François Durant

A reversible monoamine oxidase A inhibitor, befloxatone: structural approach of its mechanism of action.

Experimental and theoretical physico-chemical methods were used to investigate the interaction between several reversible monoamine oxidase A inhibitors in the oxazolidinone series and the active site of the enzyme. Phenyloxazolidinones include toloxatone and analogues, among which befloxatone was selected as drug candidate for the treatment of depression. Identification of the forces responsible for the crystal cohesion of befloxatone reveals functional groups that could interact with monoamine oxidase. Calculation of electronic properties of those compounds using ab initio molecular orbital methods lead to a description of the mode of interaction between befloxatone and the cofactor of the enzyme. Electronic absorption spectroscopy measurements confirm the hypothesis of a privileged interaction of phenyloxazolidinone-type inhibitors with the flavin cofactor of MAO. Additional sites of interaction with the protein core of MAO A are also examined with regard to the primary structure of the enzyme. As a result of this work, a model is proposed for the reversible inhibition of MAO A by befloxatone via long distance, reversible interactions with the flavin adenine dinucleotide (FAD) cofactor of the enzyme and with specific amino acids of the active site. This model is partially corroborated by experimental evidence and should be helpful in designing new potent inhibitors of monoamine oxidase.

A database study of intermolecular NH⋯O hydrogen bonds for carboxylates, sulfonates and monohydrogen phosphonates

A search of the Cambridge Structural Database (CSD, version 5.05, 1993) was performed in order to compare the geometrical features of the hydrogen bonds involving on the one hand amino groups and on the other hand carboxylates, sulfonates or monohydrogen phosponates. Phosphonates were not considered because only four entries containing amino and phosphonate moieities were located in the CSD. The hydroxylic group of monohydrogen phosphonates primarily acts as a hydrogenbond donor. The three moieties under study show NH...O hydrogen bonds with similar geometrical features. This statistical analysis has focused on the hydrogen-bond distances and angles and on the distributions of the H atoms around the acceptor O atoms of carboxylates, sulfonates or monohydrogen phosphonates.

Influence ofcis andtrans double bonds on the thermal and structural properties of monoacid triglycerides

In order to determine the importance ofcis ortrans unsaturations from a technological point of view, the study of the structural and thermal properties of monoacid triglycerides: tristearin (SSS), triolein (OOO) and trielaidin (EEE) has been undertaken. X-ray powder diffraction and differential scanning calorimetry are useful tools to elucidate the physicochemical properties of such compounds. In this work polymorphism, kinetics of polymorphism and intersolubility have been investigated. From a structural point of view, we have shown that, according to the polymorphic form, the conformational properties of EEE are similar to those of the corresponding saturated molecule SSS or to those of thecis unsaturated analogue OOO. The study of the intersolubility behavior of these three compounds has shown a different affinity of thecis andtrans unsaturated molecules vs the completely saturated one. By the same method, we have observed thattrans unsaturated hydrocarbon chains cocrystallize with bothcis-unsaturated (OOO) and totally saturated hydrocarbon chains (SSS); thetrans double bond of EEE can adapt to the two kinds of lattices. The study of the kinetics of polymorphism has shown that 5% of OOO or EEE accelerate the β′→β transition of SSS, while the reason for the two phenomena is quite different. The adaptation of EEE tocis-unsaturated and to saturated hydrocarbon chains shown in the structural and intersolubility behavior analyses also appears in the kinetic study, after adjunction of 5% of OOO into EEE. All the results confirm that, from structural and thermal points of view, EEE has an intermediate behavior between SSS and OOO.

Polymorphism of stabilized and nonstabilized tristearin, pure and in the presence of food emulsifiers

The polymorphism of tristearin (SSS) was studied by means of differential scanning calorimetry and powder X-ray diffraction. The influence of 5% in weight of different food emulsifiers—i.e., 1-monostearin, sorbitan tristearate, and sugar monostearate—was also studied. Because polymorphism is sensitive to thermal treatment, two thermal conditionings were applied. According to the dynamic process (melting, quenching, and heating at 5°C/min), SSS showed three polymorphic forms: α, β′, and β1. The presence of the emulsifiers hindered the β′→β transformation, and a destructured β2 form was recorded. According to the stabilization process (stabilization at 57°C for various periods of time), SSS showed two β′ forms: β2′ and β1′. Three hours of stabilization were necessary to recover the whole triglyceride under the β form. The emulsifiers slowed down the polymorphic transition rates. Indeed, after six hours of stabilization, mixtures of β′ and β were observed. Sugar monostearate seemed to have the most powerful effect on the transition kinetics because large amounts of α form were detected.

STRUCTURAL REQUIREMENTS OF NON-PEPTIDE NEUROTENSIN RECEPTOR ANTAGONISTS

Neurotensin has a wide range of pharmacological effects in peripheral tissues and in the central nervous system. The crystal structures of two potent and selective neurotensin receptor antagonists, SR 48692 (I) and SR 48527 (II) have been determined and are reported in this work. By using computational calculations (semiempirical molecular orbital AM1) we studied the conformational properties of those compounds, including an inactive analogue SR 49711 (III) for comparison. Considering the pharmacological properties related to SR 48692 (I) and to optically synthetic analogues SR 48527 (II) and SR 49711 (III), we propose a model of bioactive conformation adopted by those neurotensin receptor antagonists.

Design, synthesis and biological evaluation of a sulfonylcyanoguanidine as thromboxane A2 receptor antagonist and thromboxane synthase inhibitor.

The synthesis and the structure of N‐isopropyl‐N′‐[2‐(3′‐methylphenylamino)‐5‐nitrobenzenesulfonyl] urea (14) was drawn from two thromboxane A2 receptor antagonists structurally related to torasemide. Compound 14 showed an IC50 value of 22 nm for the thromboxane A2 (TXA2) receptor of human washed platelets. Compound 14 prevented platelet aggregation induced by arachidonic acid (0.6 mm) and U‐46619 (1 μm) with an IC50 value of 0.45 and 0.15 μm, respectively. Moreover, 14 relaxed the rat isolated aorta and guinea‐pig trachea precontracted by U‐46619, a TXA2 agonist. Its efficacy (IC50) was 20.4 and 5.47 nm, respectively. Finally, 14 (1 μm) completely inhibited TXA2 synthase of human platelets. The pKa value and the crystallographic data of 14 were determined and used to propose an interaction model between the TXA2 antagonists related to torasemide and their receptor.

QSAR of nortropane-substituted benzamides: use of lipophilic (RP-HPLC) and electronic (1H NMR) parameters

Abstract The pharmacological and biochemical activities of 4-benzamido-nortropanes, a subgroup of neuroleptic drugs, are correlated with experimental and calculated parameters describing structural properties, such as lipophilicity or electronic distribution. The lipophilicity was experimentally measured using the HPLC method and theoretically calculated using hydrophobic Π values. 1H NMR chemical shifts were used to describe the electronic structure. In a series of fifteen tropapride analogues with various substituents at position 5 on the benzamide moiety, a parabolic relationship was obtained between hydrophobic values and anti-dopaminergic activities, indicating that lipophilicity is certainly the major property influencing their affinity for the D2 receptor. The linear correlation between affinities and the amidic hydrogen chemical shifts in a series of eight 3-substituted derivatives shows that the stability of the intrabenzamidic hydrogen bond may play a preponderant role in some cases. The electronic properties of some substituted orthopramides are quantified by ab initio theoretical calculations in order to explain the indirect effect of the substituent at position 3.

Rhenium(V) and technetium(V) complexes with N-[2(1H-pyrolylmethyl)]-N'-(4-pentene-3-one-2)ethane 1,2-diaminate (C12H16N3O, MRP 20). X-ray crystal structures of H3MRP 20 and TcO(MRP 20)

Synthesis of N-[2(1H-pyrolylmethyl)]-N′-(4-pentene-3-one-2)ethane-1, 2-diamine has been effected and the compound characterised by X-ray diffraction. Crystal data for C12H19N3O: space group P21/c: a=10.358(3), b=7.953(1), c=15.640(4) A, β=101.63(1)°, V=1261(2) A3 to give Z=4 for D=1.165 g cm−3. Structure solution and refinement based on 2114 reflections converged at R=0.064, Rw=0.079. Reaction of this molecule with Bu4N[TcO(ethylene glycolate)2] results in the formation of a neutral technetium(V) complex [TcOL]. The X-ray structure of this complex confirms a five-coordinate, square based pyramidal geometry with no crystallographic axes of symmetry. Crystal data: orthorhombic space group P212121; a=11.701(1), b=14.949(2), c=7.516(1) A, V=1314.6 A3 to give Z=4 for D=1.68 g cm−3. Structure resolution and refinement based on 2115 reflections converged at R=0.037, Rw=0.033. Reaction of N-[2(1H-pyrolylmethyl)]-N′-(4-pentene-3-one-2)ethane-1,2-diamine with rhenium(V) oxotrichlorobistriphenylphosphine [ReOCl3(PPh3)2] or a rhenium(V) glycolato precursor yields the [ReOL] complex. The compounds have been studied by NMR, UVVis, IR spectroscopy as well as by mass spectrometry. The obtained results have been discussed in terms of the complex formation and the different transition metals.

Rational approaches towards reversible inhibition of type B monoamine oxidase. Design and evaluation of a novel 5H-Indeno[1,2-c]pyridazin-5-one derivative

The stereoelectronic properties of several potent reversible monoamine oxidase B (MAO-B) inhibitors were studied with a view to develop a pharmacophore model for reversible MAO-B inhibition. This study suggested that important specific H-bond and hydrophobic interactions are required for potent and selective MAO-B inhibition. These requirements were applied in the design and synthesis of a novel reversible and selective MAO-B inhibitor, 3-methyl-8-(4,4,4-trifluoro-butoxy)indeno[1,2-c]pyridazin-5-one, that is ca. 7000 times more selective as an inhibitor for MAO-B than for MAO-A, with K(i(MAO-B)) in the low nanomolar range.

Isosterism among analogues of torasemide: conformational, electronic and lipophilicity properties

The structures, electronic (charges, molecular electrostatic potential, molecular orbitals) and lipophilic properties of three isostere analogues of torasemide were determined and the influence of the replacement of the sulfonyl urea group on the conformation and electronic properties of the molecules is discussed. Lipophilicity of the compounds seems to be the most discriminating property along the series and affects their pharmacological activities.