Synthesis and DFT Calculations of Novel Vanillin-Chalcones and Their 3-Aryl-5-(4-(2-(dimethylamino)-ethoxy)-3-methoxyphenyl)-4,5-dihydro-1H-pyrazole-1-carbaldehyde Derivatives As Antifungal Agents

Novel ()-1-(aryl)-3-(4-(2-(dimethylamino)ethoxy)-3-methoxyphenyl) prop-2-en-1-ones were synthesized by a Claisen-Schmidt reaction of 4-(2-(dimethylamino)ethoxy)-3-methoxy-benzaldehyde () with several acetophenone derivatives . Subsequently, cyclocondensation reactions of chalcones with hydrazine hydrate afforded the new racemic 3-aryl-5-(4-(2-(dimethylamino)ethoxy)-3-methoxyphenyl)-4,5-dihydro-1-pyrazole-1-carbaldehydes when the reaction was carried out in formic acid. The antifungal activity of both series of compounds against eight fungal species was determined. In general, chalcone derivatives showed better activities than pyrazolines against all tested fungi. None of the compounds - and - showed activity against the three spp. In contrast, most of the compounds showed moderate to high activities against three dermatophytes (MICs 31.25-62.5 µg/mL), being followed by the most active structures. Interestingly, and possess fungicidal rather than fungistatic activities, with MFC values between 31.25 and 62.5 μg/mL. The comparison of the percentages of inhibition of by the most active compounds , allowed us to know the role played by the different substituents of the chalcones' A-ring. Also the most anti-cryptococcal compounds - and , were tested in a second panel of five clinical strains in order to have an overview of their inhibition capacity not only of standardized but also of clinical strains. DFT calculations showed that the electrophilicity is the main electronic property to explain the differences in antifungal activities for the synthesized chalcones and pyrazolines compounds. Furthermore, a quantitative reactivity analysis showed that electron-withdrawing substituted chalcones presented the higher electrophilic character and hence, the greater antifungal activities among compounds of series .