Michèle David

γ-Methyl-substituted-γ-butyrolactones: solid-phase synthesis employing a cyclisation–cleavage strategy

Abstract The solid-phase synthesis of several γ-methyl-substituted-γ-butyrolactones using a cyclisation–cleavage reaction is reported. Chemical modifications of polymer-bound azido (2a) and iodo alcohols (2b) were realised in order to introduce additional diversity onto the lactone structure.

Kavain analogues as potential analgesic agents

BACKGROUND Kavalactones are pharmacologically active compounds present in preparations of the root trunk of Piper methysticum Forst, known as kava. This work describes the analgesic activity of some synthesized analogues of synthetic kavain, which is the main component of kava. METHODS The essays were initially performed against the writhing test in mice, and the most promising compound was analyzed using other classical models of nociception, including formalin-, capsaicin-, glutamate-induced nociception, the hot plate test, and measurement of motor performance. RESULTS The results indicated that compound 6-(4-fluorophenyl)-4-methoxy-5,6-dihydropyran-2-one (2d) exerts potent and dose-dependent analgesic activity, inhibiting abdominal constrictions caused by acetic acid in mice, and being more active than some reference drugs. It also presented activity in the other models of pain, with the exception of the hot plate test and the measurement of motor performance. CONCLUSIONS Although compound 2d exerts antinociceptive activity, the mechanism of action remains uncertain, but it does not involve the opioid system and does not appear to be associated with non-specific effects such as changes in locomotor activity or motor coordination.

Synthesis of diverse 4,5‐dihydro‐3(2H)‐pyridazinones on Wang resin

An efficient solid‐phase synthesis of structurally diverse 4,5‐dihydro‐3(2H)‐pyridazinones is described using readily available substituted 4‐oxo‐butanoic acids. Polymer‐supported γ‐keto‐esters prepared from Wang resin reacted with several hydrazines to afford the corresponding hydrazones. A protocol developed in mild conditions without isolating the intermediate hydrazone led to pyridazinones in good yields after a cyclization cleavage approach. This successful strategy represents an attractive method for a rapid synthesis of heterocyclic libraries for biological evaluation.

Synthesis of novel kavain-like derivatives and evaluation of their cytotoxic activity

Reacoes de acoplamento do tipo Heck, Sonogashira-Hagihara, Suzuki-Miyaura e reacao de aldolisacao catalizadas por metal foram utilizadas para a obtencao de tres series de δ-valerolactonas substituidas em posicoes 3, 4, 5 e 6 do anel lactonico. As 26 δ-valerolactonas sintetizadas foram testadas contra tres linhagens celulares e cinco delas exibiram uma moderada atividade citotoxica.

Synthesis and Potential Anti-Inflammatory Activity of Some Tetrahydrophthalazinones

A solid-phase route for the preparation of 4a,5,8,8a-tetrahydrophthalazinon-1-ones employing the Diels-Alder reaction has been developed. Some of the new compounds have been tested for inhibition of LPS-stimulated TNF-α production in human whole blood from patients with chronic obstructive pulmonary disease (COPD). This evaluation revealed two compounds 17 and 18 of interest, incorporating an arylpiperazine moiety, which were found to inhibit LPS- induced TNF-α release like the well known anti-inflammatory PDE4 inhibitors, rolipram and roflumilast.

Solid‐phase Synthesis, Antiviral Activity and Cytotoxicity of Some Functionalized Lactones

Thio-substituted γ- and δ-lactones were prepared via a resin-bound epoxide by ring-opening reaction with sodium thiolates and subsequent cleavage. The compounds were ineffective against herpes simplex virus type 1 and poliovirus. However, the cytotoxicity on murine tumour lines of 3,3-dimethyl lactone appeared to be promising.

Solid-phase synthesis and evaluation of libraries of substituted 4,5-dihydropyridazinones as vasodilator agents

The solid‐phase parallel preparation of a library of 4,5‐dihydropyridazin‐3(2H)‐one derivatives substituted at position 6 with piperazinylmethyl or tetrahydroquinolinylmethyl groups and analogues (3) is reported. Polymer‐supported γ‐keto‐δ‐aminoesters prepared from Wang resin reacted with hydrazine or methylhydrazine to afford pyridazinones in good yields after a cyclization cleavage approach. We have evaluated these novel analogues and several compounds of other series (1, 2) for their vasorelaxant effect. Among the products tested, 3I and 3d proved to be efficacious and potent relaxant agents of the isolated rat aorta. Inhibitors of phosphodiesterase (PDE3), responsible for the breakdown of cyclic AMP in the vascular smooth muscle, are currently developed for cardiac heart failure because of their inotropic effect and coronary vasodilatation. We had expected that the vasodilatation induced by 3l, as efficient as reference PDE3 inhibitors, milrinone or CI‐930, to be due to PDE3 inhibition. However 3I and 3d exhibited a low inhibitory effect against PDE3 isoenzyme activity. These compounds induced a significant vasorelaxation, which could be of therapeutic interest even if their mechanism of action remains to be determined.

Expedient method for the solid-phase synthesis of some 4-substituted-4,5-dihydropyridazin-3(2H)-ones

The solid-phase synthesis of some 4-amino-4,5-dihydropyridazin-3(2H)-ones has been realised using regiospecific Michael addition and subsequent cyclorelease reactions.

A Convenient Synthesis of 2H-3,4-Dihydro-1,4-Benzothiazines

Abstract Aminothioalkenols react with paratoluenesulfonic acid in benzene or with phosphoric acid in toluene, and provide mainly heterocyclization in 2H-3,4-dihydro-1,4- benzothiazines; formation of some indenes and diene (in one case) was observed too.

Gold-Catalyzed Synthesis of Substituted 3-Trifluoromethylpyrroles from Mesylated Amino Trifluoromethylpropargylic Alcohols

A series of substituted 3-trifluoromethylpyrroles was obtained from trifluoromethylamino-ynol derivatives via a gold-catalyzed cyclization. Using fluorinated starting materials, after mesylation, allowed for the desired compounds to be obtained in good yields under mild conditions.