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-alkylamino- and 4-alkenylamino-9-hydroxypyrimidoisoquinolines.
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-hydroxypyrimidoisoquinoline. 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.
Gössnitzer
Edith
E
Institute of Pharmaceutical Chemistry and Pharmaceutical Technology, Karl-Franzens-University Graz, Graz, Austria. edith.goessnitzer@uni-graz.at
Punkenhofer
Asbjörn
A
Ryder
Neil S
NS
D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004875:Ergosterol / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000890:Anti-Infective Agents; D001372:Aza Compounds; D007546:Isoquinolines; D011725:Pyridines; D004875:Ergosterol