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.

Abstract:The paper presents an application of the asymmetry approach to spirooxindoles via Brevicolline, Cinchonidine or Cinchonine catalyzed one-pot multicomponent synthesis. Brevicolline, in comparison with Cinchonidine or Cinchonine, catalyzes the reaction of isatins, acetylacetone/ethyl 3-oxobutanoate and malononitrile, with the formation of spiro [oxindole-3,4'-4'H-pirane] derivatives in an optically active form in very good to excellent yields.

In this work new methods to obtain complexes from β-cyclodextrin and dehydroabietic acid with chromenol-triazol hybrid with the sizes limits of approximately 0.1-250 μm are reported. Kneading, co-evaporation and co-precipitation for the resolution of racemic 2-tert-butyl-3-(1H-1,2,4-triazol-1-yl)-2H-chromen-2-ol for obtaining micro- and nanoparticles have been optimized. In vitro dissolution studies of the synthesized compounds in phosphate buffer (pH 6.8) showed an improved dissolution rate of chromenol-triazol hybrid in the inclusion complexes compared to the free form. The obtained β-complexes of β-cyclodextrin loaded with dehydroabietitoic acid and chromenol hybrid showed good antibacterial activity with MIC and MBC values ranging from 0.72 to 44.45 μM.

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