Chromenol Derivatives as Novel Antifungal Agents: Synthesis, In Silico and In Vitro Evaluation

Abstract

Herein we report the synthesis of some new 1H-1,2,4-triazole functionalized chromenols (3a–3n) via tandem reactions of 1-(alkyl/aryl)-2-(1H-1,2,4-triazole-1-yl) with salicylic aldehydes and the evaluation of their antifungal activity. In silico prediction of biological activity spectra with computer program PASS indicate that the compounds have a high novelty compared to the known antifungal agents. We did not find any close analog among the over 580,000 pharmaceutical agents in the Cortellis Drug Discovery Intelligence database at the similarity cutoff of 70%. The evaluation of antifungal activity in vitro revealed that the highest activity was exhibited by compound 3k, followed by 3n. Their MIC values for different fungi were 22.1–184.2 and 71.3–199.8 µM, respectively. Twelve from fourteen tested compounds were more active than the reference drugs ketoconazole and bifonazole. The most sensitive fungus appeared to be Trichoderma viride, while Aspergillus fumigatus was the most resistant one. It was found that the presence of the 2-(tert-butyl)-2H-chromen-2-ol substituent on the 4th position of the triazole ring is very beneficial for antifungal activity. Molecular docking studies on C. albicans sterol 14α-demethylase (CYP51) and DNA topoisomerase IV were used to predict the mechanism of antifungal activities. According to the docking results, the inhibition of CYP51 is a putative mechanism of antifungal activity of the novel chromenol derivatives. We also showed that most active compounds have a low cytotoxicity, which allows us to consider them promising antifungal agents for the subsequent testing activity in in vivo assays.

Efficient selective targeting of Candida CYP51 by oxadiazole derivatives designed from plant cuminaldehyde

“…The pink areas identify the optimum range of six properties such as lipophilicity (LIPO) with log p −0.7 and +5, flexibility (FLEX); rotatable bonds less than 9, instauration (INSATU); sp3 not less than 0.25, insolubility (INSOLU); log S less than 6, polarity (POLAR); TPSA 20–130 Å, and size; Mwt 150–500 g mol −1 (ref. 44). The four active compounds were within the conformity range and with acceptable parameters for further development.…”

Synthesis of Highly Substituted 1,2,4-Triazole-Based 3-Nitrochromanes through Aza-Michael Addition Reaction under Catalyst- and Base-Free Conditions

“…The final product 12a was confirmed by 1 H NMR, 13 C NMR and HRMS spectral analysis. In the 1 H NMR spectral data, product 12a displayed two sharp singlets in the region  8.22 and 8.02 ppm for the H 15 and H 13 protons present in the 1,2,4-triazole, respectively.…”

“…1 H NMR (400 MHz, CDCl 3 ):  = 8.10 (s, 1 H), 7.99 (s, 1 H), 7.44-7.37 (m, 5 H), 6.96-6.91 (m, 2 H), 6.48 (d, J = 9.2 Hz, 1 H), 6.33-6.30 (m 1 H), 5.63-5.58 (m, 1 H), 5.50 (d, J = 10.0 Hz, 1 H), 4.41-4.08 (q, J = 7.2 Hz, 2 H), 1.43-1.39 (m, 3 H). 13…”

“…All other nine aromatic protons appeared at the respective chemical shift region, 7.45-6.72 ppm. In the 13 C NMR spectrum, a significant peak arose in the region  59.3 ppm for the C 4 carbon which signified the formation of the C-N bond between the chromene ring and 1,2,4-triazole. Similarly, C 3 and C 2 carbon peaks were attributed to the region 88.2 and 78.9 ppm, respectively.…”

“…4-amino-3hydroxy-2H-chromanes, 5 have attracted much attention of the scientific community because of their wide range of therapeutic functions including modulation of calcium and potassium channel opening for the control of blood pressure, 6 IK 5 channel blockage 7,8 and multi-ion channel blockage 9,10 (Figure 1). Besides that, these frameworks have exhibited antitumor, 11 antibacterial, 12 antifungal, 13 anticancer 14 and antioxidant effects, 15 and wide applications in photochromic lenses and as sensitizers in solar cells. 16 Considering the fascinating biological roles in pharmaceuticals and tremendous applications in the industrial field, 4-amino-3-nitro-2H-chromane derivatives have been recognized as an important scaffold to synthesize bioactive substrates.…”