NEW AZOLE ANTIFUNGALS - 3 - SYNTHESIS AND ANTIFUNGAL ACTIVITY OF 3-SUBSTITUTED-4(3H)-QUINAZOLINONES

A series of azole antifungal agents featuring a quinazolinone nucleus have been subjected to studies of structure-activity relationships. In general, these compounds displayed higher in vitro activities against filamentous fungi and shorter half-lives than the structures describe d in our preceding paper. The most potent products in vitro carried a halogen (or an isostere) at the 7-position of the quinazolinone ring. Using a murine model of systemic candidosis, oral activity was found t o be dependent on hydrophobicity, which, in turn, modulated the compou nd's half-life. The 7-Cl derivative, (1H-1,2,4-triazol-1-yl)propyl]qui nazolin-4(3H)-one (20, UR-9825), was selected for further testing due to its high in vitro activity, low toxicity, good pharmacokinetic prof ile, and ease of obtention. Compound 20 is the (1R,2R) isomer of four possible stereoisomers. The other three isomers were also prepared and tested. The enantiomer (1S,2S) and the (LR,BS) epimer were inactive, whereas the (1S,2R) epimer retained some activity. In vitro 20 was sup erior to fluconazole, itraconazole, SCH-42427, and TAK-187 and roughly similar to voriconazole and ER-30346. In vivo, 20 was only moderately active in a mouse model of systemic candidosis when administration wa s limited to the first day. This was attributed to its short half-life in that species (t(1/2) = 1 h po). Protection levels comparable to or higher than those of fluconazole, however, were observed in systemic candidosis models in rat and rabbit, where the half-life of the compou nd was found to be 6 and 9 h, respectively. Finally, 20 showed excelle nt protection levels in an immunocompromised rat model of disseminated aspergillosis. The compound showed low toxicity signs when administer ed to rats at 250 mg/kg qd or at 100 mg/kg bid during 28 days.