In vitro and in vivo candicidal activities of 2-(p-n-hexylphenylamino)-1,3-thiazoline.

The 2-amino-1,3-thiazoline, 2-(p-n-hexylphenylamino)-1,3-thiazoline (MDL 20,245) killed 10(5) logarithmic or stationary phase Candida albicans/ml in less than 1 h. Miconazole killed logarithmic phase cells at that rate, but miconazole, clotrimazole or econazole killed stationary phase cells at a slower rate of 10(2)-10(4) cells/ml in 24 h. MDL 20,245 induced efflux of K+ and L[U-14C] lysine from C. albicans, indicating that the candicidal mechanism is to exert direct damage upon the cytoplasmic membrane. The activity of MDL 20,245 in vitro was antagonized by fatty acids, triglycerides and phospholipids. Topical application of MDL 20,245 ointment (10% w/v) twice per day for 4 days to rats suppressed C. albicans-induced vaginitis 100%. Single-dose regimens of MDL 20,245, miconazole or clotrimazole correlated with 97, 90 and 73% suppression, respectively. These data suggest that MDL 20,245 may be effective in the treatment of C. albicans-induced vaginitis in humans.

Importance of the hydrophobic sulfoxide substituent on nontoxic analogs of sparsomycin.

Nontoxic analogs of sparsomycin were competitive inhibitors of puromycin in the peptidyl transferase assay with Escherichia coli polysomes. The sensitivity of HeLa cells in vitro to the analogs was used as a preliminary index of cellular toxicity. In vitro killing of HeLa cells by this class of compounds correlated well with in vivo 50% lethal doses. The data indicate that modification of the hydrophobic sulfoxide substituent on sparsomycin decreases the toxicity of the molecule for mammalian cells by several hundredfold. Such modifications have less of an effect on the inhibitory activity of the compounds for peptidyl transferase. The differential effects of an analog active against bacterial but not mammalian cells was due to a decreased uptake of the compound by HeLa cells.