Nicolas Gouault

Combined approaches for drug design points the way to novel proline racemase inhibitor candidates to fight Chagas' disease.

Chagas’ disease is caused by Trypanosoma cruzi, a protozoan transmitted to humans by blood-feeding insects, blood transfusion or congenitally. Previous research led us to discover a parasite proline racemase (TcPRAC) and to establish its validity as a target for the design of new chemotherapies against the disease, including its chronic form. A known inhibitor of proline racemases, 2-pyrrolecarboxylic acid (PYC), is water-insoluble. We synthesized soluble pyrazole derivatives, but they proved weak or inactive TcPRAC inhibitors. TcPRAC catalytic site is too small and constrained when bound to PYC to allow efficient search for new inhibitors by virtual screening. Forty-nine intermediate conformations between the opened enzyme structure and the closed liganded one were built by calculating a transition path with a method we developed. A wider range of chemical compounds could dock in the partially opened intermediate active site models in silico. Four models were selected for known substrates and weak inhibitors could dock in them and were used to screen chemical libraries. Two identified soluble compounds, (E)-4-oxopent-2-enoic acid (OxoPA) and its derivative (E)-5-bromo-4-oxopent-2-enoic acid (Br-OxoPA), are irreversible competitive inhibitors that presented stronger activity than PYC on TcPRAC. We show here that increasing doses of OxoPA and Br-OxoPA hamper T. cruzi intracellular differentiation and fate in mammalian host cells. Our data confirm that through to their binding mode, these molecules are interesting and promising as lead compounds for the development of chemotherapies against diseases where active proline racemases play essential roles.

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.

Protolichesterinic acid derivatives: α-Methylene-γ-lactones as potent dual activators of PPARγ and Nrf2 transcriptional factors

PPARγ and Nrf2 are important transcriptional factors involved in many signaling pathways, especially in the anti-infectious response of macrophages. Compounds bearing a Michael acceptor moiety are well known to activate such transcriptional factors, we thus evaluated the potency of α,β-unsaturated lactones synthesized using fluorous phase organic synthesis. Compounds were first screened for their cytotoxicity in order to select lactones for PPARγ and Nrf2 activation evaluation. Among them, two α-methylene-γ-lactones were identified as potent dual activators of PPARγ and Nrf2 in macrophages.

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 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.

FLUOROUS SUPPORTED SYNTHESIS OF PYRAZOLONE DERIVATIVES FROM ALLYLIC ALCOHOLS USING A PALLADIUM-CATALYZED STRATEGY

Ten substituted pyrazolone derivatives were easily synthesized from perfluorinated allylic alcohols, via a straightforward two steps reaction involving a Heck-coupling/isomerization reaction and subsequent condensation of hydrazines. This fluorous supported methodology, that combines a cyclo-release approach and F-SPE purification allows for the obtaining of the final products with a good purity.