Synthesis, theoretical studies, and effect on the photosynthetic electron transport of trifluoromethyl arylamides.

BACKGROUND: The photosynthetic apparatus is targeted by various herbicides, including several amides such as diuron and linuron. Considering the need for the discovery of new active ingredients to cope with weed resistance, the synthesis of a series of trifluoromethyl aryl amides is herein described whose inhibitory properties were assessed in vitro on the photosynthetic electron transport chain, and in vivo on the growth of a model cyanobacterial strain. Theoretical studies were also carried out. RESULTS: Starting with 1-fluoro-2-nitro-4-(trifluoromethyl) benzene, the preparation of the amides was achieved via a three-step sequence, namely nucleophilic aromatic substitution, reduction with SnCl2 /HCl, and acylation reactions. The measurement of ferricyanide reduction by functionally intact spinach chloroplasts showed that several derivatives are capable of inhibiting the photosynthetic apparatus. The most active amides presented IC50 values close to 1 µmol L-1 , and showed the presence of a 4-bromophenyl group as a common structural feature. The addition of these brominated amides to the culture medium of a model cyanobacterial strain, Synechococcus elongatus PCC 6301, caused various degrees of growth inhibition. Theoretical studies (molecular modeling and quantitative structure-activity relationship) of all amides and their comparison with some known herbicides confirmed these experimental findings and provided more in-depth information about the possible molecular target of these compounds. CONCLUSION: Trifluoromethyl amides herein described, which were shown to act at the PSII level, may represent a novel scaffold to be exploited aiming at the development of new active ingredients for weed control. © 2017 Society of Chemical Industry.

Simple quantitative structure-property relationship (QSPR) modeling of 17O carbonyl chemical shifts in substituted benzaldehydes compared to DFT and empirical approaches.

The geometry of 50 substituted benzaldehydes was optimized at the semiempirical PM3 level, and various electronic and steric descriptors accounting for properties of the benzene ring, aldehyde group, and their connecting carbon-carbon bond were calculated. Quantitative structure-property relationships (QSPR) between (17)O carbonyl chemical shifts and these descriptors were established using partial least-squares regression and principal component regression. These two parsimonious QSPR models were comparable with the literature empirical model and DFT (density functional theory) and capable of predicting (17)O chemical shifts for 10 benzaldehydes. Principal component analysis, hierarchical cluster analysis, and crystal structure data retrieved from the Cambridge Structural Database were additional methods for chemical verification of the regression models. The QSPR models are recommended as being more reliable than and superior to the empirical and DFT models due to the results of all validations, simplicity, and short time that regressions need for (17)O shift prediction.

Theoretical study of radical and neutral intermediates of artemisinin decomposition.

Four artemisinin reductive decomposition routes A, B1, B2, and B3 with 13 species (QHS, 1/2, 3, 4, 5, 5a, 6, 7, 18, 18a, 19, 20, and 21) were studied at the B3LYP/6-31G** level. Structures of the species were analyzed in terms of geometrical parameters, Löwdin bond orders, partial atomic charges and spin densities, electronic and free energies, and entropy. Searches in the Cambridge Structural Database for high-level quality artemisinin-related structures were also performed. Principal Component and Hierarchical Cluster analyses were performed on selected electronic and structural variables to rationalize relationships between the routes. The A and B1 routes are possibly interconnected. Structural and electronic features of all species show that there are two clusters: A-B1 and B2-B3. The latter cluster is thermodynamically more favorable (DeltaDeltaG is -64 to -88 kcal mol(-1)) than the former (DeltaDeltaG is -58 to -59 kcal mol(-1)), but kinetical preference may be the opposite. Along the artemisinin decomposition routes, especially B2 and B3, larger structural changes including formation of branched structures and CO2 release are related to increased exothermicity of the conversions, weakened attractive oxygen-oxygen interactions, and increased entropy of the formed species. The intermediate 4 definitely belongs to some minor artemisinin decomposition route.

Conformational study of (8alpha,8'beta)-bis(substituted phenyl)-lignano-9,9'-lactones by means of combined computational, database mining, NMR, and chemometric approaches.

Beta-(3,4-Methylenedioxybenzyl)-gamma-butyrolactone (MDBL) and (-)-hinokinin (HK) were obtained by partial synthesis and characterized by 1H NMR and computational methods (conformational analysis, molecular modeling, structural data mining and chemometrics). Three conformers were detected for MDBL and nine were found for HK. The energy differences are around 1 and 2 kcal mol(-1) and rotation barriers are less than 3 and 5 kcal mol(-1) for MDBL and HK conformers, respectively. The geometries of these conformers, obtained from semiempirical PM3 and density functional theory (DFT) B3LYP 6-31G** calculations agree satisfactorily with 1H NMR data (vicinal proton-proton coupling constants) and structures retrieved from the Cambridge Structural Database (torsion angles). DFT combined with some variants of the Haasnoot-de Leeuuw-Altona equations gives the best predictions for the coupling constants. The molecular conformation of MDBL, of HK, and of related systems depends not only on intramolecular interactions but also on crystal packing forces and solvent-solute interactions, in particular hydrogen bonds and polar interactions. Hydration favors more stable HK conformers, which can be important for their behavior in chemical and biological systems.

Molecular graphics approach to bacterial AcrB protein-beta-lactam antibiotic molecular recognition in drug efflux mechanism.

AcrAB-TolC is the most important multidrug efflux pump system of Gram-negative bacteria, responsible for their resistance to lipophilic and amphiphilic drugs. In this work, a molecular graphics study of the pump components AcrB and TolC, 16 beta-lactam antibiotics and 7 other substrates, as well as of AcrB-substrate complexes, was performed in order to give a mechanistic proposal for the efflux process at molecular level. AcrAB-TolC is a proton-dependent electromechanical device which opens to extrude drugs from the bacterial periplasm and perhaps cytoplasm, by means of a series of structural changes within the complex and its components AcrA, AcrB and TolC. These changes are initiated by protonation and disruption of salt bridges and certain hydrogen bonds, and are followed by conformational changes in which a number of intra- and interchain interactions are rearranged. Molecular properties of beta-lactams accounting for their lipophilicity, shape/conformation and other sterical features, polar/charge group distribution and other electronic properties, and hydrogen bonding potency determine their interaction with polar headpieces of the inner membrane, recognition and binding to receptors of AcrB and TolC. The orientation of the beta-lactam molecular dipoles with respect the efflux system is maintained during the drug efflux. Elongated cylinder-like beta-lactam antibiotics with lipophylic side chains, a significantly negative component of the dipole moment and low hydrogen bonding capacity seem to be good substrates of AcrAB-TolC.

A priori molecular descriptors in QSAR: a case of HIV-1 protease inhibitors. II. Molecular graphics and modeling.

Molecular graphics and modeling methods illustrated the chemical background of the a priori approach from part I, and visualized steric and electronic enzyme-inhibitor relationships at qualitative and quantitative level for 34 and its derivatives. The enzyme-inhibitor electron density overlap occurs at 1.5-5.5A cut-off distance, beyond van der Waals radii. Derivatives of 34 exhibit linear relationships between biological activity, molecular size and number of intermolecular interactions.

A priori molecular descriptors in QSAR: a case of HIV-1 protease inhibitors. I. The chemometric approach.

A quantitative structure-activity relationship (QSAR) study on 48 peptidic HIV-1 protease inhibitors was performed. Fourteen a priori molecular descriptors were used to build QSAR models. Hierarchical cluster analysis (HCA), principal component analysis (PCA) and partial least squares (PLS) regression were employed. PLS models with 32/16 (model I) and 48/0 (model II) molecules in the training/external validation set were constructed. The a priori molecular descriptors were related to two energetic variables using PLS. HCA and PCA on data from model II classified the inhibitors as slightly, moderately and highly active; three principal components, the chemical nature of which has been highlighted, are enough to describe the enzyme-inhibitor binding. Model I (r(2)=0.91, q(2)=0.84) is comparable to literature models obtained by various QSAR softwares, which justified the use of a priori descriptors.