Alain Valla

Synthesis and antimicrobial activities of N-substituted imides.

In the field of our research programs concerning novel antimicrobial agents, a series of N-substituted imides was synthesized. These compounds were obtained by cyclization of amido-acids in acetic anhydride/sodium acetate or hexamethyldisilazane/zinc bromide for the hydroxy-aromatic derivatives. The hydroxy-alkyl maleimides were directly prepared by condensation of the corresponding amino-alcohol with maleic anhydride in boiling toluene. Most of N-substituted maleimides showed an interesting antimicrobial activity towards bacteria from the ATCC collection (Staphylococcus aureus ATCC 25923, Enterococcus faecalis ATCC 29212, Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853) but the MIC values for P. aeruginosa were always high (128 microg/ml). The imides with alkyl substituents showed higher activities than aromatic analogues with MIC values in the range of 8-32 microg/ml. Comparatively, succinimides were practically inactive.

Antifouling activities of N-substituted imides: antimicrobial activities and inhibition of Mytilus edulis phenoloxidase

In the search for novel biodegradable antifouling agents, a series of imides (N-substituted maleimides and succinimides) have been synthesized. A large majority of N-substituted maleimides and succinimides showed an antimicrobial activity toward gram-positive and gram-negative bacteria and fungi of marine origin with minimal inhibition concentrations in the range of 6 to 24 mg/ml. The imides with an alkyl substituent showed higher activities than aromatic analogues, but structure-activity relationships were not clearly established. Some compounds were powerful inhibitors of Mytilus edulis phenoloxidase. This inhibition was noncompetitive as demonstrated with 2 maleimides, a 3-acetoxy succinimide and a succinimide. Thus, this family of products has potential interest as antifouling agents.

Atypical Oxidation Reaction by Thionyl Chloride: Easy Two‐Step Synthesis of N‐Alkyl‐1,4‐dithiines

Abstract Easy two‐step synthesis of a series of dithiines was performed from succinic anhydride via cyclization of the corresponding 4‐(alkylamino)‐4‐oxobutanoic acids (succinamic acids). The reaction, carried out in polar aprotic solvents, gave 4,8‐dithiine‐indacene‐1,3,5,7‐tetraones (diimides 3) via 3,7‐bis‐4,8‐dithia‐indacene‐1,5‐diones (diisoimides 2), which could be isolated. Surprisingly, in this reaction, thionyl chloride appeared as an oxidant, and this process seemed to be useful for the syntheses of S‐containing heterocyclic compounds such as 1,4‐dithiins. A mechanistic pathway was considered.

Synthèses Stéréosélectives des Acides 13 E et 13 Z Rétinoı̈ques via un Nouvel Intermédiaire β-Méthylènealdéhyde en C-15

Resume The methylene-de-oxo-bisubstitution reaction between dimethyl isopropylidene malonate and the C-15 β-methylenealdehyde 1 which could serve as substitute for E β-ionylideneacetaldehyde 2, produces stereoselectively the E,E olefin. Hence, new stereoselective syntheses of 13 E and 13 Z retinoic acids were described.

New preparation of an important synthon for vitamin A synthesis

Abstract The “C-18 ketone” 1, key intermediate for vitamin A synthesis, is prepared in a few steps from β-ionone 3 via β-ionylidene acetonitrile 2 (32% overall yield).

First synthesis of 9-demethyl-14-carboxyretinoic acid

Abstract A short synthesis of 9-demethyl-14-carboxyretinoic acid from β-ionone via 9-demethyl-β-ionylideneacetaldehyde is reported (48% overall yield).

A New Stereoselective Synthesis of Acitretin (= Soriatane®, Neotigason®)

A new synthesis of acitretin via a C15+C5 route is reported. The C15 unit is the key step, involving a procedure that provides the required (all-E)-C15-aldehyde with high stereoselectivity.

Stereoselective synthesis of 13Z retinoic acids via β-methylenealdehydes as synthons

Abstract A stereoselective synthesis of 13Z retinoic acids via β-methylenealdehydes is described. In methylene-de-oxo-bisubstitution reactions (Knoevenagel, Stobbe, etc.), these new synthons produce stereoselectively E olefins. Hence, a synthesis of 13Z retinoic acids is described, via a stereospecific monodecarboxylation of carboxy-14-retinoic acids.

Amino acid-pyrrole N-conjugates; a new class of antioxidants II. Effectiveness of singlet oxygen quenching by luminescence measurements

Abstract The pyrrole-amino acid and peptide N -conjugates synthesized from tyrosine, histidine and glutathione very effectively quench the 1270 nm singlet oxygen luminescence, at rates ranging from 10 8 to 10 9 M −1 s −1 . Nuclear magnetic resonance spectroscopy suggests that the electron-donating properties of the methyl groups after 2,5-dimethyl substitution on the pyrrole ring are probably an important determinant of the reactivity of singlet oxygen with the N -conjugate of glutathione. However, intramolecular interactions between the pyrrole ring and the side chain may also modulate the reactivity of the antioxidant as suggested by absorption and fluorescence spectroscopies carried out on tyrosine derivatives. Efficient fluorescence quenching of the phenol ring by the pyrrole ring occurs in the tyrosine derivatives. The reactivities of these antioxidants with 1 O 2 are comparable in methanol, ethanol and D 2 O.

N-conjugates of 2,5-disubstituted pyrrole and glutathione evaluation of their potency as antioxidants against photosensitization of NCTC 2544 keratinocytes by excess endogenous protoporphyrin IX

A novel glutathione compound in which the amino group has been derivatized by a 2,5-dimethyl pyrrole is shown to be very effective against cell photosensitization in vitro. Protoporphyrin IX either added to the medium or produced endogenously by incubation of NCTC 2544 keratinocytes with 5-aminolevulinic acid has been chosen as the photosensitizer. The antioxidant effectiveness of glutathione-pyrrole derivatives against protoporphyrin photosensitization depends critically on the type of 2,5 substitution on the pyrrole ring. This structure-function relationship may be attributed to the difference in compartmentation and/or uptake of the various glutathione-pyrrole derivatives under study. The 2,5-dimethyl pyrrole derivative is much more effective than glutathione as a protective agent against phototoxic reactions induced by protoporphyrin IX.