Microwave-assisted synthesis and in-vitro anti-tumor activity of 1,3,4-triaryl-5-N-arylpyrazole-carboxamides

doi:10.1016/j.ejmech.2010.02.026

European Journal of Medicinal Chemistry

Volume 45, Issue 6, June 2010, Pages 2427-2432

https://doi.org/10.1016/j.ejmech.2010.02.026 Get rights and content

Abstract

Regioselective 1,3-dipolar cycloaddition of nitrilimines with 5-arylidene-2-arylimino-4-thiazolidinones and with 2-(4-arylidene)thiazolo[3,2-a]benzimidazol-3(2H)-ones afforded the corresponding 1,3,4-triaryl-5-N-arylpyrazole-carboxamides and pyrazolylbenzimidazoles. All reactions were carried out under conventional thermal heating and/or microwave irradiation. Both the pyrazole-5-carboxamides and pyrazolylbenzimidazoles were examined for their in-vitro anti-tumor activities against two tumor cell lines, Hep-2 and colon CaCo-2. Most of the obtained compounds exhibited significant activity against CaCo-2 and Hep-2 cell lines.

Graphical abstract

Introduction

Pyrazole derivatives have been attracting a great deal of interest due to their various pharmaceutical applications [1]. Numerous synthetic pyrazoles were used as molecular scaffolds in several drugs such as metamizol [2], difenamizole [3], lonazolac [4], phenidone [5], and mepirizole [6].

Additionally, aryl pyrazoles have been reported to possess several biological activities including non-nucleoside HIV-1 reverse transcriptase inhibitory activity [7] and their anti-inflammatory activity such as the N-arylpyrazole derivative; Celecoxib, a well-known COX-2 inhibitor [8]. On the other hand, the pyrazole-1-carboxamide derivative MPCA was reported as antinociceptive agent [9]. Furthermore, the N-arylpyrazole-3-carboxamide; Rimonabant (SR 141716A) acted as CB1 receptor antagonist useful for the treatment of obesity [10] and as effective therapeutic agents for the treatment of hypercholesterolemia and prevention of coronary heart disease [11]. In addition, N-arylpyrazole-5-carboxamides DPC423, Razaxaban and their analogs were reported as highly potent FXa inhibitor agents for treatment of thromboembolic diseases [12].

Moreover, many pyrazole derivatives especially that bearing aryl and/or carboxamide group(s) are important for the creation of promising new anti-tumor agents [13], [14], [15], [16]. For example, some N-arylpyrazoles have remarkable activities as tumor necrosis inhibitors [17]. Recently, pyrazole-3-carboxamide derivatives showed significant activity toward Ehrlich Ascites carcinoma tumor cell [18]. It is also reported that some 3-arylpyrazoles suppressed A549 lung cancer cell growth [19].

The combination of pharmacophores may provide a synergistic effect to improve the activity and reducing the risk of side effects. On the other hand, CDK (cyclin-dependent kinases) inhibitors have been intensively pursued as potential anti-cancer agents [20]. Recently, a series of 3-(benzimidazol-2-yl)pyrazoles showed potent CDK1 inhibitory activities and inhibited in-vitro cellular proliferation in HeLa, HCT116, and A375 human tumor cell lines [21]. These results encouraged us to synthesize functionally pyrazole combined with benzimidazole moiety.

Based on the previous findings and in continuation of our interest in the synthesis of bioactive heterocycles [22], [23], [24], [25], [26], [27], [28], [29], [30] including a promising anti-tumor agents [28], [29], [30], the aim of the present study is to investigate the regioselective synthesis of some arylpyrazoles that are bearing carboxamide function or benzimidazole moiety to evaluate their in-vitro anti-tumor activities against two tumor cell lines Hep-2 and CaCo-2.

Section snippets

Chemistry

5-Arylidene-2-imino-4-thiazolidinones 3a, 3c and 3d have been synthesized by the conventional heating of 2-imino-4-thiazolidinones 2 with the appropriate aldehyde under basic or acidic conditions [31], [32]. Recently, compound 3a was prepared by a one-pot three component solvent-free reaction of N,N-diphenylthiourea 1a with chloroacetic acid and benzaldehyde under microwave irradiation [33]. In this study, we synthesized compounds 3a–d according to the latter reported procedure and their Z

General

Melting points were measured with a Gallenkamp apparatus and are uncorrected. IR spectra were recorded on Shimadzu FT-IR 8101 PC infrared spectrophotometer. NMR spectra were determined in DMSO-d₆ at 300 MHz (¹H NMR) and at 75 MHz (¹³C NMR) on a Varian Mercury VX 300 NMR spectrometer using TMS as an internal standard. Mass spectra were measured on a GCMS-QP1000 EX spectrometer at 70 eV. Elemental analyses were carried out at the Microanalytical center of Cairo University. Microwave experiments were

Acknowledgement

One of the authors (KMD) is deeply indebted to the Alexander-von-Humboldt (AvH) Foundation for donating him a CEM Discover Labmate™ microwave apparatus.

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Original articleMicrowave-assisted synthesis and in-vitro anti-tumor activity of 1,3,4-triaryl-5-N-arylpyrazole-carboxamides

Abstract

Graphical abstract

Introduction

Section snippets

Chemistry

General

Acknowledgement

Eur. J. Med. Chem.

Bioorg. Med. Chem. Lett.

Eur. J. Pharmacol.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem. Lett.

Bioorg. Med. Chem.

Chem. Abstr.

Bioorg. Med. Chem. Lett.

J. Med. Chem.

Eur. J. Med. Chem.

Bioorg. Med. Chem.

Eur. J. Med. Chem.

Arch. Pharm.

Bioorg. Med. Chem.

Org. Lett.

Heteroat. Chem.

NSAIDS and coxibs: clinical use

Chem. Pharm. Bull.

Acta Pharmacol. Toxicol.

Inflammation

Chem. Pharm. Bull.

J. Med. Chem.

Original article
Microwave-assisted synthesis and in-vitro anti-tumor activity of 1,3,4-triaryl-5-N-arylpyrazole-carboxamides