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

Abstract

Novel (<i>E</i>)-1-(aryl)-3-(4-(2-(dimethylamino)ethoxy)-3-methoxyphenyl) prop-2-en-1-ones <b>4</b> were synthesized by a Claisen-Schmidt reaction of 4-(2-(dimethylamino)ethoxy)-3-methoxy-benzaldehyde (<b>2</b>) with several acetophenone derivatives <b>3</b>. Subsequently, cyclocondensation reactions of chalcones <b>4</b> with hydrazine hydrate afforded the new racemic 3-aryl-5-(4-(2-(dimethylamino)ethoxy)-3-methoxyphenyl)-4,5-dihydro-1<i>H</i>-pyrazole-1-carbaldehydes <b>5</b> 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 <b>4</b> showed better activities than pyrazolines <b>5</b> against all tested fungi. None of the compounds <b>4a</b>-<b>g</b> and <b>5a</b>-<b>g</b> showed activity against the three <i>Aspergillus</i> spp. In contrast, most of the compounds <b>4</b> showed moderate to high activities against three dermatophytes (MICs 31.25-62.5 µg/mL), being <b>4a</b> followed by <b>4c</b> the most active structures. Interestingly, <b>4a</b> and <b>4c</b> 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 <i>C. neoformans</i> by the most active compounds <b>4</b>, allowed us to know the role played by the different substituents of the chalcones' A-ring. Also the most anti-cryptococcal compounds <b>4a</b>-<b>c</b> and <b>4g</b>, were tested in a second panel of five clinical <i>C. neoformans</i> strains in order to have an overview of their inhibition capacity not only of standardized but also of clinical <i>C. neoformans</i> 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 <b>4</b>.