Design, synthesis and evaluation of anticancer activity of novel 2-thioxoimidazolidin-4-one derivatives bearing pyrazole, triazole and benzoxazole moieties

Elhady et al. Chemistry Central Journal (2018) 12:51 https://doi.org/10.1186/s13065-018-0418-1 Open Access RESEARCH ARTICLE Design, synthesis and evaluation of anticancer activity of novel 2‑thioxoimidazolidin‑4‑one derivatives bearing pyrazole, triazole and benzoxazole moieties Heba A. Elhady1,2*, Refat El‑Sayed1,3 and Hamedah S. Al‑nathali1 Abstract A novel series of substituted 2-thiohydantoin incorporated with benzoimidazole, pyrazole, triazole and/or benzoxa‑ zole moieties has been synthesized using (E)-3-[1-(4-bromophenyl)ethylideneamino]-2-thioxoimidazolidin-4-one 1 as the key starting material. The key material 1 also, reacted with an acetic anhydride, aromatic aldehydes, secondary amines, formaldehyde and triethyl orthoformate to give the corresponding acetyl, chalcone, Mannich bases and eth‑ oxymethylene derivatives, respectively. The structures of the novel compounds were confirmed by spectral data and elemental analysis. The cytotoxic activity of all synthesized compounds was assessed in vitro against human hepato‑ cellular cancer cell line (HePG-2) and breast carcinoma cell line (MCF-7). The bioassay results revealed that compound 14 has the best activity against HePG-2 cell line (IC50 = 2.33 μg/mL), while compound 5 has the best activity against MCF-7 cell line (IC50 = 3.98 μg/mL). Keywords: 2-Thiohydantoin, Benzoimidazole, Benzoxazole, Pyrazole, HEPG-2 cell line and MCF-7 cell line Introduction 2-Thioxoimidazolidin-4-one ring (2-thiohydantoin) has been extensively studied. This five-membered heterocyclic ring is present in a wide range of biologically active compounds. The biological activities have been shown by some of their derivatives are mainly, anticonvulsant [1], antiviral [2], antiproliferative [3], anticancer [4–9], antibacterial, antifungal [10], anxiolytic [11], antidiabetic activity [12] and also used as inhibitor of a fatty acid amide hydrolase [13]. Additionally, 2-thiohydantoins are used in synthetic chemistry as in skin hyperpigmentation applications [14], in the production of antimicrobial polyurethane coatings [15], in textile printing, polymerization catalysis [16] and as a reagent for development of dyes [17]. The observed activities arise from the thiohydantoin heterocycle, but the different substituents attached to it *Correspondence: 1 Department of Chemistry, Faculty of Applied Sciences, Umm Al-Qura University, P. O. Box 13401, Makkah 21955, Saudi Arabia Full list of author information is available at the end of the article are determinant in these properties. Diverse applications of 2-thioxoimidazolidin-4-one in drug field have encouraged the medicinal chemists to synthesize and evaluate a large number of novel molecules. In this research point, we design new compounds based on the biological activity of other heterocycles such as pyrazoles [18, 19], triazoles [20, 21], benzimidazole [22], benzoxazole [23] and Schiff bases [24–26] in the field of cancer and microbial therapy. As an extension of our work on the synthesis of heterocyclic systems and evaluation of their biological activity [27–33], we reported here the synthesis of some novel substituted 2-thiohydantoin and evaluate their cytotoxic activity. (E)-3-[1-(4-bromophenyl) ethylideneamino]-2-thioxoimidazolidin-4-one 1 was prepared and used as the building block for the synthesis of the novel compounds. Results and discussion Chemistry As an extension of our interest on the chemistry of 2-thiohydantoin, we reported here the synthesis of © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Elhady et al. Chemistry Central Journal (2018) 12:51 novel derivatives using (E)-3-[1-(4-bromophenyl) ethylideneamino]-2-thioxoimidazolidin-4-one 1 as the key starting material. Compound 1 was prepared via reaction of (E)-2-[1-(4-bromophenyl)ethylidene]hydrazinecarbothioamide in the presence of sodium acetate [27, 28]. Alkylation of 1 with ethyl chloroacetate in the presence of anhydrous potassium carbonate gave (E)ethyl 2-{3-[1-(4-bromophenyl)ethylideneamino]-4-oxo2-thioxoimidazolidin-1-yl}acetate 2. The structure of 2 was confirmed by spectral data, elemental analysis and chemical transformation. Thus, hydrolysis of the ester 2 with 2 N sodium hydroxide gave (E)-2-{3-[1-(4-bromophenyl)ethylideneamino]-4-oxo-2-thioxoimidazolidin1-yl}acetic acid 3. Hydrazinolysis of 2 with hydrazine hydrate in ethanol gave (E)-2-{3-[1-(4-bromophenyl) ethylideneamino]-4-oxo-2-thioxoimidazolidin-1-yl}acetohydrazide 4, which is a suitable intermediate for the synthesis of the target compounds (Scheme 1). Cyclization of 4 with ethyl acetoacetate, acetylacetone and/or ethyl cyanoacetate in acetic acid gave the corresponding pyrazole derivatives 5, 6 and pyrazole-3,5-dione derivative 7, respectively. Also, reaction of 4 with ethoxymethylenemalononitrile (EMM) in ethanol under reflux gave pyrazole-4-carbonitrile derivative 8 (Scheme 2). To obtain a series of biologically active compounds, compound 4 was treated with phenylisothiocyanate in dimethylformamide to afford 9, which cyclized with 5% alcoholic sodium hydroxide to give 4-phenyl-5-thioxo-1,2,4-triazole derivative 10. Moreover, condensation of 4 with different aromatic aldehydes namely, isonicotinaldehyde and 4-hydroxy-3-methoxybenzaldehyde in ethanol in the presence of piperidine under reflux led to the formation of Schiff bases 11a, b (Scheme 3). To obtain substituted 2-thiohydantoin derivatives incorporated with benzoimidazole and/or benzoxazole moieties, compound 1 was reacted with triethyl orthoformate and/or diethyl oxalate in xylene in the presence of sodium metal under reflux to give 12 and/or 13, respectively. Compound 13 was condensed with o-phenylenediamine and/or 2-aminophenol in acetic acid under fusion to give 14 and/or 15, respectively (Scheme 4). Morover, new series of biologically active 2-thiohydantoin derivatives were prepared by acetylation of 1 with acetic anhydride to give 16 and 17. Condensation of 16 with aldehydes such as vanillin in the presence of piperidine under fusion gave chalcone derivative 18. Also, Mannich base was prepared by reacting 1 with diethylamine and formaldehyde in ethanol to give 19. Finally, hydrazinolysis of 1 with hydrazine hydrate in ethanol gave 20 (Scheme 5). The structures of the synthesized compounds were confirmed by spectral data and elemental analysis. Page 2 of 13 Biological assessment In vitro anticancer screening The anti-tumor activity of all synt (...truncated)