Elsevier

FlatChem

Volume 29, September 2021, 100279
FlatChem

Brønsted acid functionalized carbon catalyst for synthesis of biologically active coumarin-substituted bis(indolyl)methanes

https://doi.org/10.1016/j.flatc.2021.100279Get rights and content

Highlights

  • A novel carbon based catalyst bearing sulfonic acidic sites prepared by an ionic liquid assisted doping process.

  • Catalytic efficiency assessed in synthesis of biologically active coumarin-substituted bis(indolyl)methanes.

  • Anti cancer activity evaluated by computational studies and cytotoxicity tests.

  • Metal free approach with an advantage of low toxicity for synthesis of biologically active compounds.

Abstract

A novel carbon based catalyst has been prepared for the synthesis of potential anticancer compounds with low toxicity by an ionic liquid assisted doping process. Sulphonic acid functionalized nitrogen sulphur co-doped graphite (SO3H-NSG) based catalyst was prepared by coating the carbon surface with the sulphonic acid bearing ionic liquid and annealing the resulting compound. X-ray photoelectron spectroscopy revealed the successful doping of nitrogen and sulphur atoms in the graphitic matrix and the functionalization of the surface with sulphonic acidic sites. The catalyst was used for the synthesis of biologically active coumarin-substituted bis(indolyl)methanes that were finally evaluated for their toxicity and anticancer properties. The cytotoxicity results unveiled that the iodo derivative of the coumarin-substituted bis(indolyl)methanes showed best anti-cancer activity among the four derivatives synthesized.

Introduction

Indole nucleus is a biologically celebrated pharmacophore in medicinal compounds, making it a multifaceted heterocyclic with gamut of biological applications [1]. Among the functionalized indoles, bis(indolyl)methanes (BIMs) exemplify privileged molecules holding a broad spectrum of pharmacological activities [2]. BIMs are known to serve as bio activators, such as antibacterial agents [3], anti-inflammatory agents [4], active regulators in colon cancer [5], and inhibitors against growth of human prostate cancer cells [6]. Considering that these organic molecules cover an extensive range of medicinal uses; various synthetic strategies have been investigated for their development. A couple of common approaches comprise are the Friedel-Crafts acylation of indoles with carbonyl compounds [7], dehydrative nucleophilic substitution of indolyl alcohols [8], cross-dehydrogenative coupling via methanol activation [9], and Friedel-Crafts alkylation of substituted indoles [10]. The structural accessibility of BIMs has led to exploration of diverse synthetic methods; nonetheless, these are somehow limited to tertiary substituted derivatives. The protocols for tetrasubstituted are relatively scarce [10]. Thus, the first objective of our work was preparation of tetrasubstituted BIMs, with coumarin as the structural unit. The advancement in synthesis of coumarin skeleton and its derivatization has attracted many organic and medicinal chemists, due to its manifold industrial [11], [12] and biological [13], [14], [15] utilities. Such molecules holds great potential in the discovery of new drugs and utilizing a metal free heterogeneous catalyst for the synthesis can help to accelerate their applicability especially during the clinical trials. If the drug is synthesized via a metal free pathway, it can avoid the lengthy purification procedures adopted to achieve the desirable specification limits for residual metals in the active pharmaceutical ingredients or drugs [16].

Hybridization of drugs to form a single molecule is emerging as an efficient tool in production of new drugs, fulfilling the purpose to diversify, intensify, or utilize the drug in two-fold action [17]. Therefore, the combination of these two set of molecules (BIMs and coumarin) with fascinating bioactivities would provide a better scope for construction of beneficial compounds [18], [19]. Previously, Yuan et al [20] and Wang et al [21] synthesized coumarin- substituted bis(indolyl)methanes in a metal-Lewis acidic catalyzed reaction, carried out in a range of organic solvents (Fig. 1). Since, transition metal catalysis has several disadvantages, like toxicity, cost, air and moisture sensitivity, etc.; we aspired to conduct the study in a metal-free heterogeneous acidic carbon catalyst environment. Also, with intention of developing a greener synthetic strategy, the use of hazardous organic solvents was avoided and the reaction was performed in water.

Functionalized acidic carbon materials render unique textural and surface properties (enhanced hydrophilicity) that substantiate their applicability in acid catalyzed reactions [22]. Most of the acid catalyzed reactions are employed in water; therefore an ideal material would be the one that also maintains high acidity in water [23], [24]. In the class of solid protonic acids, SO3H-grafted carbon materials or “sulfonated carbons” are characterized as encouraging acid catalysts with high Brønsted acidity (H0 ≤  − 11) [25]. Such catalysts offer a unique way to heterogenise the homogenous catalysts used in the similar processes. Shifting from homogenous to heterogeneous catalysts always is useful to attain minimum waste generation and enhancing the reusability of the catalysts. Therefore, designing a metal free heterogeneous catalyst for biologically active compounds is highly beneficial for increasing the “greenness” of the process and speeding their clinical trials [26]. Thus, the design of the metal-free heterogeneous Brønsted acidic catalyst (SO3H-NSG) was executed by using ionic liquid,methyl 3-(4-sulfobutyl)imidazolium chlorideas the sulfonating agent and commercial graphite as the carbon precursor. Another interesting feature of SO3H-NSG is its role in controlling the regioselectivity of the reaction. As 3-acetylcoumarin has number of reactive sites, regiocontrol is a crucial task during the transformation. Here in the present work, we report an efficient carbon catalyst for the synthesis of diverse coumarin-substituted bis(indolyl)methanes (including two novel compounds) via 1,2 addition/substitution reaction (Fig. 1) through eco-friendly pathway. Also, the biological activity of the synthesized derivatives was determined against human normal kidney epithelial (NKE) cells, breast carcinoma (MCF-7) and osteosarcoma (HOS) cells by standard Amber Blue Reduction assay.

Section snippets

Materials and methods

Chemicals were purchased from Sigma Aldrich and LOBA with 99% purity. The derivatives of indole (Fig. 5) were procured from Sigma Aldrich while the precursors for ionic liquid (1-methyl imidazole and 1,4-butane sultone) synthesis were purchased from LOBA. FTIR spectra were recorded using Carry 600 spectrometer (Agilent Technologies). The surface morphology of the material was observed employing Technai G2s-Twinhigh resolution transmission electron microscope (FEI). The surface elemental

Catalyst characterization

The structural architecture of the SO3H-NSG was analysed by High Resolution Transmission Electron Microscopy (HR-TEM) (Fig. 2). It is obvious from the Fig. 2b that the material has distinct layered structure (marked by arrows), which coincides with the typical structure of graphite. Likewise in Fig. 2c, graphitic sheets are noticeable, along with some dark patches on the surface. The patches, most probably are formed as a result of heteroatom doping on the surface. These patches may also result

Conclusion

In this report, a novel acidic carbon based catalyst grafted with SO3H groups has been prepared for the synthesis of potential anticancer compounds with low toxicity, by an ionic liquid assisted doping process. The coumarin-substituted bis(indolyl)methanes, hybrids of biologically active compounds, indole and coumarin, were synthesized in the aqueous media. Among the four synthesized products, two novel derivatives were prepared and hence their anticancer activity and toxicity were determined

CRediT authorship contribution statement

NG is involved in all stages of work starting from conceputalization, supervison to compilation. JD and PM have carried out biological activity of the synthesized compunds. VS has prepared the catalyst and performed the experimental work. AD has written the manuscript, analyzed the data and actively participated in internal revision.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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