Synthesis and oral antifungal activity of novel azolylpropanolones and related compounds

Abstract

To find orally active antifungal agents, novel imidazolyl- and 1,2,4-triazolylpropanolones I and related compounds II-IV were synthesized. Compounds I were derived from ketones V (method A), alpha-diketone IX (method B), alpha-hydroxy ketones X (method C), alpha-chloro ketone XII (method D), and enones VI (method E). Diols II, synthesized from I with NaBH4, were cyclized to five-membered cyclic compounds III by using N,N'-carbonyldiimidazole, thionyl chloride, N,N'-(thiocarbonyl)diimidazole, bromochloromethane, 2,2-dimethoxypropane, and cyclohexanone dimethyl ketal. Diols IV were synthesized from I by Grignard reaction (method F), hydroxymethylation of X (method G), and reaction of ketones XXI with 1-[(trimethylsily)methyl]-1,2,4-triazole (method H). Compounds I-IV were examined for their antifungal activities in vitro by evaluation of broth dilution MIC values against three species of fungi and the inhibitory effect on pseudomycelium of Candida albicans, and they were examined for oral efficacy in vivo against subacute systemic candidiasis in mice and superficial dermatophytosis in guinea pigs. Compounds 2, 12, 38, 39, and 92 exhibited strong oral antifungal activity. An asymmetric synthesis and the structure-activity relationships of the compounds examined are discussed.

Biologically Active Metabolites from Fungi, 19: New Isocoumarins and Highly Substituted Benzoic Acids from the Endophytic Fungus,ScytalidiumSP.

“…Evidently, in addition to possible electronic effects, the pentasubstituted benzene ring effectively shields the benzylic carbonyl group. This spectral evidence and also the fact that the methylenation of 1,2-dicarbonyl compounds has ample precedence in the literature [11], confirms the structures of the methylation products 10a-10d and thus that of the polar natural constituent 10.…”

2-(4-Chlorophenyl)-2-oxoethyl benzoate

“…The dihedral angle between the phenyl (C10-C15) ring and the chloro-substituted phenyl (C1-C6) ring is 84.29 (8)°. The bond lengths (Allen et al, 1987) and angles are within normal ranges and are comparable to those closely related structures (Ogata et al, 1987;Wan et al, 2006;Zhang et al, 2006).…”

“…For applications of phenacyl benzoate derivatives, see: Rather & Reid (1919); Litera et al (2006); Huang et al (1996); Gandhi et al (1995). For related structures, see: Ogata et al (1987); Wan et al (2006); Zhang et al (2006). For reported meltingpoint details, see: Le et al (2009).…”

Enantioselective three-component aminomethylation of α-diazo ketones with alcohols and 1,3,5-triazines

“…Encouraged by these discoveries, we design a three-component reaction between α-diazo ketones, alcohols and 1,3,5-triaryl-1,3,5triazines, anticipating that a similar dual hydrogen bonding activation would be operational (Fig. 1b), thus allowing an efficient electrophile-based asymmetric activation of formaldimines and offering an enantioselective aminomethylation reaction to give chiral β-amino-α-hydroxy ketones, which are widely existed structural scaffolds in synthetic and medicinal chemistry [51][52][53][54] . The challenges for the design of this three-component reaction are three-fold: (1) the in situ-generated formaldimine from 1,3,5triazine has a low concentration in the reaction system, thus the electrophilic trapping of the active oxonium ylide species would be much less efficient and the undesired O-H insertion product 55 might be predominant; (2) 1,3,5-triaryl-1,3,5-triazines may undergo [4 + 1] cycloaddition with diazo compounds under metal catalysis 56 , which would lead to low reactivity of the desired three-component reaction; (3) it is not trivial whether the proposed dual hydrogen bonding between CPA and the two reactive intermediates could be effectively formed, which is owing to the unstable nature, low concentration and the lack of substituents on the carbon atom of the in situ-generated formaldimines.…”