Jacques Bompart

New imidazo(1,2-a)pyrazine derivatives with bronchodilatory and cyclic nucleotide phosphodiesterase inhibitory activities.

New imidazo[1,2-a]pyrazine derivatives have been synthesized either by direct cyclization from pyrazines or by electrophilic substitutions. The presence of electron donating groups on position 8 greatly enhances the reactivity of the heterocycle towards such reactions on position 3 of the heterocycle. The activities of these derivatives in trachealis muscle relaxation and in inhibiting cyclic nucleotide phosphodiesterase (PDE) isoenzyme types III and IV have been assessed. All compounds demonstrated significantly higher relaxant potency than theophylline. All the derivatives were moderately potent in inhibiting the type IV isoenzyme of PDE but only those with a cyano group on position 2 were potent in inhibiting the type III isoenzyme.

Cardiovascular effects of SCA40, a novel potassium channel opener, in rats

1 Experiments have been performed to investigate the cardiovascular actions in the rat of SCA40, a novel potassium channel opener which is a potent relaxant of guinea‐pig airway smooth muscle in vivo and in vitro. 2 SCA40 (0.01–30 μm) caused a complete and concentration‐dependent relaxation of rat isolated thoracic aorta contracted with 20 mm KCl but failed to inhibit completely the spasmogenic effects of 80 mm KCl. 3 The ATP‐sensitive K+‐channel blocker, glibenclamide (3 μm), failed to antagonize the relaxant action of SCA40 on 20 mm KCl‐contracted rat isolated thoracic aorta. 4 SCA40 (0.001–100 μm) had dual effects on rat isolated atria. At low concentrations, SCA40 produced a concentration‐dependent decrease in the rate and force of contractions. At higher concentrations (greater than 1 μm) SCA40 induced concentration‐dependent increases of atrial rate and force. 5 In vivo, in normotensive Wistar rats, SCA40 elicited a dose‐dependent (1–100 μg kg−1) decrease in mean arterial pressure which was accompanied by a moderate dose‐dependent increase in heart rate. SCA40 (100 μg kg−1) had a slightly greater hypotensive effect than cromakalim (100 μg kg−1) but the duration of the hypotension was longer with cromakalim than with SCA40. 6 The hypotensive effect of SCA40 was not reduced by propranolol, atropine, NG‐nitro‐l‐arginine methyl ester (l‐NAME) or glibenclamide. 7 It is concluded that the mechanism by which SCA40 relaxes vascular smooth muscle in vitro and in vivo involves activation of K+‐channels distinct from glibenclamide‐sensitive ATP‐sensitive K+‐channels.

Thienopyridinone antibacterials : Synthesis and antibacterial activity of some 7-aryl-2-chloro-4,7-dihydro-4-oxothieno[2,3-b]pyridine-5-carboxylic acids

Abstract A series of 7-aryl-4-oxothieno[2,3- b ]pyridine-5-carboxylic acids 8 and their methyl esters 7 were synthesized by intramolecular cyclization of the respective 3- N -arylamino-2-(2,5-dichloro-3-thenoyl) acrylates 6 . The latter are accessible from methyl 3-ethoxy-2-(2,5-dichloro-3-thenoyl) acrylate 5 which, in turn, is obtained via the parent β-keto ester 4 . Of the present series, the 7-( p -hydroxyphenyl) and 7-(2′,4′-difluorophenyl) derivatives 8e,i possess the highest activity especially against Klebsiella pneumoniae, Escherichia coli and Staphylacoccus aureus (MICs of 8e/8i ∩ 0.06:0.25, 0.5:1.0 and 1.0:2.0 μg/mL, respectively).

Variable mapping of structure-activity relationships: Application to 17-spirolactone derivatives with mineralocorticoid activity

Fifty-four steroid homologs, belonging to the series of 17-spirolactones, were modelled by molecular and quantum mechanics. We studied the affinity of these compounds for the cytosolic mineralocorticoid receptor by way of various parameters describing each structure and its molecular properties. After the failure of a classic preliminary QSAR study, demonstrating the nonlinear relationships between affinity and structural descriptors, we constructed a model allowing us to predict the affinity of new compounds. Our method is based on simple graphic tools coupled to a cluster significance analysis. A complementary study of the activity relating the prediction of the antagonist/agonist character of 37 high-affinity compounds was also carried out using the same methodology. The principal electronic and structural characteristics leading to a selective activity were revealed.

Aza-indolizine with bridgehead nitrogen. Metalation, halogen-metal exchange and directed ortho-lithiation in the imidazo[1,2-a]pyrazine series

Abstract The n-BuLi and lithium 2,2,6,6-tetramethylpiperidine (LTMP) metalation of imidazo[1,2-a]pyrazine heterocycles and subsequent quenching with electrophiles is described. Bromine atoms exhibit different behaviours towards lithiation depending on their positions (3 or 6) on the imidazo[1,2-a]pyrazine heterocycle. Halogen-metal exchange occurs readily with the bromine on position 3. On the contrary, bromine on position 6 only leads to C-5 substituted derivatives further to an ortho-directing effect.

Metabolism and Pharmacokinetics of EAPB0203 and EAPB0503, Two Imidazoquinoxaline Compounds Previously Shown to Have Antitumoral Activity on Melanoma and T-Lymphomas

For several years, our group has been developing quinoxalinic compounds. Two of them, N-methyl-1-(2-phenethyl)imidazo[1,2-a]quinoxalin-4-amine (EAPB0203) and 1-(3-methoxyphenyl)-N-methylimidazo[1,2-a]quinoxalin-4-amine (EAPB0503), have emerged as the most promising anticancer drugs. In the present work, we determined metabolism pathways using liver microsomes from four mammalian species including human. We identified the cytochrome P450 isoform(s) involved in the metabolism and then investigated the pharmacokinetics and metabolism of EAPB0203 and EAPB0503 in rat after intravenous and intraperitoneal administration. Biotransformation of the compounds involved demethylation and hydroxylation reactions. Rat and dog metabolized the compounds at a higher rate than mouse and human. In all species, CYP1A1/2 and CYP3A isoforms were the predominant enzymes responsible for the metabolism. From human liver microsomes, unbound intrinsic clearances were approximately 56 ml/(min · g) protein. EAPB0203 and EAPB0503 were extensively bound to human plasma proteins, mainly human serum albumin (HSA) (∼98–99.5%). Thus, HSA could act as carrier of these compounds in human plasma. Scatchard plots showed patterns in which the plots yielded upwardly convex hyperbolic curves. On the basis of the Hill coefficients, there appears to be interaction between the binding sites of HSA, suggesting positive cooperativity. The main in vitro metabolites were identified in vivo. Total clearances of EAPB0203 and EAPB0503 [3.2 and 2.2 l/(h · kg), respectively] were notably lower than the typical cardiac plasma output in rat. The large volumes of distribution of these compounds (4.3 l/kg for EAPB0203 and 2.5 l/kg for EAPB0503) were consistent with extensive tissue binding. After intraperitoneal administration, bioavailability was 22.7% for EAPB0203 and 35% for EAPB0503 and a significant hepatic first-pass effect occurred.

Thienopyridinone Antibacterials. Part II.1 Synthesis and Antibacterial Activity of Some 2-Chloro-7-Cyclopropyl-4,7-Dihydro-4-Oxothieno [2,3-b]Pyridine-5-Carboxylic Acids

The synthesis and properties of some new 7-cyclopropyl-4,7-dihydro-4-oxothieno[2,3-b]pyridine-5-carboxylic acids and the 7-tert-butyl analogues, incorporating substituents at positions 2 and 3, are described. The antibacterial activity of these derivatives and of the parent 7-alkyl-2-chloro compounds, unsubstituted at position 3, has been evaluated against an assortment of micro-organisms. 2-Chloro-7-cyclopropyl-4,7-dihydro-4-oxothieno[2,3-b]pyridine-5-carboxylic acid (3a) was found to possess leading in vitro activity among 4-thieno[2,3-b]pridinones known to date. However, none of the 3-nitro- or 3-amino-2-(4-methyl-1-piperazinyl) derivatives (4–6) showed interesting antibacterial activity.

Characterization of Low Affinity Complexes Between Calmodulin and Pyrazine Derivatives by Electrospray Ionization Mass Spectrometry

Electrospray ionization mass spectrometry (ESIMS) was used to study the weak non-covalent interactions occurring between 6-bromo-3-(hydroxymethyl)-8-(methylamino)imidazo [1,2-a]pyrazine (1) and calmodulin. The formation of a 2:1 (ligand: protein) complex was observed. Using 2, a (diazomethyl)carbonyl derivative of 1 which under UV irradiation generates a highly reactive carbene entity, calmodulin was photo-labeled and the mass spectrum of the covalent adduct was recorded. Under these circumstances, two species were detected, one corresponding to the binding of calmodulin to four carbenes derived from 2 and another corresponding to calmodulin five carbenes after their loss of a bromine atom. These results strongly confirm that ESIMS is a powerful technique for the characterization of low-affinity complexes, even if part of the noncovalent interactions could be lost during the ESI process.

Interest of cluster significance analysis in structure-affinity relationships for non-xanthine heterocyclic antagonists of adenosine

Summary In order to define some predictive rules for the discrimination of adenosine antagonists by their A1-receptor affinity, we performed a systematic QSAR analysis. As no significant descriptors of affinity were found, we then proposed to introduce a calculated enthalpy or entropy change for the interaction as a first approximation of the affinity descriptors. Since the structural details of the common receptor binding site remain to be determined, we utilized an indirect strategy involving the simulation of amino acid residues that are thought to interact with the ligand. Estimating enthalpic and entropic components by means of a semi-empirical quantum mechanical AM1 force calculation, we found a significant clustering of enthalpy change values. This method provides a good descriptor of interaction and also a simple tool for testing hypotheses on the nature of putative binding sites.

Lipophilic propanediamines: New building blocks for combinatorial chemistry

Abstract Combinatorial chemists need building block libraries where molecular diversity is taken into account. For this purpose, we describe the synthesis of a library of 2-alkyl and 2-alkoxypropanediamines for which a large scale of lipophilicity is investigated.