Novel high energy intermediate analogues with a triazasterol structure as potential ergosterol biosynthesis inhibitors IV: antimicrobial activity of mono-, bi-, and tricyclic 8, 13, 15-triazasteroid analogues including the synthesis of novel 4-alkyla

摘要

4-alkylamino-and 4-alkenylamino-9-hydroxy-1, 6, 7, 11b-tetrahydro-2H-pyrimido[4, 3-a]isoquinolines were designed as inhibitory tricyclic triaza-analogues of carbocationic high energy intermediates (HEI) of enzymes involved in fungal ergosterol biosynthesis. Various routes for effective synthesis of 9-hydroxypyrimidoisoquinolines from 9-methoxythiones were investigated. The ether cleavage of 9-methoxy-pyrimidoisoquinolines, a key step in the synthesis, was carried out using various protocols. The structures of the obtained 9-hydroxy compounds were confirmed using homo- and hetero-nuclear correlated 1D and 2D NMR experiments. In vitro antifungal susceptibility tests of the alkylaminohydroxypyrimidoisoquinolines revealed weak to good antimycotic effects. The maximum antifungal efficacy was found for 4-[(3R)-6-isopropyl-3-methyl-6-heptenylamino]-9-hydroxypyrimidoisoquinolin e. Furthermore, the in vitro activities of the newly synthesized 9-hydroxypyrimidoisoquinolines and of a series of prepared 8, 13, 15-triazasteroid analogues (N-alkyl-N'-(phenethyl- and cyclohexenylethyl)guanidines, N(2) -and N(2), 4-substituted imidazolin-2-amines, and N(4)-alkylaminopyrimidoisoquinolines) against representatives of gram-positive and gram-negative bacteria were investigated. The compounds showed significant antibacterial effects against gram-positive bacteria.