Synthesis of New Drug-Like Piperazine-2,5-diones by the Ugi/Tandem Process Catalyzed by TMSOTf and Their Molecular Docki
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ynthesis of New Drug-Like Piperazine-2,5-diones by the Ugi/Tandem Process Catalyzed by TMSOTf and Their Molecular Docking A. M. Jassema,*, A. M. Dhumada, and F. A. K. Almashala a
Department of Chemistry, College of Education for Pure Sciences, Basrah University, Basrah, 61004 Iraq *e-mail: [email protected] Received June 26, 2020; revised July 30, 2020; accepted November 10, 2020
Abstract—A new four-components post-Ugi transformation process has been studied. It provides an efficient access to biologically active piperazine-2,5-dione derivatives in high yield. The framework of piperazine-2,5-dione derivatives has been constructed by a tandem-decarboxylation of α-keto carboxylic acids promoted by a green catalyst trimethylsilyl trifluoromethane sulfonate (TMSOTf). Molecular docking study of piperazine-2,5-dione derivatives has been performed with various anticancer target proteins: human androgen receptor (AR) (PDB ID: 1E3G), human steroidogenic cytochrome P450 17A1 (PDB ID: 4NKV), epidermal growth factor receptor 2 HER2 (PDB ID: 3PP0), and estrogen receptor alpha (ERα) (PDB ID: 1A52), and has indicated their possible efficient interactions via hydrogen bonds. Keywords: post-Ugi transformation, TMSOTf, molecular docking study, piperazine-2,5-dione derivatives
DOI: 10.1134/S1070363220110262 INTRODUCTION Piperazine-2,5-dione structures have been incorporated in various molecules of biologically active compounds and drugs, including a vascular disrupting agent (plinabulin 1) [1], anti-microtubule agent (phenylahistin
2) [2], potent antitumor products tryprostatin B 3 [3], and alkaloid 4 (Aspergillus oryzae) [4] (Fig. 1). A number of synthetic methods for piperazine2,5-diones has been reported, nevertheless, there is a considerable demand in new approaches to their synthesis
Fig. 1. Some pharmacologically active piperazine-2,5-dione derivatives.
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JASSEM et al. Scheme 1. Synthetic approach to piperazine-2,5-dione derivatives 12 and 13.
[5]. Among available methods for piperazine-2,5-dione moiety are multicomponent reactions (MCRs). The Ugi and its post-transformation reactions are considered as an efficient synthetic tool which facilitates the approach to novel pharmacologically active compounds, including drug-like heterocycles [6–8]. Some examples of post-Ugi transformation reactions include Ugi/Heck [9], Ugi/Knoevenagel [10], Ugi/Pictet– Spengler [1], Ugi/Diels–Alder [2], Ugi/aza–Wittig [13], and Ugi/aldol [14]. A wide range of catalysts has been
tested in post-Ugi transformation reactions, such as TFA [15], BF3·2CH3COOH [16], PTSA [17], and Ugi/metalcatalyzed processes (Pd [18], Ag [19], and In(III) [20]). The current study is a part of our ongoing attempts in development of new methods of synthesis of biology related piperazine derivatives. For the first time here is demonstrated the application of Ugi/TMSOTf based on high electrophilic character of the carbonyl carbon of the ketoimide group. The process led to piperazine-2,5-dione derivatives 12 and 13 (Scheme 1). Molecular docking
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