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

European Journal of Pharmaceutical Sciences

Volumn 19, Issue 2-3, 2003, Pages 151-164

  Gößnitzer, Edith ^a   Punkenhofer, Asbjörn ^a   Amon, Anton ^a   Favre, Bertrand ^b  

^a UNIVERSITY OF GRAZ   (Austria)

^b NOVARTIS RESEARCH INSTITUTE   (Austria)

Author keywords

4 Alkylaminotetrahydro 2H pyrimido 4,3 a isoquinoline salts; 8,13,15 Triazasteroids; Antifungal activity; High energy intermediate analogues; Structure activity relationships; Synthesis and structure investigations

Indexed keywords

BIOSYNTHESIS; CATALYSIS; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY;

HIGH ENERGY INTERMEDIATES;

AMINES;

9 METHOXY N4 (3,7 DIMETHYL 6 OCTENYL) 1,6,7,11B TETRAHYDRO 2H PYRIMIDO[4,3 A]ISOQUINOLIN 4 AMINE HYDROIODIDE; 9 METHOXY N4 (3,7 DIMETHYLOCTYL) 1,6,7,11B TETRAHYDRO 2H PYRIMIDO[4,3 A]ISOQUINOLIN 4 AMINE HYDROIODIDE; 9 METHOXY N4 (6 ISOPROPYL 3 METHYL 6 HEPTENYL) 1,6,7,11B TETRAHYDRO 2H PYRIMIDO[4,3 A]ISOQUINOLIN 4 AMINE HYDROIODIDE; 9 METHOXY N4 OCTYL 1,6,7,11B TETRAHYDRO 2H PYRIMIDO[4,3 A]ISOQUINOLIN 4 AMINE HYDROIODIDE; ALKENYL GROUP; ALKYL GROUP; AMINE; ANTIFUNGAL AGENT; AROMATIC COMPOUND; CATION; ENZYME; ERGOSTEROL; GUANIDINE; IODINE DERIVATIVE; ISOQUINOLINE; ISOQUINOLINE DERIVATIVE; METHYL GROUP; N4 (3,7 DIMETHYL 6 OCTENYL) 1,6,7,11B TETRAHYDRO 2H PYRIMIDO[4,3 A]ISOQUINOLIN 4 AMINE HYDROIODIDE; N4 (3,7 DIMETHYLOCTYL) 1,6,7,11B TETRAHYDRO 2H PYRIMIDO[4,3 A]ISOQUINOLIN 4 AMINE HYDROIODIDE; N4 (6 ISOPROPYL 3 METHYL 6 HEPTENYL) 1,6,7,11B TETRAHYDRO 2H PYRIMIDO[4,3 A]ISOQUINOLIN 4 AMINE HYDROIODIDE; N4 OCTYL 1,6,7,11B TETRAHYDRO 2H PYRIMIDO[4,3 A]ISOQUINOLIN 4 AMINE HYDROIODIDE; OCTYLAMINE; SECOSTEROID; SQUALENE; STEROL; TRIAZINE; TRIAZOLE DERIVATIVE; UNCLASSIFIED DRUG;

ANTIBIOTIC SENSITIVITY; ANTIFUNGAL ACTIVITY; ARTICLE; ASPERGILLUS FUMIGATUS; BIOSYNTHESIS; CANDIDA ALBICANS; CATALYSIS; CHEMISTRY; CONTROLLED STUDY; CRYPTOCOCCUS NEOFORMANS; DERMATOPHYTE; DRUG DESIGN; DRUG EFFECT; DRUG EFFICACY; DRUG POTENCY; DRUG STRUCTURE; DRUG SYNTHESIS; ENERGY; FUNGUS; GROWTH, DEVELOPMENT AND AGING; IN VITRO STUDY; MICROBIOLOGICAL EXAMINATION; MINIMUM INHIBITORY CONCENTRATION; NONHUMAN; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; PRIORITY JOURNAL; SACCHAROMYCES CEREVISIAE; STEROL SYNTHESIS; STRUCTURE ACTIVITY RELATION; TRICHOPHYTON; YEAST;

EID: 0037506822     PISSN: 09280987     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0928-0987(03)00086-1     Document Type: Article

References (28)

1. Anet F.A.L. Conformational analysis of cyclohexenes. Rabideau P.W. The Conformational Analysis of Cyclohexenes, Cyclohexadienes, and Related Hydroaromatic Compounds. 1989;VCH, Weinheim.
2. Burden R.S., Cooke D.T., Carter G.A. Inhibitors of sterol biosynthesis and growth in plants and fungi. Phytochemistry. 28:1989;1791-1804.
3. Ceruti M., Balliano G., Viola F., Grosa G., Rocco F., Cattel L. 2,3-Epoxy-10-aza-10,11-dihydrosqualene, a high-energy intermediate analogue inhibitor of 2,3-oxidosqualene cyclase. J. Med. Chem. 35:1992;3050-3058.
4. Corey E.J., Virgil S.C. An experimental demonstration of the stereochemistry of enzymic cyclization of 2,3-oxidosqualene to the protosterol system, forerunner of lanosterol and cholesterol. J. Am. Chem. Soc. 113:1991;4025-4026.
5. Fung A.K.L., Baker W.R., Fakhoury S., Stein H.H., Cohen J., Donner B.G., Garvey D.S., Spina P.S., Rosenberg S.H. (1α,2β,3β,4α)-1,2-Bis[[N-propyl-N-(4-phenoxybenzyl) amino]carbonyl]cyclobutane-3,4-dicarboxylic acid (A-87049): A novel potent squalene synthase inhibitor. J. Med. Chem. 40:1997;2123-2125.
6. 2-substituted 2-imidazolinamines. Arch. Pharm.-Pharm. Med. Chem. 335:(11):2002;535-546.
7. Gößnitzer E., Punkenhofer A. Novel high energy intermediate analogues with triazasterol-related structures as potential inhibitors of the ergosterol biosynthesis. II. Optimization of the synthesis of 1,6,7,11b-tetrahydro-2H-pyrimido[4,3-a]isoquinolin-4-amines as parent compounds of novel 8,13,15-triazasteroids. Monatsh. Chem. 134:2003;. (in press).
8. Günther H. NMR Spectroscopy. 1998;Wiley, New York.
9. Hiemstra H., Sno M.H.A.M., Vijn R.J., Speckamp W.N. Silicon directed N-acyliminium ion cyclizations. Highly selective syntheses of (±)-isoretronecanol and (±)-epilupinine. J. Org. Chem. 50:1985;4014-4020.
10. Jaeger R.H., Robinson R. A simple synthesis of 'queen substance'. Tetrahedron. 14:1961;320-321.
11. 13C-NMR-Spektroskopie. 1984;Thieme, Stuttgart.
12. 7-isomerase in fungi. Biochem. Soc. Trans. 18:1989;59-61.
13. Köller W. Antifungal agents with targets sites in sterol functions and biosynthesis. Köller W. Target Sites of Fungicidal Action. 1992;119-206 CRC Press, Boca Raton, FL.
14. Koltin Y. Targets for antifungal drug discovery. Annu. Rep. Med. Chem. 25:1990;141-148.
15. 4. Application to gibberellins. Tetrahedron Lett. 23:1982;4293-4296.
16. Miller D., Bilodeau F., Burnell R.H. Stereoselective syntheses of isomers of 3,7-dimethylnonadecane, a sex pheromone of the alfalfa blotch leaf miner (Agromyza frontella (Rondani)). Can. J. Chem. 69:1991;1100-1106.
17. Reference method for broth dilution antifungal susceptibility testing of yeasts; approved standard. NCCLS Document M27-A. 1997;NCCLS, Wayne, PA.
18. Reference method for broth antifungal susceptibility testing of conidium-forming filamentous fungi; proposed standard. NCCLS Document M38-P. 1998;NCCLS, Wayne, PA.
19. Polak A., Hartmann P.G. Antifungal chemotherapy. Are we winning? Prog. Drug Res. 37:1992;181-269.
20. 7-sterol isomerase and of cycloeucalenol-obtusifoliol isomerase by N-benzyl-8-aza-4α,10-dimethyl-trans-decal-3β-ol, an analogue of carbocationic high energy intermediate. Phytochemistry. 24:1985;1223-1232.
21. Sutherland A.J., Sutherland J.K., Crowley P.J. Synthesis of C-D-ring analogues of the azasteroid A2522. J. Chem. Soc. Perkin Trans. 1:1996;349-354.
22. Takai K., Fuijmura O., Kataoka Y., Utimoto K. Preparation of alkenyl sulfides and enamines by alkylenidation of carboxylic acid derivatives. Tetrahedron Lett. 30:1989;211-214.
23. Taton M., Benveniste P., Rahier A. N-(1,5,9-Trimethyldecyl)-4α,10-dimethyl-8-aza-trans-decal-3β-ol, a novel potent inhibitor of 2,3-oxidosqualene cycloartenol and lanosterol cyclases. Biochem. Biophys. Res. Commun. 138:1986;764-770.
24. Taton M., Benveniste P., Rahier A. Inhibition of sterol biosynthesis by analogues of carbenium ion intermediates. Bioorg. Chem. Healthcare Technol. 207:1991;23-37.
25. Van den Bossche H. Itraconazole: a selective inhibitor of the cytochrome P-450 dependent ergosterol biosynthesis. Fromtling R.A. Recent Trends in the Discovery, Development, and Evaluation of Antifungal Agents. 1987;207 J.R. Prous, Barcelona.
26. Van Tamelen E.E. Bioorganic characterization and mechanism of the 2,3-oxidosqualene lanosterol conversion. J. Am. Chem. Soc. 104:1982;6480-6481.
27. Van Tamelen E.E., Leopold E.J., Marson S.A., Waespe H.R. Action of 2,3-oxidosqualene lanosterol cyclase on 15′-nor-18,19-dihydro-2,3-oxidosqualene. J. Am. Chem. Soc. 104:1982;6479-6480.
28. Walsh T.J. Invasive fungal infections: Problems and challenges for developing new antifungal compounds. Sutcliff J.A., Georgopapadakou N.H. Emerging Targets in Antibacterial and Antifungal Chemotherapeutics. 1992;349-373 Chapman and Hall, New York. Chapter 13.