One-pot synthesis of tricyclic dihydropyrimidine derivatives and their biological evaluation

doi:10.1016/j.tet.2014.11.039

Tetrahedron

Volume 71, Issue 2, 14 January 2015, Pages 332-337

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Abstract

A series of tricyclic dihydropyrimidine derivatives were synthesized using a one-pot, three-component Traube–Schwarz reaction in the presence of catalyst Zn(ClO₄)₂·6H₂O. All the purified compounds were evaluated for their in vitro anticancer activity against three different cancer cell lines such as prostate cancer cells (PC3), lung cancer cells (NCI-H1299) and colon cancer cells (HCT116). In vitro DNA-intercalation ability of the compounds was investigated by UV–vis absorption spectroscopy, showing the insertion of compound into the DNA base pairs and a strong interaction with the DNA double helix.

Graphical abstract

Introduction

In recent decades, research interests have been focused on a search for more efficient organic synthesis strategies that can authenticate the rapid generation of complex organic molecules from simple and readily accessible starting materials.¹ The organic medicinal compounds, which are synthesized through steadfast reactions and possesses medicinal activities are generally receive most attention, thus, eventually facilitating the rapid development of new chemical entities (NCEs) available for biological evaluation. Recently, dihydropyrimidines (DHPs) occupy a distinct and unique place in the medicines because of their wide medicinal application scenario including calcium-channel antagonists,² anti-bacterial agents,³ anti-inflammatory agents,⁴ anti-tubercular agents,⁵ anti-malarial agents,⁶ anti-hypertensive agents,⁷ and cytotoxic activity.⁸ The anticancer agent, monastrol, is specifically known to affect mitosis via a mechanism consisting of specific and reversible inhibition of the motility of the motor protein, mitotic kinesin Eg5.⁹

Due to the importance of DHPs, various methods for the synthesis of these compounds have been developed. At the same time, use of multicomponent condensation reactions (MCRs)¹⁰ has been recognized with wide range of applicability in the field of synthetic organic chemistry, which provides easy and rapid admission to large number of libraries of organic compounds.¹¹ Among MCRs, Biginelli (aldehydes or β-keto esters with urea/thiourea)¹² and Traube–Schwarz (α,β-unsaturated carbonyl compounds with amidines, guanidines or heterocyclic amines)¹³ reactions are served as powerful tools in the development of 3,4-dihydropyrimidin-2(1H)-ones and tricyclic 1,6-dihydropyrimidines in the presence of promoters such as base,^13a microwave,^13b thiamine hydrochloride,¹⁴ H₃BO₃,¹⁵ melamine trisulfonate,¹⁶ ionic liquid (1,1,3,3-N,N,N′,N′-tetramethylguanidinium trifluoroacetate or [bmim]BF₄),13(c), 17 N,N′-dichlorobis(2,4,6-trichlorophenyl) urea,¹⁸ α-zirconium sulfophenylphosphonate,¹⁹ H₂NSO₃H²⁰ and tetrabutylammonium hydrogen sulfate (TBAHS).^13d Recently, we have reported the effective and efficient synthesis of pyrimidone derivatives using Biginelli reactions.²¹ Herein, we report the development of a one-pot three-component Traube–Schwarz reaction with β-keto esters, aldehyde, and 2-aminobenzimidazole in the presence of Zn(ClO₄)₂·6H₂O to yield benzo[4,5]imidazo[1,2-a]pyrimidine derivatives (Scheme 1). Furthermore, the biological activities of benzo[4,5]imidazo[1,2-a]pyrimidine derivatives were evaluated under in vitro conditions against three different cancer cell lines including PC3 (prostate cancer cells), NCI-H1299 (lung cancer cells) and HCT116 p53 (−/−) (colon cancer cells).

Section snippets

Results and discussion

When a low-cost, readily available Lewis acid (Zn(ClO₄)₂·6H₂O) was used, a one-pot three-component reaction involving aldehyde 2a, ethyl acetoacetate (3), and 2-aminobenzimidazole (4) in methanol produced a benzo[4,5]imidazo[1,2-a]pyrimidine derivative 1a in a good yield in 5 h (Table 1, entry 1). Various benzo[4,5]imidazo[1,2-a]pyrimidine derivatives 1a–j were prepared with good yields by one-pot three-component condensation reactions in methanol from various aldehydes (2a–j), ethyl

Conclusions

In summary, we synthesized a series of benzo[4,5]imidazo[1,2-a]pyrimidine derivatives using a one-pot, three-component condensation reactions of aldehyde, ethyl acetoacetate, and 2-aminobenzimidazole in the presence of Zn(ClO₄)₂·6H₂O. Relatively, compound 1j is more active against PC3 (IC₅₀=37 μM) and NCI-H1299 (IC₅₀=40 μM) cancer cell lines as compared to other synthesized compounds 1a–i. However, in in vitro DNA-intercalation ability, compound 1j showed the insertion of it into the DNA base

General

Unless otherwise specified, chemicals were purchased from commercial suppliers and used without further purification. TLC was performed on glass sheets pre-coated with silica gel (Kieselgel 60 PF₂₅₄, Merck). Mps were determined with a Fisher-Johns melting point apparatus and were uncorrected. The ¹H and ¹³C NMR spectra were generated using a Bruker 400-Mhz NMR Spectrometer (Bruker, Billerica, MA, USA) operated at 400 MHz for ¹H and 100 MHz for ¹³C nuclei. The spectra were internally referenced

Acknowledgements

This work was supported by the India-Korea Joint Program of Cooperation in Science & Technology (2011-0027710) and the CSIR (Project No: 01(2417)/10/EMR-II) project. T. Aree is thankful for partial financial support from the Ratchadapisek Sompoch Endowment Fund, Chulalongkorn University (CU-56-007-FC) and the National Research University Project of Thailand (WCU-016-FW-57).

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One-pot synthesis of tricyclic dihydropyrimidine derivatives and their biological evaluation

Abstract

Graphical abstract

Introduction

Section snippets

Results and discussion

Conclusions

General

Acknowledgements

Eur. J. Med. Chem.

Tetrahedron Lett.

Med. Chem. Commun.

RSC Adv.

Org. Lett.

J. Org. Chem.

Org. Lett.

Org. Biomol. Chem.

Chem. Soc. Rev.

RSC Adv.

Chem. Commun.

Org. Biomol. Chem.

J. Am. Chem. Soc.

Angew. Chem., Int. Ed.

Chem. Rev.

J. Comb. Chem.

J. Comb. Chem.

Green. Chem.

J. Am. Chem. Soc.

J. Org. Chem.

J. Org. Chem.

J. Am. Chem. Soc.

J. Am. Chem. Soc.

Chem. Ber.

Chem. Ber.

Acc. Chem. Res.

Tetrahedron

Chem. Ber.

Heterocycles

Bioorg. Med. Chem. Lett.

Comb. Chem. High. Throughput Screen

Bioorg. Med. Chem. Lett.

Eur. Pat. Appl. EP

Synth. Commun.

Heterocycles

J. Org. Chem.

Green. Chem.

Der Pharma Chem.

Asian J. Chem.

J. Heterocycl. Chem.

Tetrahedron Lett.

Chin. J. Chem.

Chem. Sci.

J. Chem. Soc., Dalton Trans.

Organometallics

J. Phys. Chem. B

Biomacromolecules

Chem. Soc. Rev.

J. Am. Chem. Soc.

Chem. Rev.

J. Am. Chem. Soc.

J. Am. Chem. Soc.