Flavonoid modulation of murine neutrophil cytokinesis.

Flavonoids are known to produce a wide range of immunomodulatory effects. In this study, flavone and six hydroxylated analogues were examined for their effect on the FMLP-directed and the random migration of murine peritoneal exudate neutrophils. Flavone significantly (p less than 0.01) inhibits both directed and random migration at an assay concentration of 100 microM. In contrast, fisetin, kaempferol, chrysin, flavonol, morin and quercetin (in decreasing order of activity) significantly (p less than 0.05 to less than 0.01) enhance both directed and random migration at concentrations of 1.0 to 100 microM. Hydrophobicity does not appear to play a key role in the observed compound activity but the number and position of the hydroxyl substitutions might be important. In addition, the [Ca++] modulator chlorpromazine was found to significantly (10 microM; p less than 0.01) inhibit fisetin-enhanced FMLP-directed migration.

In vitro and in vivo anti-picornavirus activity of some p-benzoylphenoxypyridines.

Fifteen p-benzoylphenoxypyridines were initially evaluated for their in vitro activity against rhinoviruses (RV) 1A, 2 and 64 and coxsackie virus (Cox) A21 and for their oral prophylactic and therapeutic activity in Swiss albino mice lethally challenged with Cox A21. One compound, (4-[(5-methylsulfonyl-2-pyridinyl)oxy]phenyl) phenyl methanone, was selected for additional evaluation. These studies showed the compound to possess MIC50 values of less than or equal to 5 micrograms/ml against only 6 of 20 (30.0%) RV serotypes tested. In contrast, the compound was active at concentrations of less than or equal to 5.0 micrograms/ml against 10 of 12 (83.3%) enteroviruses evaluated. In vivo studies showed the compound to significantly protect mice lethally infected with Cox A21 after a single oral dose of 37.5 mg/kg (P less than 0.02) and during a regimen of continuous oral doses of at least 4.7 mg/kg per day (P less than 0.001). Mechanism of action studies indicated that the compound inhibits picornavirus uncoating or some earlier virus-host cell-associated event. Isotopic studies show that (4-[(5-methylsulfonyl-2-pyridinyl)oxy]phenyl) phenyl methanone perturbs HeLa cell macromolecular synthesis at concentrations of as low as 3.12 micrograms/ml. This concentration is only 4-fold higher than the concentration of compound necessary to inhibit Cox A21 RNA synthesis by 90%. This narrow therapeutic ratio limits the potential clinical utility of this compound to all but the most serious picornavirus infections.

In vitro and in vivo antipicornavirus activity of some phenoxypyridinecarbonitriles.

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 micrograms/ml or less against 11 of 20 RV serotypes tested. The compound was only moderately active (MIC50, 5 to 7 micrograms/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 micrograms/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 less than 0.01) and during a regimen of continuous oral doses of 37.5 mg/kg per day (P less than 0.001). Mechanism of action studies indicated that the compound inhibited picornavirus uncoating or some earlier virus-host cell-associated event.