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Many heterocyclic compounds containing thiazole or 1,3,4-thiadiazole ring in their skeletons have been reported to possess various pharmacological activities especially anticancer activities.
Gomha et al Chemistry Central Journal (2017) 11:105 DOI 10.1186/s13065-017-0335-8 RESEARCH ARTICLE Open Access A facile access and evaluation of some novel thiazole and 1,3,4‑thiadiazole derivatives incorporating thiazole moiety as potent anticancer agents Sobhi M. Gomha1* , Mohamad R. Abdelaziz2, Nabila A. Kheder1,3, Hassan M. Abdel‑aziz4, Seham Alterary5 and Yahia N. Mabkhot5* Abstract Background: Many heterocyclic compounds containing thiazole or 1,3,4-thiadiazole ring in their skeletons have been reported to possess various pharmacological activities especially anticancer activities Results: 4-Methyl-2-phenylthiazole-5-carbohydrazide (2) was used as a synthon to prepare 2-(4-methyl-2-phe‑ nylthiazole-5-carbonyl)-N-phenylhydrazinecarbothioamide (3) and 2-(2-(4-methyl-2-phenylthiazole-5-carbonyl) hydrazono)-N′-phenylpropane hydrazonoyl chlorides 5a–c In addition, thioamide was used as starting material for preparation of a new series of thiadiazole derivatives via its reaction with hydrazonoyl chlorides 5a–c in dioxane using triethylamines as catalyst In addition, a series of thiazole derivatives was synthesized by reaction of thioamide with a number of α-halo compounds, namely, 3-chloropentane-2,4-dione (8) or 2-chloro-3-oxo-N-phenyl butanamide (10) phenacyl bromide 12 ethyl chloroacetate (14) in EtOH in the presence of triethylamine The structures assigned for all the new products were elucidated based on both elemental analyses and spectral data and the mechanisms of their formation was also discussed Moreover, the new products was evaluated in vitro by MTT assays for their anticancer activity against cell lines of Hepatocellular carcinoma cell line (HepG-2) The best result observed for compounds 7b (IC50 = 1.61 ± 1.92 (μg/mL)) and 11 (IC50 = 1.98 ± 1.22 (μg/mL)) The structure–activity relationships have been sug‑ gested based on their anticancer results Conclusions: A novel series of new pharmacophores containing thiazole moiety have been synthesized using a facile and convenient methods and evaluated as potent anticancer agents Keywords: Thiazoles, Thiadiazoles, Hydrazonoyl chlorides, Phenacyl bromide, Thioamide, Anticancer activity Introduction Identification of novel structure leads that may be of use in designing new, potent, selective and less toxic anticancer agents remains a major challenge for medicinal chemistry researchers Compounds containing thiazole core have diverse biological activities as antihypertension, *Correspondence: s.m.gomha@gmail.com; yahia@ksu.edu.sa Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt Department of Chemistry, College of Science, King Saud University, P O Box 2455, Riyadh 11451, Saudi Arabia Full list of author information is available at the end of the article antifungal, antimicrobial, anti-inflammatory, antioxidant, antitubercular [1–7], and anticancer [8–12] Also, thiazole ring present in many drugs such as Nizatidine, Abafungin, and Amiphenazole (Fig. 1) Many biological activities were reported for the compounds containing 1,3,4-thiadiazole ring such as antituberculosis, anti-inflammatory, antidepressant and anxiolytic, antioxidant, anticonvulsants [13–17] and anticancer activities [18–20] In addition, many drugs containing 1,3,4-thiadiazole ring are available in the market such as acetazolamide, methazolamide, and megazol (Fig. 2) © 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) 11:105 Page of of 4-methyl-2-phenylthiazole-5-carbohydrazide (2) with phenyl isothiocyanate in EtOH (Scheme 1) The reaction of compound with the appropriate hydrazonoyl chlorides 4a–c [32] in refluxing ethanol yielded the corresponding condensation product (Scheme 2) The IR spectra of the latter products revealed a carbonyl and two NH absorption bands (see “Experimental” part) Their 1HNMR showed two D 2O exchangeable signals of two NH protons in the regions δ 10.03–10.06 and δ 10.57–10.59 ppm Also, their mass spectra confirmed the assigned structure (Scheme 2) Treatment of thioamide derivative with the appropriate hydrazonoyl halides of type 5a–c in refluxing EtOH In continuation of our studies dealing with the utility of hydrazonoyl halides for synthesis of various bioactive bridgehead nitrogen polyheterocycles [21–30], we wish to report herein a new facile synthesis of new heterocycles containing thiazole and 1,3,4-thiadiazole or two thiazole rings in one molecular frame We anticipated that the synthesized compounds would have potent pharmacological activities Results and discussion Chemistry 2-(4-Methyl-2-phenylthiazole-5-carbonyl)-N-phenylhydrazinecarbothioamide (3) [31] was prepared via reaction Fig. 1 Some marketed drugs containing thiazole ring Fig. 2 Examples of drugs containing a 1,3,4-thiadiazole ring O S Ph N O OEt CH3 Scheme 1 Synthesis of thiazoles 2,3 NH2 NH2 H2 O Ph S N H N CH3 O NH2 PhNCS / EtOH S Ph N NH HN S CH3 HN Ph Gomha et al Chemistry Central Journal (2017) 11:105 Page of Scheme 2 Synthesis of thiadiazole derivatives 7a–c containing TEA gave the corresponding thiadiazole derivatives 7a–c (Scheme 2) Their structures were elucidated on the basis of their spectral data and elemental analysis (see “Experimental”) Next, refluxing of compound with 3-chloropentane2,4-dione (8) or 2-chloro-3-oxo-N-phenyl butanamide (10) in EtOH in the presence of triethylamine afforded the thiazole derivatives and 11, respectively (Scheme 3).The structure of compounds and 11 were elucidated based on their elemental analysis and spectral data (see “Experimental”) In a similar manner, thioamide reacted with phenacyl bromide 12 under the same experimental condition to afford one isolable product 13 named as N′-(3,4-diphenylthiazol2(3H)-ylidene)-4-methyl-2-phenyl thiazole-5-carbohydrazide (Scheme 3) The structure of thiazole 13 was established based on its elemental analysis and spectral data (see “Experimental”) Finally, thioamide derivative reacted with ethyl chloroacetate (14) to afford thiazole 15 as showed in Scheme Its IR spectrum showed absorption bands at v 3331 (NH), and 1726, 1648 (2C=O) cm−1 In addition, its 1HNMR spectrum showed singlet signal at δ 4.23 ppm due to the thiazolidinone (CH2) group (Cisplatin) in the same assay to compare the potency of the synthesized compounds The IC50 (the concentration of test compounds required to kill 50% of cell population) was determined (Table 1, Fig. 3) The results of Table 1 revealed that the ascending order of the cytotoxic activity of the newly synthesized compounds towards the human Hepatocellular carcinoma cell line (HepG-2) were as follow: 5c