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Unlike amantadine (1-adamantanamine), tromantadine (N-1-adamantyl-N-[2-(dimethyl amino)ethoxy]acetamide hydrochloride) inhibits herpes simplex virus type 1 (KOS strain)-induced cytopathic effect and virus replication with limited toxicity to the cells. Vero and HEp-2 cells tolerated up to 2 mg of tromantadine per 2 x 106 cells for 24-, 48-, or 96-h incubation periods with little change in cell morphology. Treatment of the cells with 10 to 50 p.g of tromantadine reduced herpes simplex virus-induced cytopathic effect. Treatment with 100 to 500 pg of tromantadine inhibited herpes simplex virus-induced cytopathic effect and reduced virus production. Complete inhibition of virus production was observed with treatments of 500 jig to 1 mg. The antiherpetic activity of tromantadine was dependent upon the viral inoculum size and the time of addition of the compound with respect to infection. Virion synthesis and viral polypeptide synthesis were inhibited by addition of tromantadine at the time of infection or 4 h postinfection. The results are consistent with tromantadine inhibition of an early event in herpes simplex virus infection, before macromolecular synthesis, and a late event, such as assembly or release of virus.Tromantadine (N-1-adamantyl-N-[2-(dimethylamino)ethoxy]acetamide hydrochloride) (10,11,16,20) is one of relatively few amantadine (1-adamantanamine) derivatives which have antiherpetic activity. Amantadine has been shown to inhibit an early event before viral macromolecular synthesis in influenza A virus replication and is an alternative to vaccination against influenza A virus (15). Tromantadine has been reported to inhibit herpes simplex virus type 1 (HSV-1) and HSV-2 replication and to be effective as a topical antiherpetic drug (1,4,7,9,12,16,20,25). In this paper, we report an improved synthetic scheme for the compound and describe its activity against HSV-1 infection. An indication of the HSV replication step(s) inhibited by tromantadine is discussed. Tromantadine was prepared by addition of N,N-dimethylethanolamine to N-(1-adamantyl)-2-chloroacetamide. First, the lithium alkoxide of N,N-dimethylethanolamine was prepared by the addition of 4.3 ml (0.009 mol) of 2.1 M n-butylithium in hexane to a cold solution of the amino alcohol (0.78 g, 0.0088 mol) in 10 ml of dry THF. A solution of N-(1-adamantyl)-2-chloroacetamide (2.0 g, 0.0088 mol) in 15 ml of dry THF was then added slowly, and the mixture was stirred overnight. The solution was next poured into 50 ml of 10% HCI, and the resulting solution was washed with ether. Addition of NaOH solution liberated the tromantadine, which was extracted into two 100-ml portions of ether. The combined ether extracts were dried over anhydrous Na2SO4, and the ether was evaporated to yield a viscous oil. The oil was dissolved in benzene, and tromantadine was precipitated by 1031 on April 1, 2019 by guest http://aac.asm.org/ Downloaded from

We utilized gas phase hydrogen/deuterium (H/D) exchange reactions and ab initio calculations to investigate the complexation between a model peptide (Arg-Gly-Asp[triple bond]RGD) with various alkali metal ions. The peptide conformation is drastically altered upon alkali metal ion complexation. The associated conformational changes depend on both the number and type of complexing alkali metal ions. Sodium has a smaller ionic diameter and prefers a multidentate interaction that involves all three amino acids of the peptide. Conversely, potassium and cesium form different types of complexes with the RGD. The [RGD + 2Cs - H]+ species exhibit the slowest H/D exchange reactivity (reaction rate constant of approximately 6 x 10(-13) cm3molecule(-1)s(-1) for the fastest exchanging labile hydrogen with ND3). The reaction rate constant of the protonated RGD is two orders of magnitude faster than that of the [RGD + 2Cs - H]+. Addition of the first cesium to the RGD reduces the H/D exchange reaction rate constant (i.e., D0) by a factor of seven whereas sodium reduces this value by a factor of thirty. Conversely, addition of the second alkali metal ions has the opposite effect; the rate of D0 disappearance for all [RGD + 2Met - H]+ species (Met[triple bond]Na, K, and Cs) decreases with the alkali metal ion size.

Reactions involving methyl b-cellobioside and several oxygen species were used to investigate cleavage of glycosidic linkages in cellulose by reaction with photochemical hydroxyl radicals. The intent is not to reproduce delignification conditions, but rather to study the specific behavior of carbohydrate models toward hydroxyl radical. Experiments show that hydroxyl radicals are responsible for the degradation of glycosidic linkages in methyl b-cellobioside by substitution reactions displacing cellobiose, D-glucose, methyl b-D-glucoside, and methanol. Once the glycosidic linkages are broken, the reducing carbohydrates undergo a series of reactions forming 67