Novel (N-ferrocenylmethyl)amines and (N-ferrocenylmethylen)imines derived from vicinal steroid amino alcohols and amines: synthesis, molecular structure, and biological activity.
Novel steroidal (N-ferrocenylmethyl)amines with potential biologic activity and of potential interest as chiral ligands for metal complexation were synthesized. The new compounds were screened in vitro for their potential as antimicrobial agents. The synthesis of the new steroidal ferrocenes, including two X-ray crystal structures and biologic assays, are described. The 16-(ferrocenylmethyl)amino-estratrienes 4a-d, 7b, and 10b exhibited outstanding broad antimicrobial activity particularly against mycobacteria and multi-resistant staphylococci. Thus, they can be considered as new lead structures. In contrast, the analogous 3 alpha-(ferrocenylmethyl)amino-cholestanes 12 possessed only weak activity. The reaction of the four isomeric amino alcohols 1a-d (Scheme 1) with ferrocenecarbaldehyde was studied. 1b and 1c with 16/17-trans configuration yielded nearly quantitatively the (E)-Schiff bases 2b and 2c (Scheme 2). In contrast to the trans-compounds, condensation of the cisconfigurated amino alcohols 1a and 1d furnished tautomeric mixtures of the Schiff bases (2a and 2d, respectively) and their corresponding 1,3-oxazolidines (3a and 3d, respectively). The novel (N-ferrocenylmethyl)amines 4a-d were obtained in excellent yields by reduction of the tautomer mixtures and the uniform Schiff bases with sodium borohydride in ethanol. Starting with the 16 beta-hydroxy compound 5a, the synthesis of 16 beta- and 16 alpha-amino-3-methoxy-estra-1,3,5(10)-triene (6b, 9b) is described. The corresponding 16-(N-ferrocenylmethyl)amines 7b and 10b and the 3 alpha-(N-ferrocenylmethyl)amino-cholestanes 12 were synthesized (Scheme 3) for comparison in biologic tests.
Krieg
R
R
Institut für Anatomie/Anatomie II, Klinikum der Universität Jena, Germany.
Wyrwa
R
R
Möllmann
U
U
Görls
H
H
Schönecker
B
B
D000438:Alcohols / Q000737:chemistry*; D000588:Amines / Q000737:chemistry*; D000890:Anti-Infective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007097:Imines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D013055:Spectrophotometry, Infrared; D014961:X-Ray Diffraction
D000438:Alcohols; D000588:Amines; D000890:Anti-Infective Agents; D007097:Imines