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 micrograms/ml, respectively, against C. immitis Silveira; minimum fungicidal concentrations were > 100 micrograms/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 > or = 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 > or = 10-fold superior to fluconazole in prolonging survival and clearing infection with C. immitis.
Clemons
K V
KV
Department of Medicine, Santa Clara Valley Medical Center, San Jose, CA 95128, USA.
Stevens
D A
DA
D000818:Animals; D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D003045:Coccidioides / Q000187:drug effects; D003047:Coccidioidomycosis / Q000097:blood / Q000188:drug therapy*; D005260:Female; D015725:Fluconazole / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D009025:Morpholines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D014230:Triazoles / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
D000935:Antifungal Agents; D009025:Morpholines; D014230:Triazoles; C104730:UR 9746; C104729:UR 9751; D015725:Fluconazole