Efficacies of two novel azole derivatives each containing a morpholine ring, UR-9746 and UR-9751, against systemic murine coccidioidomycosis

UR-9746 and UR-9751 are novel azole derivatives each containing a morpholine ring, They were examined for both in vitro and in vivo activities against Coccidioides immitis. In vitro, UR-9746 and UR-9751 were active, with MICs of 25 and 3.1 mu g/ml, respectively, against C. immitis Silveira; minimum fungicidal concentrations were >100 mu g/ml, the highest concentration tested, for both compounds, Antifungal activity in serum showed the desirable characteristic of remaining severalfold above the MIC at all times. Against systemic murine coccidioidomycosis, UR-9746 and UR-9751 prolonged survival at dosages of greater than or equal to 10 mg/kg/day and showed increased reduction of infectious burden in the spleens, livers, and lungs of treated mice with escalating dosage, Both compounds lacked observable toxicity and on a milligram-per-kilogram of body weight basis were greater than or equal to 10-fold superior to fluconazole in prolonging survival and clearing infection with C. immitis.