Synthesis, characterization, and antimicrobial evaluation of a small library of ferrocene-containing acetoacetates and phenyl analogs: the discovery of a potent anticandidal agent

• Published in: Molecular diversity Vol. 18; no. 3; pp. 497 - 510
• Main Authors: Radulovic, Niko S, Mladenovic, Marko Z, Stojanovic-radic, Zorica, Bogdanovic, Goran A, Stevanovic, Dragana, Vukicevic, Rastko D
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.08.2014; Springer Nature B.V
• Subjects: Acetoacetates - chemical synthesis; Acetoacetates - chemistry; Acetoacetates - pharmacology; Anti-Infective Agents - chemical synthesis; Anti-Infective Agents - chemistry; Anti-Infective Agents - pharmacology; Antimicrobial agents; Bacteria - drug effects; Biochemistry; Biomedical and Life Sciences; Biosynthesis; Candida albicans; Candida albicans - drug effects; Chemistry Techniques, Synthetic; Crystallography; Drug Discovery; Ferrous Compounds - chemistry; Full-Length Paper; Life Sciences; Metallocenes; Organic Chemistry; Pharmacy; Polymer Sciences; Yeast; X-ray crystallography; Antimicrobial screening; Methyl benzylacetoacetate; Anticandidal activity; Methyl (ferrocenylmethyl)acetoacetate
• ISSN: 1381-1991; 1573-501X
• DOI: 10.1007/s11030-014-9511-0

A library of 16 2-substituted methyl acetoacetates containing ferrocenyl or phenyl units was designed to disclose differences in the antimicrobial activity of ferrocene-containing compounds and their phenyl analogs. Two methyl acetoacetates, whose structures do not contain an aromatic nucleus, were also included in order to probe the inherent activity of the scaffold itself. The acetoacetates were synthesized (low-to-good yields) and fully characterized by spectral (MS, IR, UV–Vis, 1D and 2D NMR) and electrochemical (cyclic voltammetry) techniques. Single-crystal X-ray analysis has been performed for methyl 2-acetyl-2-(ferrocenylmethyl)-5-methylhex-4-enoate. All compounds have demonstrated in vitro antimicrobial activity against six bacterial (three Gram-positive and three Gram-negative) and two fungal strains with minimal inhibitory concentration values of 0.0050–20.6  μ mol mL - 1 . The most active compound was 2-acetyl-2-(ferrocenylmethyl)-4-methylpent-4-enoate whose activity was comparable to that of nystatin against the yeast Candida albicans . Agglomerative hierarchical clustering statistical analysis of the antimicrobial assay data demonstrated that ferrocene-containing compounds have statistically different and greater antimicrobial activity when compared to their phenyl analogs.