Studies via X-ray analysis on intermolecular interactions and energy frameworks based on the effects of substituents of three 4-aryl-2-methyl-1H-imidazoles of different electronic nature and their in vitro antifungal evaluation

Abstract

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.

Catalyst- and solvent-free synthesis of 2-fluoro-N-(3-methylsulfanyl-1H-1,2,4-triazol-5-yl)benzamide through a microwave-assisted Fries rearrangement: X-ray structural and theoretical studies

“…The dispersion term has a 2D character connecting molecules preferentially to form (001) sheets. The different distribution of the electrostatic and dispersion terms to the total energy in molecules with structural similarities was also observed in other 4-aryl-2-methyl-1H-imidazoles (Macías et al, 2018b).…”

Intermolecular interaction energies and molecular conformations in N-substituted 4-aryl-2-methylimidazoles with promising in vitro antifungal activity

“…In (4f), there are ortho and para substitutions in the aryl rings increasing the cited effect. The electronic influence of the aryl groups on the supramolecular assembly was previously observed in three 4aryl-2-methyl-1H-imidazoles [(3a)-(3c), see Fig 1(a)], with changes in intermolecular interactions due to an electrondonating/withdrawing tendency of the substituent groups in the benzene rings that affected the acid-base properties of the imidazolic nucleus, varying the strength of the intermolecular N-HÁ Á ÁN interactions (Macías, Elejalde et al, 2018).…”

“…As part of our research towards the synthesis of novel diazole derivatives with both biological and photophysical interest (Vargas-Oviedo et al, 2017;Elejalde et al, 2018;Macías, Elejalde et al, 2018;Orrego-Herná ndez & Portilla, 2017;García et al, 2019), particularly of imidazole derivatives (Vargas-Oviedo et al, 2017;Elejalde et al, 2018;Macías, Elejalde et al, 2018), we have carried out a structural study by X-ray diffraction of N-substituted 4-aryl-2-methylimidazoles and tested them for their antifungal properties against Candida albicans (Ca) and Cryptococcus neoformans (Cn). Similar systems such as miconazole (MCZ), ketoconazole (KTZ), econazole (ECZ) and tioconazole (TCZ) are antifungal imidazoles that have not only the imidazole ring, but also the 2-haloaryl-2-alcoxyethyl group at position 1 (Borgers, 1980;Fromtling, 1988;Di Santo et al, 2005;Espinel-Ingroff, 2009;Strushkevich et al, 2010;Emami et al, 2017).…”

“…2(b)] (Kastelic et al, 2010;Tsutsumi et al, 2011;Dayo-Owoyemi et al, 2019). In our most recent work (Macías, Elejalde et al, 2018), a complete study by X-ray diffraction of the electronic effects of the 4-aryl substituent of NH-imidazoles (3a)-(3c) and their in vitro antifungal evaluation was reported. These compounds were by-products in the synthesis of N-phenacylimidazoles (4), but at that time (Elejalde et al, 2018) their antifungal activities were not evaluated and crystals of suitable size and quality had not been achieved for the respective X-ray diffraction analysis [ Fig.…”

Influence of Steric Effect on the Pseudo-Multicomponent Synthesis of N-Aroylmethyl-4-Arylimidazoles

“…Thus, the methods for imidazole synthesis are extensive and can be classified in three general ways: (i) cyclocondensation reactions (the most usual), (ii) a scaffold approach, and (iii) multicomponent reactions (MCRs) [2,7,[16][17][18][19][20][21][22]. Several methods have been perfected using microwave-assisted organic synthesis (MAOS) as a powerful tool for various chemical transformations with superior results compared to conventional methods [20,[23][24][25][26].…”