Green Synthesis of Spiro Compounds with Potential Anticancer Activity through Knoevenagel/Michael/Cyclization Multicomponent Domino Reactions Organocatalyzed by Ionic Liquid and Microwave-Assisted

Abstract

In this work a microwave-assisted Knoevenagel/Michael/cyclization multicomponent domino methodology, using ethanol as solvent and the ionic liquid 1-methylimidazolium chloride as catalyst was developed for the synthesis of spiro compounds. The reaction conditions considered ideal were determined from a methodological study varying solvent, catalyst, amount of catalyst, temperature, and heating mode. Finally, the generality of the methodology was evaluated by exploring the scope of the reaction, varying the starting materials (isatin, malononitrile, and barbituric acid). Overall, the twelve spiro compounds were synthesized in good yields (43–98%) and the X-ray structure of compound 1b was obtained. In addition, the in vitro antiproliferative activities of the spirocycles against four types of human cancer cell lines including HCT116 (human colon carcinoma), PC3 (prostate carcinoma), HL60 (promyelocytic leukemia), and SNB19 (astrocytoma) were screened by MTT-based assay. It is noteworthy that spiro compound 1c inhibited the four cell lines tested with the lowest IC50 values: 52.81 µM for HCT116, 74.40 µM for PC3, 101 µM for SNB19, and 49.72 µM for HL60.

Recent advances in microwave-assisted multicomponent synthesis of spiro heterocycles

“…Various starting materials (isatin, malononitrile, dimedone, and barbituric acid) were used in the microwave-assisted MCR at 80 °C. 203 …”

“…Various starting materials (isatin, malononitrile, dimedone, and barbituric acid) were used in the microwave-assisted MCR at 80 °C. 203 The single-crystal X-ray structures of 7 0 -amino-5-bromo-2,2 0 ,4 0 -trioxo-1 0 ,2 0 ,3 0 ,4 0 -tetrahydrospiro[indoline-3,5 0 -pyrano[2,3d]pyrimidine]-6 0 -carbonitrile and 7,2-amino-5-bromo-2,2 0 ,4 0 -trioxo-1 0 ,2 0 ,3 0 ,4 0 were determined. In addition, the antiproliferative activities of the spiro heterocycles against human colon carcinoma HCT116, prostate carcinoma PC3, promyelocytic leukemia HL60, and astrocytoma SNB19 cell lines were screened using an MTT-based assay.…”

Recent developments on microwave-assisted organic synthesis of nitrogen- and oxygen-containing preferred heterocyclic scaffolds

“…The reaction carried out between thiocarbohydrazide 235 and isatin derivatives 236a-b in ethanol under microwave irradiation afforded good isolated yields (73-91%) of 237a-b which, on further treatment with aryl aldehydes 238a-h, afforded the Greco and co-workers introduced a microwave-assisted Knoevenagel/Michael/cyclization multicomponent domino approach for producing isatin-based spiro compounds 241a-h, with ethanol serving as the solvent and 1-methylimidazolium chloride as a catalyst. 163 They undertook a thorough methodological investigation involving alterations to solvent, catalyst, amount of catalyst, temperature, and heating mode to identify optimal reaction conditions. Additionally, the scope of the reaction was examined by varying the starting materials (isatin, malononitrile, and barbituric acid), which resulted in the synthesis of 12 spiro compounds with good yields ranging from 43% to 98% (Scheme 85).…”

The Synthesis of Nitrogen- and Oxygen-Containing Heterocyclic Scaffolds Assisted by Ionic Liquids: A 2022 Literature Survey

“…The synthesized compounds have been also investigated for their anticancer activity against numerous cell lines. 103 Scheme 42 A green synthetic strategy for the synthesis of spiro compounds using imidazolium-based ILs Al Ghatta and Hallett have synthesized 2,5-furandicarboxylic acid (133) from glucose or fructose (131) by using [bmim][Cl], which helps in the in situ oxidation of hydroxymethyl furfural 132 using MnO 2 and oxygen (10 bar) via an easier separation method at a lower concentration by an efficient antisolvent methodology (Scheme 43). 104 Overall, the synthetic method was very fruitful with an isolated yield of 51-98% of 133, whilst the IL could be recycled effectively.…”

“…The synthesized compounds have been also investigated for their anti-cancer activity against numerous cell lines. 102 This article is protected by copyright. All rights reserved.…”