The demonstration of the essential role of fatty acid amide hydrolase (FAAH) in hydrolyzing endogenous bioactive fatty acid derivatives has launched the quest for the discovery of inhibitors for this enzyme. Along this line, a set of 58 imidazolidine-2,4-dione and 2-thioxoimidazolidin-4-one derivatives was evaluated as FAAH inhibitors. Among these compounds, 3-substituted 5,5′-diphenylimidazolidine-2,4-dione and 3-substituted 5,5′-diphenyl-2-thioxoimidazolidin-4-one derivatives were previously described as CB 1 cannabinoid receptor ligands. In the present study, we synthesized several derivatives exhibiting interesting FAAH inhibitory activity and devoid of affinity for the CB 1 and CB 2 cannabinoid receptors. For instance, 3-heptyl-5,5′-diphenylimidazolidine-2,4-dione (14) and 5,5′-diphenyl-3-tetradecyl-2-thioxo-imidazolidin-4-one (46) showed pI 50 values of 5.12 and 5.94, respectively. In conclusion, it appears that even though several 3-substituted 5,5′-diphenyl-2-thioxoimidazolidin-4-one and 3-substituted 5,5′-diphenylimidazolidine-2,4-dione derivatives have been previously shown to behave as CB 1 cannabinoid receptor ligands, appropriate substitutions of these templates can result in FAAH inhibitors devoid of affinity for the cannabinoid receptors.

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DD-ligases catalyze the synthesis of the D-Ala-D-Ala and D-Ala-D-Ser dipeptides or the D Ala-D-Lac depsipeptide in an early step of peptidoglycan synthesis. Their function is essential for bacterial growth and specific to bacteria, making them attractive targets for the development of novel antibiotics. This review examines the biochemical and structural features of these enzymes and presents the main families of inhibitors described so far. Over the last 20 years, 7 structures of DD-ligases have been solved by X-ray crystallography, giving a detailed view of the general topology of the active site and of the residues in the catalytic pocket that play a central role in substrate recognition. This has paved the way to the rational design of inhibitors, which can be classified as (i) analogues of substrates, (ii) analogues of the product of the reaction, (iii) analogues of the transition state, and (iv) original scaffolds discovered by screening or by rational computer-aided design. The three first strategies have led to molecules that are polar by nature and have therefore poor access to their cytosolic target. The fourth one is potentially most promising as it yields more diverse structures. The most active molecules show affinity constants in the microM range, but microbiological evaluation remains scarce (typical MIC 1-8 mg/L for the tested compounds). These data strongly suggest targeting DD-ligases is a promising approach for discovery of new antibiotics. Future research should, however, aim at finding more potent inhibitors endowed with the appropriate pharmacokinetic properties that ensure access to their intracellular target.

A glyceride derivative of chlorambucil (2), 1,3-dipalmitoyl-2-[4-[bis (2-chloroethyl)amino]benzenebutanoyl]glycerol (1), was synthesized and tested as an orally administrable antineoplastic drug endowed with lymphotropic properties. A significantly higher efficacy (increased life span) and a reduced toxicity of 1, relative to 2, were apparent when both compounds given per os were evaluated against P388 leukemia subcutaneously implanted in mice, a situation where the tumor cells disseminate along the lymphatic route. In order to assess the selective absorption of 1 by the intestinal lymphatic system after oral administration, we determined plasma and intestinal lymphatic concentrations and compared them with that obtained with 2. The results clearly demonstrate that the esterification of 2 to a diacylglycerol moiety brings about considerably higher levels in the lymph and reduces plasma levels. Moreover, pharmacokinetic and biological data suggest that 1 is most probably acting by itself rather than as a prodrug of chlorambucil.

A glyceride derivative of L-Dopa, 1,3-dihexadecanoyl-2-[(S)-2-amino-3-(3,4-dihydroxyphenyl)propan oyl] propane-1,2,3-triol (1), was synthesized and tested as an orally administrable prodrug endowed with lymphotropic properties. In the oxotremorine and reserpine tests, 1 exhibited an anti-Parkinsonian activity of longer duration than L-Dopa. The time course of concentration of 1 in the intestinal lymph of rat was determined and compared to that of L-Dopa. The results clearly demonstrate that 1 is selectively absorbed from the intestinal tract by the lymphatic route without any chemical or enzymatic degradation. In the blood of rats and mice, 1 functions as a prodrug to release L-Dopa by hydrolysis. In comparison with L-Dopa itself, higher L-Dopa levels for a longer period of time were observed as well as much more favorable L-Dopa/dopamine ratios. Ultimately, studies using mice show that the administration of 1 brings about a prolonged increase of L-Dopa and dopamine levels in the brain, without initial transient peak in concentration observed after an equimolecular dose of L-Dopa.