Preparation and in vitro antifungal activities of some quinolizidine derived hemiaminals and beta-tert-amino sulfides.
New alpha-thiohemiaminals, 7alpha-phenylthio-7-epideoxynupharidin-6-ol, the diasteriomeric 7beta-phenylthiodeoxy-nupharidin-6-ol, and 3-methyl-3-methylthio-4-hydroxyquinolizidine, were prepared and reduced to the corresponding beta-tert-amino sulfides. The configuration at C-7 of the beta-tert-amino sulfides was determined by observing the direction of the solvent-induced shift of the C-7 methyl proton resonance. The configuration at C-7 of the new alpha-thiohemiaminals was established by correlations with the beta-tert-amino sulfides and confirmed, in the case of the deoxynupharidine derivatives, by circular dichroism and ascertaining the sterochemistry of deuteride incorporation upon sodium borodeuteride reduction of the alpha-thiohemiaminal. The in vitro antifungal activities of six compounds possessing the quinolizidine skeleton, including all the newly synthesized compounds as well as some previously reported ones, and amphotericin B were tested against several human pathogenic fungi. Besides amphotericin B, only the two deoxynupharidine alpha-thiohemiaminals were active, especially against Histoplasma capsulatum and Blastomyces dermatitidis. The observations indicate activity is derived from the 3-furyl group and the functionality from which alpha-thioimmonium ions can be produced.
D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001758:Blastomyces / Q000187:drug effects; D002942:Circular Dichroism; D006658:Histoplasma / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D008864:Microsporum / Q000187:drug effects; D011807:Quinolizines / Q000138:chemical synthesis* / Q000494:pharmacology; D013175:Sporothrix / Q000187:drug effects; D013440:Sulfides / Q000138:chemical synthesis / Q000494:pharmacology; D014249:Trichophyton / Q000187:drug effects
D000935:Antifungal Agents; D011807:Quinolizines; D013440:Sulfides