A facile synthesis and anticancer activity of some novel thiazoles carrying 1,3,4-thiadiazole moiety

Gomha et al. Chemistry Central Journal (2017) 11:25 DOI 10.1186/s13065-017-0255-7 Open Access RESEARCH ARTICLE A facile synthesis and anticancer activity of some novel thiazoles carrying 1,3,4‑thiadiazole moiety Sobhi M. Gomha1*, Nabila A. Kheder1,2, Mohamad R. Abdelaziz3, Yahia N. Mabkhot4 and Ahmad M. Alhajoj5 Abstract Background: Thiazoles and 1,3,4-thiadiazoles have been reported to possess various pharmacological activities. Results: A novel series of thiazoles carrying 1,3,4-thiadiazole core were designed and prepared via the reaction of the 2-(4-methyl-2-phenylthiazole-5-carbonyl)-N-phenylhydrazinecarbo-thioamide with the appropriate hydrazonoyl chlorides. The structures of the newly synthesized compounds were confirmed based on elemental and spectral analysis as well as their alternative syntheses. The cytotoxic potency of the newly synthesized thiadiazoles was evaluated by their growth inhibitory potency in liver HepG2 cancer cell line. Also, the structure activity relationship was studied. Conclusions: All the newly synthesized compounds were evaluated for their anticancer activity against liver carcinoma cell line (HepG2) using MTT assay. The results revealed that the compounds 12d, 12c, 6g, 18b, 6c, and 6f (IC50 = 0.82, 0.91, 1.06, 1.25, 1.29 and 1.88 µM, respectively) had good antitumor activity against liver carcinoma cell line (HepG2) when compared with the standard drug Doxorubicin (IC50 = 0.72 µM). Keywords: Thiazoles, 1,3,4-Thiadiazoles, Hydrazonoyl chlorides, Anticancer activity, Structure activity relationship Background Cancer is the most common life-threatening disease representing a major health problem for many decades. The clinical application of chemotherapy still considered as a major compartment in treating cancer, however, it is often limited by the severity of the side effects and the development of tumor cell resistance to these cytotoxic agents. Clinical administration of high doses of anticancer drugs to overcome resistance leads to severe toxicities [1]. Therefore, the development of novel effective anticancer drugs and strategies is eagerly being pursued. Also, it was reported that liver cancer is one from the top ten human cancers worldwide and among the top five of cancers in terms of mortality [2, 3]. A literature survey revealed that thiazole derivatives had many biological activities as antihypertension [4], antifungal [5], antimicrobial [6, 7], anti-inflammatory [8], antioxidant [9], antitubercular [10], and anticancer [11–14]. Moreover, 1,3,4-thiadiazole derivatives had many biological activities such as antibacterial, antifungal, antituberculosis, anti-hepatitis B viral, antileishmanial, anti-inflammatory, analgesic, CNS depressant, antioxidant, antidiabetic, molluscicidal, antihypertensive, diuretic, analgesic, antimicrobial, antitubercular, anticonvulsant and anticancer [15–24]. These important biological activities encouraged several researchers to find out different methods for synthesis of new thiadiazoles using different synthons, such as thiosemicarbazides, thiocarbazides, dithiocarbazates, thioacylhydrazines, acyl hydrazines, and bithioureas [25]. As a part of our research projects to synthesize new bioactive compounds [26–34], we intended in this research to synthesize a new series of thiazoles carrying 1,3,4-thiadiazole moiety in order to study their anticancer activity against liver carcinoma cell line (HepG2). *Correspondence: 1 Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt Full list of author information is available at the end of the article © The Author(s) 2017. 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. Gomha et al. Chemistry Central Journal (2017) 11:25 Results and discussion Chemistry 2-(4-Methyl-2-phenylthiazole-5-carbonyl)-N-phenylhydrazinecarbothioamide (3) [35] was prepared via reaction of 4-methyl-2-phenylthiazole-5-carbohydrazide (2) with phenyl isothiocyanate in ethanol (EtOH) as depicted in Scheme 1. The presence of the thioamide hydrazine moiety as a side chain in compound 3 prompted us to utilize it for constructing 1,3,4-thiadiazole ring through its reaction with many hydrazonoyl chlorides. Thus, treatment of compound 3 with the appropriate hydrazonoyl chlorides 4a–g [36] led to the formation of the respective 1,3,4-thiadiazoles 6a–g, rather than thiadiazines 7a–g or 1,3-thiazoles 8a–g (Scheme 1). The elemental analysis together with the spectral data are consistent with the proposed structure 6. The IR spectra of products 6 showed in each case the presence of two absorption bands around 1700, 1650 cm−1 for the two carbonyl groups, in addition to Scheme 1 Synthesis of thiadiazoles 6a–g Page 2 of 9 another band near v 3350 cm−1 for the NH function. The HNMR spectra of 6 showed in each case the presence of broad singlet signals assigned for the NH proton near δ 11.19 ppm, in addition to the expected signals for the two CH3, and the aryl protons. Also, the mass spectrum of each of products 6 revealed the presence of a molecular ion peak (see materials and methods). A suggested mechanism for the synthesis of 1,3,4-thiadiazole derivatives 6 is outlined in Scheme 1. To explain the synthesis of 1,3,4-thiadiazole 6a–g, we assumed that the reaction started with S-alkylation to afford the non-isolable intermediate 5 followed by intramolecular cyclization and elimination of aniline molecule to give the respective thiadiazole derivatives 6a–g (Scheme 1). The structure of 6 was proved chemically via an alternative method (Scheme 1). Thus, the reaction of 5-(4-methyl-2-phenylthiazol-5-yl)-1,3,4-oxadiazole2(3H)-thione (9) [37] with 4a in ethanol in the presence of triethylamine under reflux led to the formation of a 1 Gomha et al. Chemistry Central Journal (2017) 11:25 product which is identical in all respects (mp, mixed mp, and IR) with compound 6a. Next, to test of the biological activities of a vast array of these compounds, we reacted compound 3 with the appropriate hydrazonoyl chlorides 10a–d [38], under the same experimental conditions, which gave the corresponding 1,3,4-thiadiazole derivatives 12a–d (Scheme 2). The IR and 1H-NMR spectra of 12a taken as an example of the prepared series revealed the presence of the ester group and the disappearance of the hydrazone-NH function. Also, the mass spectrum of the reaction products 12a–d showed, in each case, a peak corresponding to their molecular ions. The structure assigned for produc (...truncated)