Synthesis of Thiazoles and 1,3,4-Thiadiazoles Bearing Spectral Studies, Biological Evaluation and Structure Activity relationship
Abstract
A novel series of thiazole based-1,3,4-thiadiazoles were designed and prepared via the reaction of the 2-(4- methyl-2-phenylthiazole-5-carbonyl)-N-phenylhydrazinecarbothioamide with the appropriate hydrazonoyl chlorides. The structures of the newly synthesized compounds were established based on spectroscopic evidences and their alternative syntheses. Thirteen new 1,3,4-thiadiazoles have been evaluated for their anticancer activity against liver carcinoma cell line (HepG2). Also, their structure activity relationship (SAR) was studied. The 1,3,4-thiadiazoles 12d, 12c, 6g,18b, 6c, and 6f(IC50 = 0.82, 0.91, 1.06, 1.25, 1.29 and 1.88 µM, respectively) have promising antitumor activity against liver carcinoma cell line (HepG2)
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Introduction
Cancer is a devastating and 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, is often limited by the severity of the side effects and the development of tumor cell resistance against 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 ranked in the top ten human cancers worldwide and among the top five of cancers in terms of mortality [2,3]. A literature survey revealed that a great deal of interest has been focused on the synthesis of functionalized thiazole derivatives due to their synthetic and biological potentialities as antihypertention [4], antifungal [5], antimicrobial [6,7], anti-inflammatory [8], antioxidant [9], antitubercular [10], and anticancer agents [11-14]. 1,3,4- Thiadiazole derivatives have attracted considerable interest due to their wide spectra of biological activities such as antibacterial, antifungal, antituberculosis, antihepatitis B viral, antileishmanial, anti-inflammatory, analgesic, CNS depressant, antioxidant, antidiabetic, molluscicidal, antihypertensive, diuretic, analgesic, antimicrobial, antitubercular, anticonvulsant and anticancer activities [15–24]. These important biological activities encouraged several research groups to find out different methods for synthesis of new thiadiazoles using different synthones, such as thiosemicarbazides, thiocarbazides, dithiocarbazates, thioacylhydrazines, acylhydrazines, and bithioureas [25]. In the light of the above-mentiond findings and in continuation of our efforts to synthesize new bioactive compounds [26-34], this work aims to synthesis a new series of thiazoles and 1,3,4-thiadiazoles bearing thiazole moiety and to study their anticancer activity against Liver carcinoma cell line (HepG2).
Conclusion
In this context, a series of novel thiazoles and 1,3,4-thiadiazoles bearing thiazole were synthesized. The structure of the newly prepared compounds was established based on both elemental analysis and spectroscopic data and by an alternative method wherever possible. Moreover, the mechanisms of formation of the title compounds were discussed. Some of the synthesized compounds were evaluated for their anti-cancer activity against the human hepatocellular carcinoma (HepG2) cell line. The results showed that the thiadiazole derivatives 12d, 12c, 6g,18b, 6c and 6f having IC50 values 0.82, 0.91, 1.06, 1.25, 1.29 and 1.88 µM, respectively, were found to be the highly active compounds of the prepared series. Based on the experimental results of the antitumor activity, the structure-activity relationships were discussed.