A nitrobenzene derivative, MDL-860, was found to inhibit plaque formation, cytopathic effect, or both in 11 of 12 picornaviruses at concentrations which did not affect cell growth. The A search in The Dow Chemical Company laboratories for agents active against the picornaviruses led to the identification of the broadly active 2-(3,4-dichlorophenoxy)-5-nitrobenzonitrile (MDL-860). This agent exhibited high in vitro activity against the picornaviruses but not against viruses of other classes. This report is concerned with the spectrum of activity of MDL-860 and the results of some preliminary observations on its mechanism of action. The accompanying report (5) presents a more extensive evaluation of the antiviral spectrum of the compound.
MATERIALS AND METHODSCompound. MDL-860 was synthesized by L. Markley of The Dow Chemical Company, Midland, Mich. For easier dissolution in aqueous cell culture medium, the compound is first dissolved in 0.05 ml of dimethyl sulfoxide per 3 mg of MDL-860 and then diluted more than 100-fold in aqueous cell culture medium to produce a suspension of small particles.Viruses. Rhinovirus (RV) types 5, 8, 64, and Hank and RV types 1-A and 2, obtained from J. Gwaltney
Nineteen phenoxypyridinecarbonitriles were initially evaluated for their in vitro activity against rhinoviruses (RV) 1A, 2, and 64 and coxsackievirus (Cox) A21 and for their oral prophylactic and therapeutic activity in Swiss albino mice challenged with Cox A21. On the basis of the results of these studies, one compound, 6-(3,4-dichlorophenoxy)-3-(ethylthio)-2-pyridinecarbonitrile, was selected for further evaluation. Expanded in vitro spectrum of activity studies showed that the MIC causing a 50% reduction in viral cytopathic effect in infected cultures (MIC50) was 3.0 ,ug/ml or less against 11 of 20 RV serotypes tested. The compound was only moderately active (MIC50, 5 to 7 ,ug/ml) against four of the RV serotypes evaluated, while RV 4, 5, 8, 13 and Hank's were relatively resistant to compound inhibition. Of the nine enteroviruses studied, only Cox A21, echovirus 12, poliovirus 2, and enterovirus 70 were inhibited at compound concentrations of less than 2.0 ,ug/ml. The compound provided significant protection to mice infected with a normally lethal dose of Cox A21 when administered in a single oral dose of 150 mg/kg (P < 0.01) and during a regimen of continuous oral doses of 37.5 mg/kg per day (P < 0.001). Mechanism of action studies indicated that the compound inhibited picornavirus uncoating or some earlier virus-host cell-associated event.
The 6-substituted 2-(3',4'-dichlorophenoxy)-2H-pyrano[2,3-b]pyridines MDL 20,610 (6-SO2CH3), MDL 20,646 (6-Br), and MDL 20,957 (6-Cl) are potent antirhinovirus compounds with median plaque 50% inhibitory concentrations (IC1/2s) of 0.03, 0.006, and 0.006 micrograms/ml, respectively, against the 32 serotypes evaluated. The 6-halogenated analogs produced 99% reductions in progeny virion yields at concentrations as low as 0.004 micrograms/ml. However, these analogs perturbated HeLa cell metabolism at lower concentrations (at or above 5 micrograms/ml) than did the 6-methylsulfonyl analog (at or above 20 micrograms/ml). Compound MDL 20,610 was also active against human, simian, and bovine rotaviruses (cytopathic effect IC1/2s of 0.8 to 1.5 micrograms/ml) and possessed variable enterovirus and paramyxovirus activity.
The purpose of this study was to probe the antirhinovirus (RV) mechanism of action of MDL 20,610. Evaluation of the compound's effects on RV RNA synthesis, uncoating of neutral red-sensitized RV, plasma membrane penetration by RV, stabilization of RV against heat (56 degrees C) and low pH (5.0) inactivation, and studies with MDL 20,610-resistant RV mutants indicate that MDL 20,610 binds directly to the RV capsid with subsequent inhibition of acid-mediated virion uncoating.
This study describes the evaluation of a murine bacteraemia model for assessing antibiotic efficacy in normal and neutropenic mice infected with coagulase-negative staphylococci. In one such evaluation, it was found that there was no significant (P greater than 0.05) difference in the ability of teicoplanin or vancomycin to protect normal or neutropenic CD-1 mice, lethally-infected with Staphylococcus haemolyticus. However, about a four-fold increase of either antibiotic was needed to protect the immunocompromised animals.
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