RMI 15,731 (1-[5-tetradecyloxy-2-furanyl]-ethanone), a new antirhinovirus compound

Abstract

RMI 15,731 (1-[5-tetradecyloxy-2-furanyl]-ethanone) is a new antiviral compound with activity specific for rhinoviruses. Virus synthesis in R-HeLa cells was susceptible to low concentrations (0.25 /g/ml) of the compound. RMI 15 by the plaque method on R-HeLa cell sheets (80% confluent) contained in 35-mm petri dishes. Each assay was performed in duplicate. A 0.1-mi amount of virus was adsorbed to the cul layer for 90 min at 35°C; 4 ml of overlay medium (0.5% Methocel in BME) containing added magnesium (2) was used on each dish after the adsorption period. Infected cells were incubated for 48 h at 35°C before fixation with Formalin and crystal violet staining.Measurement of cytotoxicity. The toxic effect of RMI 15,731 was assessed by two methods: (i) measurement of cellular protein concentration by the Lowry method as modified by Oyama and Eagle (3) (cell sheets were solubilized in 0.4 N NaOH after washing with saline [3]); and (ii) measurement of total cell number per culture after trypsinization. In all cases duplicate cultures were examined in each experiment at each concentration of compound.Measurement of RMI 15,731 binding to cells. Cell cultures in 35-mm petri dishes were exposed to different concentrations of carbonyl-'4C-labeled RMI 15,731 in 1 ml of BME at 35°C. At various times the medium was removed from duplicate cultures, and the cell sheets were washed three times with phosphatebuffered saline, pH 7.2. The cells in each culture were dissolved in 1 ml of hyamine hydroxide (Sigma Chemical Co., St. Louis, Mo.) and counted by liquid scintillation spectrometry in a toluene-based fluid (4.2 g of 2,5-diphenyloxazole and 52 mg of phenyloxazolylphenyloxazolyl-phenyl per liter).Chemicals. RMI 15,731 is a water-insoluble powder. This compound homogenized into aqueous media was an effective antirhinovirus compound. We found,

Lack of quantitative correlation between inhibition of replication of rhinoviruses by an antiviral drug and their stabilization

“…Reference compounds chalcone [10], dichloroflavan [4], MDL 20,610 [13], MDL 860 [26], and RM115,731 [3], were kindly supplied by Nippon Roche, Wellcome Research and Merrell Dow respectively. Other reference compounds such as enviroxime [7], disoxaril or WIN 51711 [21], and the Sandoz antirhinovirus compound (ethyl-2-[4-[(2,5-dimethylphenyl)methyl]-l-piperazinyl]-4-thiazolecarboxylate monohydrochloride, European Patent Publication number 187618) were synthesized in our own laboratories.…”

“…All compounds except RMI 15,731 were dissolved in dimethyl sulphoxide (10 mg/ml) and then diluted in growth medium to achieve the final concentration needed. RMI 15,731 was initially dissolved in ethanol as described by Ash [3].…”

Antirhinovirus activity of purine nucleoside analogs

“…The search for effective antirhinovirus agents has yielded a wealth of compounds belonging to widely varying chemical classes: thiosemicarbazones (20), isoquinolines (35,43), triazinoindoles (27), guanidines (5), benzoates (30), furanyls (2), benzimidazoles (12), thiourea (18), diketones (14,16,17), flavans (3,32), flavones (25), chalcones (24), nitrobenzenes (34,41), and isoxazoles (15,31). The most recently developed antirhinovirus compounds (3,15,24,31) reach their MICs within the range of 0.001 to 0.01 ,ug/ml.…”

Picornavirus inhibitors

“…731 RMI 15,731 (1-[5-tetradecyloxy-2-furanyl]-ethanone) ( Fig. 12) directly inactivates rhinovirus particles (Ash et al, 1979). The mode of action of this agent has still not been investigated in detail.…”

“…The mode of action of this agent has still not been investigated in detail. It is possible that the compound blocks uncoating (Ninomiya et al, 1985), but it may have other effects because it was active if cells were pretreated and then washed, or if the agent was added 6 hr after infection (Ash et al, 1979). The chemical structure of RMI 15,731 is similar to that of 5-(tetradecyloxy)-l-furoic acid (TOFA), an inhibitor of poliovirus genome replication (see Section 6.11).…”