Abstract
Background: Multicomponent Reactions are being widely used in the synthesis of heterocyclic compounds. Spiroheterocyclic compounds also have various physiological activities such as anti-tumor and antifungal, and they are important in drug discovery. In order to find novel spiroheterocyclic compounds having potential antifungal activity, we found a fast and efficient approach to the synthesis of novel 4'-phenyldispiro[indoline-3,2'-pyrrolidine-3',3''-thiochromane]-2,4''-dione, and the antifungal activity of the novel spiroheterocyclic compounds were tested.
Methods: A variety of different substituents of 3-arylidene-thiochroman-4-one (1mmol) with isatin (1mmol) and different substituted amino acids (sarcosine, proline, leucine, glycine, phenylglycine, alanine, phenylalanine, glutamic acid or arginine, 1mmol) were mixed in [Bmim]Cl (2mL) and then gave microwave irradiation. After the reaction have finished, the reaction system was added in 10mL water, and a lot of white precipitation was obtained and filtrated. The pure objects were recrystallization by mixture of ethanol and water. The antifungal activity was determined by consecutive double dilution method.
Results: Microwave irradiation dramatically decreases reaction time from hours to minutes for this multicomponent reaction, and the yields were also slightly increased. Neutral and acidic amino acids can successfully occur 1, 3-dipolar cycloaddition reactions but basic amino acids such as arginine can not. The solvent—[Bmim]Cl can be recycled to reuse after treatment. Compounds 6c and 6d have good inhibition than fluconazole for the two invasive fungi (C.n. and M.r.) and some compounds show moderate inhibition activities for tested fungi.
Conclusion: A microwave-enhanced, fast, and efficient three-component reaction in [Bmim]Cl for generation of series novel 4'-phenyldispiro[indoline-3,2'-pyrrolidine-3',3''-thiochromane]-2,4''-dione compounds has been developed. Among these compounds, several show better anti-invasive fungal activity than fluconazole and some show moderate inhibiton activity.
Keywords: 1, 3-dipolar cycloaddition, amino acids, antifungal activity, ionic liquid, microwave, thiochroman-4-one.
Graphical Abstract
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