A convenient one‐pot synthesis of 4‐aryl‐2‐methyl‐N‐phenacylimidazoles (4) through a microwave‐assisted pseudo‐tricomponent reaction of α‐bromoacetophenones (1) with acetamidine hydrochloride (2) is reported. Ketones (4) were successfully used as substrates for the preparation of the respective N‐(2‐hydroxyethyl)imidazoles (5) with yields up to 87%. The synthesized compounds were characterized by NMR and high‐resolution mass spectrometry analyses, and several structures were confirmed and studied by single‐crystal X‐ray diffraction. The analysis of the whole‐of‐molecule interactions shows that, despite the difference in the atom–atom contacts forming the crystals, dispersion energies make the largest contribution to the formation of the solids, giving an isotropic tendency in the topology of the energy framework diagrams for pairs of molecules. In addition, the in vitro antifungal activity of both families of compounds [ketones (4) and alcohols (5)] against Candida albicans and Cryptococcus neoformans was evaluated, where the 2,4‐dichlorophenyl‐substituted alcohol (5f), an isomer of the drug miconazole, showed the highest activity (IC50 = 7.8 µg ml−1 against C. neoformans).
The crystal structures of 2‐methyl‐4‐phenyl‐1H‐imidazole, C10H10N2, (3a), 4‐(4‐chlorophenyl)‐2‐methyl‐1H‐imidazole hemihydrate, C10H9ClN2·0.5H2O, (3b), and 4‐(4‐methoxyphenyl)‐2‐methyl‐1H‐imidazole, C11H12N2O, (3c), have been analyzed. It was found that the electron‐donating/withdrawing tendency of the substituent groups in the aryl ring influence the acid–base properties of the 2‐methylimidazole nucleus, changing the strength of the intermolecular N—H…N interactions. This behaviour not only influences the crystal structure but also seems to have an important effect on the antifungal activity. Considering the substituent groups, that is, H in (3a), Cl in (3b) and OMe in (3c), the formation of strong N—H…N connections has the probability (3a) > (3b) > (3c), while compound (3c) proves to be more active than (3a) and (3b) at all concentrations against C. neoformans.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.