Ethyl 4-hydroxy­methyl-2-methyl­pyridine-5-carboxyl­ate

The title compound, C10H13NO3, was obtained as a by-product of the aldolization reaction of furo[3,4-c]pyridin-3(1H)-one with thio­phene-2-carboxaldehyde. The substituents on the pyridine ring are nearly coplanar, with an 8.1 (2)° rotation of the hydroxmethyl group from this plane. The mol­ecules assemble in the crystal structure as chains via O—H⋯N hydrogen bonding between the pyridine N atom and a neighbouring hydroxy­methyl OH group

Développement d'une nouvelle plate-forme hétérocyclique dérivée de dipeptide: la 1,3,5-triazépane-2,6-dione (Synthèse, propriétés structurales et évaluation de l'intérêt pharmacologique)

L industrie pharmaceutique a fait naître une demande croissante et sans cesse renouvelée de nouvelles petites molécules, cycliques ou polycycliques, capables de distribuer efficacement des groupements pharmacophores dans l espace. Ces composés, le plus souvent issus de la chimie combinatoire, doivent remplir plusieurs critères, tels qu une méthode de synthèse simple et versatile et une conformation rigide autour de laquelle peuvent s articuler plusieurs sites de diversité.La 1,3,5-triazépane-2,6-dione est une nouvelle structure, dérivée de dipeptide, qui remplit toutes les conditions citées précédemment. Obtenues en sept étapes à partir d acides aminés commerciaux, les 1,3,5-triazépane-2,6-diones ont été caractérisées précisément par diffraction des rayons X. Le développement de réactions de N-alkylation a permis l introduction de chaînes latérales supplémentaires comportant des fonctions réactives qui ont été transformées pour préparer des produits biologiquement actifs. Afin d augmenter la diversité des molécules disponibles, une méthode de synthèse avec réactifs supportés a été développée. Cette stratégie sera appliquée à la réalisation d une chimiothèque.Des tests prospectifs réalisés à partir d une petite collection de 1,3,5-triazépane-2,6-diones ont permis d identifier plusieurs inhibiteurs modérés du stade hépatique de la malaria. Parallèlement, une approche originale a été mise en œuvre pour découvrir des cibles biologiques potentielles. C est suite au criblage virtuel inverse de cinq 1,3,5-triazépane-2,6-diones contre une banque de données comportant 2148 structures d enzymes que les phospholipases A2 ont été identifiées comme cibles potentielles. Des tests in vitro ont confirmé cette prédiction avec l identification de plusieurs inhibiteurs spécifiques des hsPLA2 groupe V et X (IC50 ~ 10 M). L optimisation de ces touches est aujourd hui en cours.Pharmaceutical industry has raised a constant and increasing demand in cyclic/polycyclic molecular frameworks that can efficiently distribute selected pharmacophores in the 3D space. These compounds, usually resulting from combinatorial chemistry, should match criterias such as a simple and versatile synthetic method and a rigid conformation around which several sites of diversity can be positioned.1,3,5-Triazepane-2,6-dione is a dipeptide-derived structure, previously unreported, which fulfils the aforementioned conditions. Prepared in seven steps from commercially available -amino acids, those compounds have been precisely characterised by X-ray diffraction. The development of N-alkylation reactions has permitted the introduction of additional side chains containing reactive functions that have been elaborated to prepare biologically active compounds. In order to increase the diversity of molecules available, a polymer assisted synthesis approach has been developed. This strategy should prove useful for large scale library construction.Prospecting tests with a small collection of 1,3,5-triazepane-2,6-diones revealed moderate inhibitors of the malaria liver stage. In parallel, an original approach has been settled for the discovery of possible biological targets. An inverse virtual screening of five 1,3,5-triazepane-2,6-diones against a databank containing 2148 entries of enzyme structures led to the identification of Phospholipases A2 as possible targets. In vitro tests confirmed the activity of 1,3,5-triazepane-2,6-diones which exhibited an IC50 in the 10 M range on hsPLA2 group V and X. The optimisation of hits has been undertaken.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

In silico-guided target identification of a scaffold-focused library: 1,3,5-triazepan-2,6-diones as novel phospholipase A2 inhibitors.

A collection of 2150 druggable active sites from the Protein Data Bank was screened by high-throughput docking to identify putative targets for five representative molecules of a combinatorial library sharing a 1,3,5-triazepan-2,6-dione scaffold. Five targets were prioritized for experimental evaluation by computing enrichment in individual protein entries among the top 2% scoring targets. Out of the five proposed proteins, secreted phospholipase A2 (sPLA2) was shown to be a true target for a panel of 1,3,5-triazepan-2,6-diones which exhibited micromolar affinities toward two human sPLA2 members

Exploration of a series of 5-arylidene-2-thioxoimidazolidin-4-ones as inhibitors of the cytolytic protein perforin

A series of novel 5-arylidene-2-thioxoimidazolidin-4-ones were investigated as inhibitors of the lymphocyte-expressed pore-forming protein perform. Structure activity relationships were explored through variation of an isoindolinone or 3,4-dihydroisoquinolinone subunit on a fixed 2-thioxoimidazolidin-4-one/thiophene core. The ability of the resulting compounds to inhibit the lytic activity of both isolated perform protein and perforin delivered in situ by natural killer cells was determined. A number of compounds showed excellent activity at concentrations that were nontoxic to the killer cells, and several were a significant improvement on previous classes of inhibitors, being substantially more potent and soluble. Representative examples showed rapid and reversible binding to immobilized mouse perforin at low concentrations

Exploration of a series of 5-arylidene-2-thioxoimidazolidin-4-ones as inhibitors of the cytolytic protein perforin

A series of novel 5-arylidene-2-thioxoimidazolidin-4-ones were investigated as inhibitors of the lymphocyte-expressed pore-forming protein perform. Structure activity relationships were explored through variation of an isoindolinone or 3,4-dihydroisoquinolinone subunit on a fixed 2-thioxoimidazolidin-4-one/thiophene core. The ability of the resulting compounds to inhibit the lytic activity of both isolated perform protein and perforin delivered in situ by natural killer cells was determined. A number of compounds showed excellent activity at concentrations that were nontoxic to the killer cells, and several were a significant improvement on previous classes of inhibitors, being substantially more potent and soluble. Representative examples showed rapid and reversible binding to immobilized mouse perforin at low concentrations

Exploration of a Series of 5‑Arylidene-2-thioxoimidazolidin-4-ones as Inhibitors of the Cytolytic Protein Perforin

A series of novel 5-arylidene-2-thioxoimidazolidin-4-ones were investigated as inhibitors of the lymphocyte-expressed pore-forming protein perforin. Structure–activity relationships were explored through variation of an isoindolinone or 3,4-dihydroisoquinolinone subunit on a fixed 2-thioxoimidazolidin-4-one/thiophene core. The ability of the resulting compounds to inhibit the lytic activity of both isolated perforin protein and perforin delivered in situ by natural killer cells was determined. A number of compounds showed excellent activity at concentrations that were nontoxic to the killer cells, and several were a significant improvement on previous classes of inhibitors, being substantially more potent and soluble. Representative examples showed rapid and reversible binding to immobilized mouse perforin at low concentrations (≤2.5 μM) by surface plasmon resonance and prevented formation of perforin pores in target cells despite effective target cell engagement, as determined by calcium influx studies. Mouse PK studies of two analogues showed <i>T</i>_1/2 values of 1.1–1.2 h (dose of 5 mg/kg iv) and MTDs of 60–80 mg/kg (ip)