Synthesis and Evaluation of a Series of 2′-Deoxy Analogues of The Antiviral Agent 5,6-Dichloro-2-Isopropylamino-1-(β-L-Ribofuranosyl)-1H-Benzimidazole (1263W94)

Abstract

A series of 2′-deoxy analogues of the antiviral agent 5,6-dichloro-2-isopropylamino-1-(β-L-ribofuranosyl)-1H-benzimidazole (1263W94) were synthesized and evaluated for activity against human cytomegalovirus (HCMV) and for cytotoxicity. The 2-substituents in the benzimidazole moiety correspond to those that were used in the 1263W94 series. In general, as was found in the 1263W94 series, cyclic and branched alkylamino groups were needed for potent activity against HCMV. Three analogues 3a, 3b and 3d were as potent as 1263W94. Further evaluation of two analogues, 3a and 3b, suggested that these 2′-deoxy analogues may act via a novel mechanism of action similar to that of 1263W94. These 2′-deoxy analogues generally lacked cytotoxicity in vitro. Pharmacokinetic parameters in mice and protein binding properties of 3a were quite similar to 1263W94. However, the oral bioavailability of 3a was only half of that observed for 1263W94.     

Exposure to sublethal doses of fipronil and thiacloprid highly increases mortality of honeybees previously infected by Nosema ceranae

BACKGROUND: The honeybee, Apis mellifera, is undergoing a worldwide decline whose origin is still in debate. Studies performed for twenty years suggest that this decline may involve both infectious diseases and exposure to pesticides. Joint action of pathogens and chemicals are known to threaten several organisms but the combined effects of these stressors were poorly investigated in honeybees. Our study was designed to explore the effect of Nosema ceranae infection on honeybee sensitivity to sublethal doses of the insecticides fipronil and thiacloprid. METHODOLOGY/FINDING: Five days after their emergence, honeybees were divided in 6 experimental groups: (i) uninfected controls, (ii) infected with N. ceranae, (iii) uninfected and exposed to fipronil, (iv) uninfected and exposed to thiacloprid, (v) infected with N. ceranae and exposed 10 days post-infection (p.i.) to fipronil, and (vi) infected with N. ceranae and exposed 10 days p.i. to thiacloprid. Honeybee mortality and insecticide consumption were analyzed daily and the intestinal spore content was evaluated 20 days after infection. A significant increase in honeybee mortality was observed when N. ceranae-infected honeybees were exposed to sublethal doses of insecticides. Surprisingly, exposures to fipronil and thiacloprid had opposite effects on microsporidian spore production. Analysis of the honeybee detoxification system 10 days p.i. showed that N. ceranae infection induced an increase in glutathione-S-transferase activity in midgut and fat body but not in 7-ethoxycoumarin-O-deethylase activity. CONCLUSIONS/SIGNIFICANCE: After exposure to sublethal doses of fipronil or thiacloprid a higher mortality was observed in N. ceranae-infected honeybees than in uninfected ones. The synergistic effect of N. ceranae and insecticide on honeybee mortality, however, did not appear strongly linked to a decrease of the insect detoxification system. These data support the hypothesis that the combination of the increasing prevalence of N. ceranae with high pesticide content in beehives may contribute to colony depopulation.     

Diet-induced obesity in rats leads to a decrease in sperm motility

Background  

Obesity is rapidly becoming a worldwide epidemic that affects children and adults. Some studies have shown a relationship between obesity and infertility, but until now it remains controversial. Thus, the aim of the present study was to investigate the effect of high-fat diet-induced obesity on male reproductive parameters.     

Neurological and physiological disorders in Artemia harboring manipulative cestodes

There are many impressive examples of host manipulation by parasites, but mechanisms underlying these ethological changes, as well as their physiological consequences, are not well characterized. Here, we analyzed part of the cerebral proteome of brine shrimp Artemia infected by manipulative cestodes, using for the first time the ProteinChip Surface-Enhanced Laser Desorption Ionization and Time of Fly Mass Spectrometry (SELDI-TOF MS) system, which has been proposed as an excellent way to analyze the host genome during the host-parasite interaction processes. We found 2 peptides downregulated in individuals infected by the dilepidid, Anomotaenia tringae (4.5 kDa), and by the 2 hymenolepidids, Flamingolepis liguloides and Confluaria podicipina (3.9 kDa), which are potential candidates for involvement with the manipulation process. The identification of 2 head peptides (4.1 and 4.2 kDa) overexpressed in all the categories in brine shrimp living at the surface (both infected individuals and uninfected controls) suggests its association with the different environmental conditions experienced at the water surface. In parallel, brine shrimp infected by C. podicipina showed significant values of triglycerides, potentially augmenting their profitability and attractiveness for the predaceous definitive host (grebes). We discuss our findings in relationship with current ideas on the complexity of parasitically modified organisms.     

High-dosage isosorbide dinitrate therapy for angina.

We investigated the possibility that high dosages (480 mg/d) of isosorbide dinitrate might reduce the frequency of angina attacks in selected patients who had not responded to low dosages of the drug (40 mg/d), and that the patients could tolerate the high levels of medication and maintain their responsiveness over the long term. In the single-blind phases of this trial 24 patients with grade 3 stable angina pectoris were given a placebo for 4 weeks and then increasing doses of isosorbide dinitrate for a further 6 weeks. The 19 patients who both responded to and tolerated high doses of the drug kept taking 480 mg/d for an average of 1 year. The average weekly rate of angina attacks fell by 74%, from 6.05 in the placebo phase to 1.6 during long-term active treatment (p less than 0.01). Nitroglycerin consumption decreased accordingly. The patients'' assessments of their levels of activity and well-being and their angina thresholds showed improvement among most of them. The trend of angina frequency was stable in 12 cases, downward in 6 and upward in only 1 case. Exercise performance as evaluated by a graded treadmill test showed a small but nonsignificant improvement of 18%. It was concluded that some patients who do not respond to the antianginal action of low-dosage isosorbide dinitrate and cannot be given beta-blockers may respond to high dosages and tolerate them for over a year. Isosorbide dinitrate may be clinically useful in patients with coronary heart disease even though their exercise performance is not significantly improved.     

Beneficial effect of fluorocarbon emulsion media on the function of neuromuscular preparations in vitro

The effects of liquid fluorocarbons as bathing media were determined by use of in vitro neuromuscular preparations. Rat hemidiaphragms were bathed in either oxygenated fluorocarbon (FC) emulsion or standard oxygenated Krebs solution. Contractile force in response to simple supramaximal nerve stimuli as well as to high frequency stimulation was greater, while twitch:tetanus ratio was smaller in FC emulsion. With such medium, post-tetanic potentiation of contraction was also more consistently observed. Indirectly stimulated diaphragms survived longer in FC emulsion. After cessation of oxygenation, oxygen tension (ρO(2)) of the medium declined more rapidly with Krebs than with FC emulsion; ρO(2) directly correlated with force of contraction. Similarly, in the chick biventer cervicis preparation, FC emulsion enhanced nerve-stimulated force of contraction; returning the preparation to standard Krebs solution reversed this phenomenon. Dose-resonse curves of muscle contraction in response to acetycholine and KCl administration were shifted upward during FC emulsion superfusion. Frequency of miniature endplate potentials was lower in FC emulsion than that observed in Krebs solution, measured from the same cell of the rat diaphragm. Resting membrane potentials were also greater in muscle cells sampled from FC emulsion-bathed preparations. These data suggest that FC emulsion is superior to standard Krebs solution as a bathing medium for in vitro neuromuscular preparations by virtue of the high solubility of oxygen in it.