Jérôme Guillard

Synthesis and in vitro antitumour evaluation of benzothiazole-2-carbonitrile derivatives

Novel benzothiazole derivatives have been synthesised via the corresponding imino-1,2,3-dithiazoles. The cytotoxicity of some of these polyheterocyclic compounds was studied. Our results show that 2-cyano derivatives exhibit a medium in vitro antitumour activity.

Multistep synthesis of thiazoloquinazolines under microwave irradiation in solution

Abstract Thiazolo[5,4- f ]quinazolines are synthesised in six or seven steps from 2-amino-5-nitrobenzonitrile. Both heterocyclic rings are fused onto the central benzene ring via imino-1,2,3-dithiazoles which are readily obtained from primary aromatic amines and 4,5-dichloro-1,2,3-dithiazolium chloride (Appel salt). Four of the steps were improved in yield or reaction time or both, compared to conventional heating, by microwave irradiation of solutions of the reactants in a focused open microwave oven.

Expeditious routes to 4-alkoxyquinazoline-2-carbonitriles and thiocarbamates via N-arylimino-1,2,3-dithiazoles using microwave irradiation☆

Abstract Conversion of N -arylimino-4-chloro-5 H -1,2,3-dithiazole 11 into the 4-alkoxyquinazoline-2-carbonitriles 13a-i and of the aryl isothiocyanates 15 into aryl thiocarbamates 16a-j with sodium alkoxides in the corresponding alcohol, either by conventional thermolysis or by microwave irradiation are described and directly compared. Microwave irradiation of the solutions in open vessels in a monomode system with focused irradiation and continuous temperature control (Synthewave S402 reactor) usually gave cleaner, faster and higher yielding reactions. These reactions could be safely and beneficially scaled up to multigram quantities in a larger reactor (Synthewave S1000).

4,4-Dimethyl-1,2,3,4-tetrahydroquinoline-based PPARα/γ agonists. Part I: Synthesis and pharmacological evaluation

Type-2 diabetes (T2D) is a complex metabolic disease characterized by insulin resistance in the liver and peripheral tissues accompanied by a defect in pancreatic beta-cell. Since their discovery three subtypes of Peroxisomes Proliferators Activated Receptors were identified namely PPARalpha, PPARgamma and PPARbeta/(delta). We were interested in designing novel PPARgamma selective agonists and/or dual PPARalpha/gamma agonists. Based on the typical topology of synthetic PPAR agonists, we focused our design approach on 4,4-dimethyl-1,2,3,4-tetrahydroquinoline as novel cyclic tail.

Synthesis of novel dioxinobenzothiazole derivatives

Abstract The synthesis of new dioxinobenzothiazoles is described. Introduction of the thiazole moiety of these new polyheterocyclic systems was realised by the use of imino-1,2,3-dithiazoles. Several steps in these multistep synthesis were transposed to a focused microwave oven.

Synthesis of potential Rho-kinase inhibitors based on the chemistry of an original heterocycle: 4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one.

A new series of substituted 4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one have been prepared via condensation of 3,3-dimethylacryloyl chloride with aniline. Details of synthetic procedures are shown. Our aim was to investigate the potency of our original heterocycle in the inhibition of the Rho-kinase enzyme, known to be of major importance in the cascade reactions leading to arterial hypertension. Biological activity for the seven compounds has been investigated and is presented.

4,4-Dimethyl-1,2,3,4-tetrahydroquinoline-based PPARα/γ agonists. Part. II: Synthesis and pharmacological evaluation of oxime and acidic head group structural variations

Type-2 diabetes (T2D) is a complex metabolic disease characterized by insulin resistance in the liver and peripheral tissues accompanied by a deficiency in pancreatic beta-cells. Since their discovery, three subtypes of peroxisome proliferator activated receptors have been identified, namely PPARalpha, PPARgamma and PPARbeta/(delta). In this study, we were interested in designing novel PPARgamma selective agonists and/or dual PPARalpha/gamma agonists. Based on the typical topology of synthetic PPAR agonists, we focused our design approach on using 4,4-dimethyl-1,2,3,4-tetrahydroquinoline as a novel cyclic scaffold with oxime and acidic head group structural variations.

New synthetic route to diaminonitropyrazoles as precursors of energetic materials

Treatment of nitropyrimidine derivatives with (N-substituted) hydrazines (2 equiv.) gave 1-(substituted)-3,5-diamino-4-nitropyrazole, providing a very mild conversion of pyrimidines into pyrazoles. This reaction provided a convenient route to precursors for new efficient and insensitive explosives.

New syntheses of aryl isothiocyanates

Primary aromatic amines are readily converted into arylimino-1,2,3-dithiazoles 2 and the derived cyanothioformanilides 6, both of which are rapidly cleaved by ethylmagnesium bromide in hot THF to give the corresponding isothiocyanates. The transformation 2→6→ArNCS can be performed as a ‘one-pot’ operation. The imines 2 are also converted, more slowly, into the isothiocyanates by sodium hydride in hot THF, via the cyanothioformanilides 6. Conversion of the anilides 6 into isothiocyanates is much faster under microwave irradiation in 2,6-lutidine. Mechanisms are proposed for these reactions.

Rapid synthesis of 2-cyanobenzothiazole, isothiocyanate and cyanoformanilide derivatives of dapsone

New derivatives of the leprostatic drug dapsone are prepared by way of imino-1,2,3-dithiazoles obtained by condensation of aromatic primary bisamines, including dapsone, with 4,5-dichloro-1,2,3-dithiazolium chloride (Appel salt). Reactions, including microwave irradiation, initiated by nucleophilic attack at different sites of the dithiazole ring transform the bisiminodithiazoles into the symmetrical, and some unsymmetrical, title compounds.