Novel high energy intermediate analogues with triazasterol-related structures as inhibitors of ergosterol biosynthesis. III. Synthesis and antifungal activity of N4-alkyl-1,6,7,11b-tetrahydro-2H-pyrimido[4,3-a]isoquinolin-4-amine salts.
A series of N4-alkyl-1,6,7,11b-tetrahydro-2H-pyrimido[4,3-a]isoquinolinamine hydroiodides with triazasterol-related structures was designed and synthesized to mimic, as stable analogues, native high energy intermediates (HEI) of ergosterol biosynthesis. The title compounds can be regarded as 8,13,15-triaza-13,17-secosteroids with aromatic ring A bearing the positive charge in the guanidinium moiety. Hence, these compounds present structural similarities with corresponding carbocationic intermediates occurring during the enzyme catalyzed transformation of squalene into ergosterol. The N4-alkylaminopyrimidoisoquinolinium salts were prepared by reaction of respective S-methylthiotetrahydropyrimidoisoquinoline hydroiodides with octylamine, and appropriately methyl-branched alkyl- and alkenylamines. In order to prepare (3R)-6-isopropyl-3-methyl-6-hepten-1-amine several synthetic routes were investigated. The structures of all reported compounds were proved and completely assigned on the basis of homo- and heteronuclear correlated 1D and 2D NMR spectroscopy. The in vitro antifungal susceptibility tests of the title compounds with a standard panel of eight pathogenic fungi revealed especially against the used dermatophytes and yeasts with MICs in the range of 1-32 microg/ml moderate to good antimycotic effects. Depending on the nature of the N4-alkyl substituents structure-activity relationships were found with a maximum of antifungal efficacy of the N4-3,7-dimethyloctylaminopyrimidoisoquinolinium iodide.
Gössnitzer
Edith
E
Institute of Pharmaceutical Chemistry and Pharmaceutical Technology, Karl-Franzens-University of Graz, Schubertstrasse 1, A-8010 Graz, Austria. edith.goessnitzer@uni-graz.at
Punkenhofer
Asbjörn
A
Amon
Anton
A
Favre
Bertrand
B
D000935:Antifungal Agents / Q000737:chemistry / Q000494:pharmacology*; D001232:Aspergillus fumigatus / Q000187:drug effects / Q000254:growth & development; D002176:Candida albicans / Q000187:drug effects / Q000254:growth & development; D003455:Cryptococcus neoformans / Q000187:drug effects / Q000254:growth & development; D004875:Ergosterol / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests / Q000706:statistics & numerical data; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000254:growth & development; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*; D014249:Trichophyton / Q000187:drug effects / Q000254:growth & development
D000935:Antifungal Agents; D007546:Isoquinolines; D014230:Triazoles; C039109:isoquinoline; D004875:Ergosterol