NEW AZOLE ANTIFUNGALS - 2 - SYNTHESIS AND ANTIFUNGAL ACTIVITY OF HETEROCYCLECARBOXAMIDE DERIVATIVES OF 3-AMINO-2-ARYL-1-AZOLYL-2-BUTANOL

A series of 92 azole antifungals containing an amido alcohol unit was synthesized. The nature and substitution of the amide portion was syst ematically modified in search of improved antifungal activity, especia lly against filamentous fungi. The compounds were tested in vitro agai nst a variety of clinically important pathogens and in vivo (po) in a murine candidosis model. Thiazole and thiophene carboxamides carrying both a substituted phenyl ring and a small alkyl. group were best suit ed for activity against filamentous fungi. In a subset of these compou nds, the amide portion was conformationally locked by means of a pyrim idone ring and it was proven that only an orthogonal orientation of th e phenyl ring yields bioactive products. A tendency to display long pl asma elimination half-lives was observed in both series. Two compounds , 74 and 107, representative of the open and cyclic amides, respective ly, were chosen for further studies, based on their excellent activity in in vivo murine models of candidosis and aspergillosis. This work d escribes the SARs found within this series. The next paper displays th e results obtained in a related series of compounds, the quinazolinone s.