Design, synthesis and antiparasitic evaluation of click phospholipids

A library of seventeen novel ether phospholipid analogues, containing 5-membered heterocyclic rings (1,2,3-triazolyl, isoxazolyl, 1,3,4-oxadiazolyl and 1,2,4-oxadiazolyl) in the lipid portion were designed and synthesized aiming to identify optimised miltefosine analogues. The compounds were evaluated for their in vitro antiparasitic activity against Leishmania infantum and Leishmania donovani intracellular amastigotes, against Trypanosoma brucei brucei and against different developmental stages of Trypanosoma cruzi. The nature of the substituents of the heterocyclic ring (tail) and the oligomethylene spacer between the head group and the heterocyclic ring was found to affect the activity and toxicity of these compounds leading to a significantly improved understanding of their structure\u2013activity relationships. The early ADMET profile of the new derivatives did not reveal major liabilities for the potent compounds. The 1,2,3-triazole derivative 27 substituted by a decyl tail, an undecyl spacer and a choline head group exhibited broad spectrum antiparasitic activity. It possessed low micromolar activity against the intracellular amastigotes of two L. infantum strains and T. cruzi Y strain epimastigotes, intracellular amastigotes and trypomastigotes, while its cytotoxicity concentration (CC50) against THP-1 macrophages ranged between 50 and 100 \ub5M. Altogether, our work paves the way for the development of improved ether phospholipid derivatives to control neglected tropical diseases

Melatonin receptor antagonist luzindole: A facile new synthesis

A new, convenient and high yield route to luzindole, the most commonly used melatonin receptor antagonist, is described. The new method involves the Sonogashira coupling reaction between 2-iodoaniline and 3-phenyl-1-propyne followed by cyclisation of the adduct formed, C-3 indole nitroolefination with 1-(dimethylamino)-2-nitroethylene/TFA, reduction to the respective tryptamine and finally acetylation. © 2008 Bentham Science Publishers Ltd

CYTOPLASMIC LOCALISATION OF AUSTRALIA ANTIGEN IN THE LIVER

Australia (Au) antigen was detected by immunofluorescence in liver specimens from 9 patients with chronic liver disease and circulating Au antigen, and from 22 Au-antigen carriers with histologically normal livers. This antigen was not found in the livers of 23 seronegative patients. Au antigen was located in the cytoplasm of hepatocytes. No nuclear fluorescence specific for Au antigen was detected. The number of fluorescent liver cells and the intensity of fluorescence were much greater in Au-antigen carriers than in patients with liver disease. No γ-globulin or β-1C was found in any the liver specimens. These results agree with the view that Au antigen may be a virus-coat material produced in excess in the cytoplasm of liver cells and suggest that its presence in the liver is unrelated to do cytopathic effects of hepatitis virus B. Most apparently healthy Au-antigen carriers may have a balanced intracellular infection which produces large amounts of Au antigen in cytoplasm of the hepatocytes but few or no infectious viruses. © 1972

Design, synthesis, and melatoninergic activity of new azido- and isothiocyanato-substituted indoles

To develop irreversibly binding ligands for the melatonin receptor(s) as tools for tracing the primary melatonin binding site, we report on the design and synthesis of new melatoninergic azido- and isothiocyanato-substituted indoles. All active compounds were partial agonists or antagonists in the Xenopus melanophore assay, the most potent being the 5-OMe C3-substituted azido 45 and isothiocyanato 46 analogues. © 2007 American Chemical Society

Benzocyclobutane, benzocycloheptane and heptene derivatives as melatonin agonists and antagonists

Two series of analogues were designed, synthesised and evaluated as potential human melatonin type 1 and 2 receptor (hMT1 and hMT2) ligands. Their biological effects were assessed by a well-established, specific model of melatonin action, the pigment response of Xenopus laevis melanophores. Compounds containing a benzocyclobutane scaffold and a methoxy group in the "melatonin" orientation were found to be potent agonists, with one of the analogues exhibiting activity comparable to melatonin. In contrast, analogues with a methoxy group in non-melatonin positions or with multiple methoxy groups showed either weaker agonist activity or were antagonists. Benzocycloheptene derivatives with one methoxy group are found to be weak agonists, whereas those with two methoxy groups were found to be antagonists, as were all of the benzocycloheptane derivatives evaluated. The most active compounds were assessed in a human receptor radio ligand binding assay but showed little discrimination between MT1 and MT2. These results again show that the indole nitrogen of melatonin is not a necessary component for analogue activity and also illustrate that replacement of the indole ring with a 4-membered carbocycle can provide highly active compounds when the methoxy group is in the melatonin position. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Controlled release from solid pharmaceutical formulations of two nalkanoyl-4-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-ethanamines with melatoninergic activity

The design, pharmacological properties and delivery characteristics in gastric and intestinal fluids of N-alkanoyl-4-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-ethanamines, (I) and (II), are described. The biological activity of compounds (I) and (II) was determined in a specific model of melatonin action, the pigment aggregation response of Xenopus laevis melanophores. Both analogues were found to be powerful melatonin receptor agonists and showed satisfactory release characteristics, comparable to melatonin, from solid pharmaceutical formulations. © 2015 Bentham Science Publishers

Comparative In Vitro Controlled Release Studies on the Chronobiotic Hormone Melatonin from Cyclodextrins-Containing Matrices and Cyclodextrin: Melatonin Complexes

A series of hydrophilic matrix tablets was prepared and tested with respect to their ability to release the hormone melatonin in a controlled manner, in order to alleviate sleep onset and sleep maintenance dysfunctions. Besides the active ingredient, the tablets were comprised of combinations of the following: HPMC K 15M, low viscosity sodium alginate, microcrystalline cellulose (Avicel PH 102), magnesium stearate, and the cyclodextrins, α-CD, β-CD, γ-CD, HP-β-CD, sulfated β-CD, HP-α-CD and HP-γ-CD, and MLT (guest):CD (host) complexes of the above cyclodextrins, in 1:1 ratio. The controlled release studies were conducted in two aqueous dissolution media at pH 1.2 and 7.4. The stoichiometry of the formed complexes was examined by applying the continuous variation method (Job plot), while the stability constants were calculated by monitoring the spectrophotometric properties of free and CD-encapsulated melatonin (UV-Vis). Host-guest interactions were studied by Nuclear Magnetic Resonance (NMR) spectroscopy. The dissolution data suggest that melatonin is released faster from the MLT:CD complexes than from the rest matrix systems. This enhancement in the dissolution rate and the % release of melatonin from the complexes is due to the increased solubility of the MLT:CD complexes

B2 microglobulin: Is it a reliable marker of activity in inflammatory bowel disease?

OBJECTIVES: The aims of this study were to investigate a possible positive correlation between B2-microglobulin (B2-M) serum levels and the severity and activity of inflammatory bowel disease (IBD); and to examine whether B2-M levels reflect IBD extent. METHODS: We examined B2-M serum levels in 87 ulcerative colitis (UC) patients, 74 with Crohn’s disease (CD) and 68 control subjects, using an enzymatic method. The reliability of the measuring method was assessed by evaluating serum B2-M in 18 patients suffering from chronic renal failure (CRF). The severity and activity of IBD was estimated using the van Hees Activity Index and the True-love-Witts criteria for CD and UC patients respectively. Endoscopic evaluation for UC patients was done according to Baron’s et nl. classification; Riley’s et al. criteria were used for histological evaluation. RESULTS: B2-M serum levels were significantly increased in all CD patients except those in remission. After 6 months treatment a second blood sample taken from CD patients with initially elevated B2-M levels proved to be compatible with CD severity at that time. Such a positive correlation was not assessed in UC patients; therefore, a second blood sample was considered unnecessary. Furthermore, CD patients with pancolitis, ileal-caecal, or small intestinal disease had higher B2-M levels than those with left-sided, anal, or perianal disease. CONCLUSIONS: B2-M serum levels could prove to be a useful marker in assessing not only the activity, severity, and extent of CD but the treatment efficacy as well. (C) 2001 by Am. Cell. of Gastroenterology

Symmetrical derivatives of C2-substituted pyrrolo[2,3-f]quinolines: Synthesis, cytotoxicity and drug delivery studies

The synthesis, pharmacological properties and delivery characteristics in simulated aqueous gastric fluid of a series of symmetrical nitrogenated C2-substituted pyrrolo[2,3-f]quinolines are described. The cytotoxicity of the target molecules (5a-h) was evaluated in the human non-small lung cancer cell line NSCLC-N16-L16 in vitro. One compound (5e) showed sufficient activity (IC50 = 26.4 μ M) and satisfactory release characteristics from solid pharmaceutical formulations. © 2007 Bentham Science Publishers Ltd