Cécile Enguehard-Gueiffier

Recent Progress in the Pharmacology of Imidazo[1,2-a]pyridines

Imidazo[1,2-a]pyridine is a bicyclic system with a bridgehead nitrogen atom, of growing interest in medicinal chemistry. The paper deals with the recent progress realised in the comprehension of the pharmacological properties of this scaffold. From the many imidazo[1,2-a]pyridine analogues described in the literature, those discussed herein will be presented in three parts concerning first the enzyme inhibitors, then the receptor ligands and finally the anti-infectious agents.

Influence of 6-or 8-substitution on the antiviral activity of 3-arylalkylthiomethylimidazo[1.2-a]pyridine against human cytomegalovirus (CMV) and varicella-zoster virus (VZV) : Part II

The synthesis of original imidazo[1,2-a]pyridines bearing a thioether side chain at the 3 position and diversely substituted on the 6 or 8 position, and their antiviral activities are reported. From the synthesized compounds, the imidazo[1,2-a]pyridines bearing a 5 membered heterocycle (thiophene, furane or pyrrole) in the 6 position or a phenylthio group in the 6 or 8 position were the most potent against human cytomegalovirus (CMV) and varicella-zoster virus (VZV), whereas several other congeners, while less potent, were more selective in their inhibitory activity against VZV and CMV. These compounds showed similar activity against thymidine kinase competent (TK+) and deficient (TK-) VZV strains, demonstrating a mechanism of action independent of the viral thymidine kinase.

PIP3EA and PD-168077, two selective dopamine D4 receptor agonists, induce penile erection in male rats: site and mechanism of action in the brain

PIP3EA (2‐[4‐(2‐methoxyphenyl)piperazin‐1‐yl‐methyl]imidazo[1,2‐a]pyridine) and PD‐168077 (N‐[4‐2‐cyanophenylpiperazin‐1‐ylmethyl]‐3‐methylbenzamide maleate), two selective dopamine D4 agonists, administered systemically, intracerebroventricularly or into the paraventricular nucleus of the hypothalamus induce penile erection in male Sprague–Dawley rats. A U‐inverted dose–response curve was found with either compound when given subcutaneously (1–100 µg/kg) or intracerebroventricularly (0.1–20 µg/rat), but not into the paraventricular nucleus (10–200 ng/rat). The pro‐erectile effect of PIP3EA and of PD‐168077 occurs concomitantly with an increased nitric oxide (NO) production in the paraventricular nucleus, as measured by the increased concentration of nitrites and nitrates found in the dialysate obtained from the paraventricular nucleus by intracerebral microdialysis. These effects of PIP3EA and PD‐168077 were reduced by L‐745,870 (3‐[4‐(4‐chlorophenyl)piperazin‐1‐ylmethyl]‐1H‐pyrrolo[2,3‐b]pyridine trihydrochloride), a selective dopamine D4 receptors antagonist, by ω‐conotoxin, a blocker of voltage‐dependent Ca2+ channels of the N‐type, by S‐methyl‐thiocitrulline, a neuronal nitric oxide synthase inhibitor, and by d(CH2)5Tyr(Me)2‐Orn8‐vasotocin, an oxytocin receptor antagonist, given into the lateral ventricles, but not into the paraventricular nucleus. Comparison of the dose–response curves of PIP3EA and PD‐168077 revealed that PIP3EA is as potent as PD‐168077 when given into the paraventricular nucleus, but more potent when given systemically. However, both compounds are less efficacious (e.g. induce a lower number of penile erection episodes) than apomorphine, a classical mixed dopamine receptor agonist, irrespective of the route of administration. These results confirm previous findings showing that central D4 receptors mediate penile erection and show that dopamine D4 receptor agonists act in the paraventricular nucleus to facilitate penile erection by increasing central oxytocinergic neurotransmission.

Proerectile effects of dopamine D2-like agonists are mediated by the D3 receptor in rats and mice.

Dopamine D2-like agonists induce penile erection (PE) and yawning in a variety of species, effects that have been suggested recently to be specifically mediated by the D4 and D3 receptors, respectively. The current studies were aimed at characterizing a series of D2, D3, and D4 agonists with respect to their capacity to induce PE and yawning in the rat and the proerectile effects of apomorphine [(R)-(-)-5,6,6a,7-tetrahydro-6-methyl-4H-dibenzo-[de,g]quinoline-10,11-diol hydrochloride] in wild-type and D4 receptor (R) knockout (KO) mice. All D3 agonists induced dose-dependent increases in PE and yawning over a similar range of doses, whereas significant increases in PE or yawning were not observed with any of the D4 agonists. Likewise, D2, D3, and D4 antagonists were assessed for their capacity to alter apomorphine- and pramipexole (N′-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine dihydrochloride)-induced PE and yawning. The D3 antagonist, PG01037 [N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide hydrochloride], inhibited the induction of PE and yawning, whereas the D2 antagonist, L-741,626 [3-[4-(4-chlorophenyl)-4-hydroxypiperidin-l-yl]methyl-1H-indole], reversed the inhibition of PE and yawning observed at higher doses. The D4 antagonist, L-745,870 [3-(4-[4-chlorophenyl]piperazin-1-yl)-methyl-1H-pyrrolo[2,3-b]pyridine trihydrochloride], did not alter apomorphine- or pramipexole-induced PE or yawning. A role for the D3 receptor was further supported because apomorphine was equipotent at inducing PE in wild-type and D4RKO mice, effects that were inhibited by the D3 antagonist, PG01037, in both wild-type and D4R KO mice. Together, these studies provide strong support that D2-like agonist-induced PE and yawning are differentially mediated by the D3 (induction) and D2 (inhibition) receptors. These studies fail to support a role for the D4 receptor in the regulation of PE or yawning by D2-like agonists.

Antifungal Activity of Resveratrol Derivatives against Candida Species

trans-Resveratrol (1a) is a phytoalexin produced by plants in response to infections by pathogens. Its potential activity against clinically relevant opportunistic fungal pathogens has previously been poorly investigated. Evaluated herein are the candidacidal activities of oligomers (2a, 3-5) of 1a purified from Vitis vinifera grape canes and several analogues (1b-1j) of 1a obtained through semisynthesis using methylation and acetylation. Moreover, trans-ε-viniferin (2a), a dimer of 1a, was also subjected to methylation (2b) and acetylation (2c) under nonselective conditions. Neither the natural oligomers of 1a (2a, 3-5) nor the derivatives of 2a were active against Candida albicans SC5314. However, the dimethoxy resveratrol derivatives 1d and 1e exhibited antifungal activity against C. albicans with minimum inhibitory concentration (MIC) values of 29-37 μg/mL and against 11 other Candida species. Compound 1e inhibited the yeast-to-hyphae morphogenetic transition of C. albicans at 14 μg/mL.

Physicochemical properties and membrane interactions of anti-apoptotic derivatives 2-(4-fluorophenyl)-3-(pyridin-4-yl)imidazo[1,2-a]pyridine depending on the hydroxyalkylamino side chain length and conformation: an NMR and ESR study.

Three imidazo[1,2-a]pyridine derivatives 3a-c have been synthesized from p38 kinase inhibitor structures and evaluated as anti-apoptosis agents. These drugs were designed to interact with nucleic acids and membrane interactions by varying the chain length in position 6, from hydroxyethylamino (3a), to hydroxybutylamino (3b) and hydroxyhexylamino (3c). First experiments showed that 3a and 3b were insoluble in water while 3c could be solubilized in water despite its partition coefficient (logP=3.2). This latter feature was explained by the formation of a fifth intramolecular cycle thus allowing supramolecular structure formation (NMR and MD calculations). The interactions with membranes have been studied using (1)H, (2)H, (31)P Nuclear Magnetic Resonance (NMR), Electron Spin Resonance (ESR) and High Resolution-Magic Angle Spinning (HR-MAS). Despite the insolubility of 3a and 3b in water, these derivatives could be partially solubilized by synthetic phospholipidic model membranes (small unilamellar vesicles, SUV). (1)H NMR paramagnetic broadening experiments performed on the same models showed that 3a was located in the external layer, probably close to the surface while 3b only formed external superficial adducts. Supplementary (31)P, (2)H NMR and ESR experiments on phospholipid dispersions confirmed the location of 3a close to the polar headgroup of the external layer of the membrane, this resulting in a 2K lowering of the transition temperature. Moreover, no significant interaction was detected on the deep part of the layer ((2)H NMR and 16NS ESR experiments). This binding was also found in the presence of cell cultures, as revealed by HR-MAS NMR experiments. Conversely, no significant interaction with membranes was found with 3b or 3c. From both the unexpected solubility of 3c and 3a interactions with membranes, further chemical modifications were finally proposed.

High performance thin layer chromatography–densitometry: A step further for quality control of cranberry extracts

A method for selective quantitation of catechin, proanthocyanidin (PAC) A2 and PAC-B1 in American cranberry (Vaccinium macrocarpon) extracts using high performance thin layer chromatography (HPTLC)-densitometry is presented. Methylene chloride/ethyl acetate/formic acid (6:10:1, v/v) as the mobile phase and 1% vanillin hydrochloric solution as staining reagent were used. In these conditions, three standards considered as quality markers, catechin, PAC-A2 and PAC-B1, were well resolved allowing simultaneous quantitation on one plate. All standards were quantified in the range of 0.7-5 μg with RSD of repeatability and intermediate precision not exceeding 5%. Catechin, PAC-A2 and PAC-B1 profiles of cranberry extracts were analysed regarding global PAC amounts obtained by BL-DMAC assay. It appears clearly that HPTLC-densitometry process provides additional information which, combined with BL-DMAC results, allows qualitative and quantitative control of cranberry extracts. Particularly, densitometric assay highlighted degradation of PACs in a 7 day-extract, leading to high overestimation with BL-DMAC protocol.

Regiocontrolled Microwave Assisted Bifunctionalization of 7,8-Dihalogenated Imidazo(1,2-a)pyridines: A One Pot Double-Coupling Approach

The reactivity of the 7-chloro-8-iodo- and 8-chloro-7-iodoimidazo[1,2-a]pyridines 1a–e diversely substituted on the 2 position, towards Suzuki-Miyaura, Sonogashira, and Buchwald-Hartwig cross-coupling reactions as well as cyanation was evaluated. Various methodologies are proposed to introduce aryl, heteroaryl, alkyne, amine or cyano groups in the two positions depending on the nature of the substituent present in position 2. In both series, the substitution of the iodine atom was totally regioselective and the difficulty was to substitute the chlorine atom in a second step. Until now, only hetero(aryl) groups could be introduced though Suzuki-Miyaura cross-coupling. We overcame this problem evaluating both regioisomers in parallel. The double coupling approach was also studied allowing the one pot Suzuki/Suzuki, cyanation/Sonogashira and cyanation/Buchwald reactions leading to polyfunctionnalized imidazo[1,2-a]pyridines.

Antibacterial Polyketide Heterodimers from Pyrenacantha kaurabassana Tubers

Two heterodimers comprising anthraquinone and methylbenzoisocoumarin moieties (1 and 2) were isolated, together with emodin and physcion from the tubers of Pyrenacantha kaurabassana. The structures of 1 and 2 were established by NMR spectroscopy, including the analysis of a 2D INADEQUATE spectrum. On the basis of the data obtained, the structures that were previously proposed in the literature for these compounds were revised. Compounds 1 and 2 showed antibacterial activity against three different strains of Staphylococcus aureus. Compound 2 also showed bactericidal activity against Helicobacter pylori.

New flavonoids C-glycosides from Rhabdophyllum arnoldianum

Two new flavone glycosides, 3″-O-acetyl-7-O-methylvitexin (1) and 6″-α-rhamnopyranosyl-7-O-methylvitexin (2), along with nine known compounds (3–11) were isolated from the leaves of Rhabdophyllum arnoldianum (Ochnaceae). The structures of the new compounds were established by detailed spectroscopic studies and mass spectrometry, while known compounds were characterised by direct comparison of their reported NMR data with those found in the literature. All these compounds were the first reported from Rhabdophyllum genus. The biological assays on crude extracts and compounds of this plant demonstrated that the crude extracts possess significant antimicrobial activity against Gram-positive bacteria.