antitumor (2), antioxidant (3), anti HIV (4), vasodilator, antiviral, antiallergic (5) and neuroprotective . Some flavonoids inhibit the histamine release from human basophils and rat mast cells (6). Moreover, it is known that some flavonoids have antifeedant activity against some phytophagous insects and a Coptotermes sp. subterranean termite (7, 8). The importance of flavones and their derivatives has led to the development of various methods for their synthesis; for example the Kostanecki-Robinson strategy (9a), from chalcones (9b), or via the Baker-Venkataraman rearrangement to 1,3-diaryl 1,3diketones (9c, 10). The latter compounds give 2-arylchromones on cyclocondensation. Different media have been employed for performing it, for example using excess of sulfuric acid in glacial acetic acid (11, 12); cationic exchange resins in isopropanol (13) glacial acetic acid-anhydrous sodium acetate or aqueous potassium carbonate (14). Greener procedures have been recently described, for example using CuCI2 in ethanol and microwave irradiation (2). Environmental pollution is a usual drawback caused from the use of common acid catalysts like sulfuric, phosphoric, hydrofluoric acids, or boron trifluoride; frequently corrosion problems appear (15). Nevertheless, it is possible avoid them by using an insoluble acid, for example a heteropolyacid (ΗΡΑ) as catalyst HP As are useful solid catalysts because of their superacidic properties (16); catalysis by HP As or some of their derivatives is a field of increasing importance worldwide. There is a great activity in basic research as well as in developing of technological processes involving them (17-19). Varied reactions are currently catalyzed by HPAs, being important dehydration (20), cyclization (15), esterification (21), amine oxidation and olefin epoxidation (22). HPAs are widely applicable in production of fine chemicals (23). Heteropolycompounds with Keggintype primary structure are polynuclear complexes mainly composed by Mo, W or V as polyatoms (M) and P, Si or Ge as central atoms (X). The Keggin structure involves a central tetrahedron X04 surrounded by 12 octahedra M06 . Keggin catalysts could be either multi-electron oxidants or strong acids, with an acid strength higher than that of the classical mineral acids. These properties can be controlled by a proper choice of the heteroatom and polyatoms (15).

The conformation-independent QSPR approach for predicting the oxidation rate constant of water micropollutants

In advanced water treatment processes, the degradation efficiency of contaminants depends on the reactivity of the hydroxyl radical toward a target micropollutant. The present study predicts the hydroxyl radical rate constant in water (kOH) for 118 emerging micropollutants, by means of quantitative structure-property relationships (QSPR). The conformation-independent QSPR approach is employed, together with a large number of 15,251 molecular descriptors derived with the PaDEL, Epi Suite, and Mold2 freewares. The best multivariable linear regression (MLR) models are found with the replacement method variable subset selection technique. The proposed five-descriptor model has the following statistics for the training set: Rtrain2=0.88

A solvent-free synthesis of coumarins using a Wells-Dawson heteropolyacid as catalyst

{R}_{\mathrm{train}}^2=0.88