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

• Published in: European journal of pharmaceutical sciences 2003-06, Vol.19 (2-3), p.151-164
• Main Authors: Gössnitzer, Edith, Punkenhofer, Asbjörn, Amon, Anton, Favre, Bertrand
• Format: Article
• Language: English
• Subjects: Antifungal Agents - chemistry; Antifungal Agents - pharmacology; Aspergillus fumigatus - drug effects; Aspergillus fumigatus - growth & development; Candida albicans - drug effects; Candida albicans - growth & development; Cryptococcus neoformans - drug effects; Cryptococcus neoformans - growth & development; Ergosterol - antagonists & inhibitors; Ergosterol - biosynthesis; Isoquinolines - chemistry; Isoquinolines - pharmacology; Microbial Sensitivity Tests - statistics & numerical data; Saccharomyces cerevisiae - drug effects; Saccharomyces cerevisiae - growth & development; Structure-Activity Relationship; Triazoles - chemistry; Triazoles - pharmacology; Trichophyton - drug effects; Trichophyton - growth & development
• ISSN: 0928-0987

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.