Synthesis and Biological Evaluation of Theophylline Methyl 1,3,4-Oxadiazole as Anticancer Agents
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ynthesis and Biological Evaluation of Theophylline Methyl 1,3,4-Oxadiazole as Anticancer Agents Vindya K. Gopinathaa, Ujjayinee Rayb, Kempegowda Mantelingua, Sathees C. Raghavanb, and Kanchugarakoppal S. Rangappaa, 1 aDepartment b
of Studies in Chemistry, Manasagangotri, University of Mysore, Mysuru, 570006 India Department of Biochemistry, Indian Institute of Science, Bangalore, 560012 India Received February 8, 2020; revised February 18, 2020; accepted February 24, 2020
Abstract—A series of theophylline methyl 1,3,4-oxadiazole small molecules were obtained via cyclization of theophylline-7-acetohydrazide with different benzoic acids. The compounds (IVa–j) were synthesized and characterized by using conventional methods. The new compounds obtained were evaluated for their cytotoxic effect in three different cancer lines, the activity obtained varies depending upon the structure of a molecule. The compound (IVb) and (IVf) showed promising effect than other compounds of the series. Thus, these two derivatives have the potential for developing as anticancer agents. Keywords: theophylline, cytotoxicity, oxadiazole, cancer DOI: 10.1134/S106816202005009X
INTRODUCTION Cancer is a disease characterized by uncontrolled cell growth, finding an effective treatment for cancer is one of the major global challenge. Development of novel small molecule inhibitors against cancers is an area of active research [1]. The five-member heterocyclic compounds, particularly nitrogen and oxygen heterocycles are commonly used scaffolds. 1,3,4-Oxadiazoles are non-naturally occurring five-membered aromatic heterocycles received special attention in pharmaceutical chemistry due to their diverse medicinal potential [2, 3]. They have demonstrated a broad spectrum of biological activities such as anticancer [4], antituberculosis [5, 6], antifungal [7], antiviral [8], antimicrobial [9], anticonvulsant [10], anti-inflammatory and analgesic [11, 12]. Considering the importance of this scaffold, we focused our research on the synthesis and characterization of novel theophylline methyl 1,3,4-oxadiazole derivatives with different substituents on the phenyl ring. Moderate to excellent yields of theophylline methyl 1,3,4-oxadiazole derivatives were obtained and investigated for their potential as anticancer agents. Of these, two derivatives (IVb) and (IVf) showed good efficacy in killing cancer cells at concentrations as low as 28 μM. RESULTS AND DISCUSSION Chemistry In continuation of our work on the synthesis of bioactive heterocyclic compounds [13–15], the series of 1 Corresponding author: e-mail: [email protected].
novel theophylline methyl 1,3,4-oxadiazole derivatives, which possess different substituents on the phenyl ring were synthesized according to Scheme 1. When theophylline acetic acid was treated with ethanol in the presence of H2SO4 provided the compound (II) in a quantitative yield, the compound (II) in turn reacted with hydrazine hydrate and resulted in a very good yield of theophylline acetohydrazide (III). Lastly, the cyclization p
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