Synthesis of New Thiazole-Pyridine Hybrids and Their Anticancer Activity
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ynthesis of New Thiazole-Pyridine Hybrids and Their Anticancer Activity A. A. Bayazeeda,* and R. B. Alnomanb a Chemistry
Department, College of Applied Sciences, Umm Al-Qura University, Makkah, 21955 Saudi Arabia Department, Faculty of Science, Taibah University, Yanbu Branch, Yanbu, 46423 Saudi Arabia *e-mail: [email protected]
b Chemistry
Received August 1, 2020; revised September 10, 2020; accepted September 28, 2020
Abstract—A series of new thiazole incorporated pyridine derivatives containing the phenoxyacetamide moiety as a linking bridge has been synthesized. The synthetic strategy involves condensation of 2-(4-formylphenoxy)-N(thiazol-2-yl)acetamide with cyanoacetic hydrazide followed by heterocyclization with acetylacetone, treatment of the produced acrylamides with malononitrile and substituted acetophenones, then heating the generated chalcones with mononitrile in acetic acid and ammonium acetate. In vitro anticancer activity of the newly synthesized thiazolepyridine hybrids has been evaluated against prostate (PC3), liver (HepG2), laryngeal (Hep-2), and breast (MCF-7) cancer cell lines. One of thiazole-pyridine compounds 8c demonstrates higher activity (IC50 5.71 μM) against breast cancer than 5-fluorouracil used as a reference (IC50 6.14 μM). Molecular docking procedure has provided valuable information on the binding sites of the synthesized compounds with rho-associated protein kinase 1 (ROCK-1). Keywords: thiazole, 2-cyanoacetanilide, malononitrile, pyridone, cytotoxicity, molecular docking
DOI: 10.1134/S1070363220100254 INTRODUCTION Thiazole and its derivatives are used in medicine for treatment of hypertension [1], inflammation [2], schizophrenia [3], bacterial infections and HIV infections [4, 5]. Pyridine derivatives play an inmportant role in design of many pharmaceutically active compounds [6], and have been reported to possess various biological properties including anticancer activity [7–9]. In this respect, we have developed and synthesized a number of novel structural hybrids incorporating the thiazole and pyridine ring systems and evaluated their anticancer activity. Such combination of the structural blocks could help in understanding the influence of such hybridization on biological activity of the new compounds. Evaluation of anticancer properties of the constructed thiazole-pyridine hybrids was carried out against four cell lines, prostate cancer (PC3), liver carcinoma (HepG2), laryngeal carcinoma (Hep-2), and breast cancer (MCF-7). RESULTS AND DISCUSSION The key precursor 2-(4-formylphenoxy)-N-(thiazol2-yl)acetamide (2) was synthesized by reacting 2-chloro-N-(thiazol-2-yl)acetamide (1) [10] with 4-hydroxybenzaldehyde in DMSO containing potassium carbonate via nucleophilic substitution of chlorine
atom of 2-chloro-N-(thiazol-2-yl)acetamide (1) by oxygen nucleophilic center of hydroxybenzaldehyde (Scheme 1). The proposed structure of 2-(4-formylphenoxy)-N-(thiazol-2-yl)acetamide (2) was supported by spectral data and elemental analysis. Reactivity of the formyl function in prec
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