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Based on a line of evidence (logP, pKa, 1 H-, and 13 C-NMR, and molecular modeling studies), it appears that cocaine undergoes a hydrophobic collapse which may account for its unprecedented ADME properties, in particular, its exceptional capacity to cross biological membranes. Using molecular simulation techniques, the hypothesis of hydrophobic collapse undergone by the protonated form of cocaine was substantiated using semi-empirical quantum calculations (mainly AM1 and PM3) performed as well as ab initio quantum calculations (6-31 G**). A molecular electrostatic potential map of the internally hydrogen-bonded structure was acquired under AM1 and showed a continuum of high electron density in the central part of the molecule around the methyl ammonium and the two ester moieties. This picture is consistent with the picture of the ammonium being locked between the two C=O and forming a strong canonical primary H bond with the methyl ester and a weaker secondary H bond (non-canonical) with the benzoate ester. Cocaine represents the prototypical example of molecular concision because the pharmacophore and the vector are embedded in the same molecular scaffold. © 2012 Springer Science+Business Media, LLC.

Chalcones featuring an analgesic/anti-inflammatory pharmacophore, i.e., the 2(3H)-benzoxazolone heterocycle, on the one hand, and a radical scavenger moiety, i.e., 2,6-di-t-butylphenol, on the other hand were synthesized by condensation of a ketone 2(3H)-benzoxazolone precursor with 3,5-di-t-butyl-4-hydroxybenzaldehyde. Among the various methods explored (acid homogenous or heterogenous catalysis, base catalysis), heterogenous catalysis conditions using KSF Montmorillonite were found to be the most convenient. The E-geometry of the so-obtained chalcones was ascertained both by 1H and 13C-nuclear magnetic resonance (NMR) spectroscopy as well as B3LYP/6-31G** quantum mechanics calculations. Chalcones 1–8 were pharmacologically evaluated in vitro for their ability to prevent human low-density lipoprotein (LDL) copper-induced oxidation using Cu2+ as oxidizing agent. Compound 4 emerged as the most promising agent as it was able to inhibit copper-mediated human LDL oxidation with an activity ten times greater than that of Probucol, a reference antioxidant drug.

Monoglyceride lipase (MGL) is the enzyme responsible for the termination of 2-arachidonoylglycerol (2-AG) signalling, an endogenous ligand for the G-protein coupled cannabinoid receptors CB1 and CB2. Its known abundance and physiological roles emphasize the interest of MGL as an attractive therapeutic target. Search for MGL inhibitors was undertaken by screening an arylthioamide series. The evaluation of arylthioamides derivatives activity as MGL inhibitors measured by the hydrolysis of [H-3]-2-oleoylglycerol by human purified MGL led to the identification of (2-chloro-phenyl)-morpholin-4-yl-methanethione (2) and (3-nitro-phenyl) morpholin-4-yl-methanethione (12), which moreover exhibit good selectivity compared with human fatty acid amide hydrolase inhibition.