Antibacterial properties of 5-substituted derivatives of rhodanine-3-carboxyalkyl acids

Medicinal Chemistry Research, Mar 2017

A series of rhodanine 3-carboxyalkanoic acid derivatives possessing 4′-(N,N-dialkyl-amino or diphenylamino)-benzylidene moiety as a substituent at the C-5 position were synthesised and their antibacterial activity was screened. All the rhodanine derivatives showed bacteriostatic or bactericidal activity to the reference gram-positive bacterial strains, but lack of activity to the reference Gram-negative bacterial strains and yeast strains was observed.

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Antibacterial properties of 5-substituted derivatives of rhodanine-3-carboxyalkyl acids

Med Chem Res Antibacterial properties of 5-substituted derivatives of rhodanine- 3-carboxyalkyl acids Waldemar Tejchman 0 1 2 3 4 ● Izabela Korona-Glowniak 0 1 2 3 4 ● Anna Malm 0 1 2 3 4 ● Marek Zylewski 0 1 2 3 4 ● Piotr Suder 0 1 2 3 4 0 Jagiellonian Center of Innovation, NMR Laboratory , Bobrzyńskiego 14, Kraków 30-348 , Poland 1 Department of Pharmaceutical Microbiology, Medical University of Lublin , Chodzki 1, Lublin 20-093 , Poland 2 Departament of Chemistry, Institute of Biology, Pedagogical University of Cracow , Podchorazych 2, Kraków 30-084 , Poland 3 Academic Centre for Materials and Nanotechnology, AGH University of Science and Technology , Mickiewicza 30, Kraków 30-059 , Poland 4 Department of Biochemistry and Neurobiology, AGH University of Science and Technology , Mickiewicza 30, Kraków 30-059 , Poland A series of rhodanine 3-carboxyalkanoic acid derivatives possessing 4′-(N,N-dialkyl-amino or diphenylamino)-benzylidene moiety as a substituent at the C-5 position were synthesised and their antibacterial activity was screened. All the rhodanine derivatives showed bacteriostatic or bactericidal activity to the reference gram-positive bacterial strains, but lack of activity to the reference Gramnegative bacterial strains and yeast strains was observed. Rhodanine ● Thiazolidine-4-one ● Rhodanine-3- acetic acid ● Antibacterial activity Introduction The 2-thiazolidine-4-one derivatives traditionally named rhodanine have been known for over 100 years, and due to their fascinating properties they are still examined (Lesyk and Zimenkovsky 2004) . These compounds have a broad spectrum of biological effects (Jain et al. 2012). Rhodanine derivatives show antimalarial (Kumar et al. 2007) , antitubercular (Alegaon et al. 2012) , cytotoxic (Chandrappa et al. 2009) , antitumor (Rao et al. 2011; Lesyk et al. 2011) , antiviral (Kaminskyy 2015), and antibacterial activity (Bhatti et al. 2013; Kavitha et al. 2006; Song et al. 2014) . The research to obtain new antibacterial compounds is vitally important. Recently, due to excessive and improper use of antibiotics, there has been an increasing rate of antibiotic resistance in the bacterial strains (Woodford 2003) , thus new groups of compounds which may be useful as antibacterial agents have been examined. A few reports has been published regarding the rhodanine derivatives with a carboxyalkyl acid moiety at the N-3 position (Xu et al. 2012) . Biological activity of hybrid compounds possessing chalcone and rhodanine-3-acetic acid has been also studied (Chen et al. 2010) . Such hybrids demonstrated synergistic effect. Antibacterial activity of rhodanine derivatives and their oxygen analogues derived from 2,4-thiazolidinedione was also compared (Zvarec et al. 2012) . However, the results of present study suggested that rhodanine derivatives showed greater antibacterial activity than their analogues from the 2,4-thiazolidinedione group having at the C-2 position exocyclic oxygen atom. It was shown that the activity of the rhodanine derivative correlates with the size of the substituent at the C-5 position (Pardasani et al. 2001) . The research conducted by Miao et al. (2013) and Patel et al. (2013) indicated that antibacterial activity of the acid derivatives occurred when a major hydrophobic group was introduced to the arylidene substituent at the C-5 position. The best results were achieved when an aryl group additionally with an electron-withdrawing group was introduced. The rhodanine derivatives possessing a 4-(N,Ndimethylamino)-benzylidene substituent at the C-5 position were also examined. These compounds acted as β-lactamase inhibitors (Grant et al. 2000) . Taking into account the data presented by other authors, we decided to synthesise a series of derivatives having carboxyalkyl (acetic, propionic, butyric) acid fragment at N-3 position and benzylidene para-substituent with dimethyloamino, diethylamino, dibuthyloamino or diphenylamino group at C-5 position. Chemistry Our initial research proved that the antibacterial activity of the rhodanine derivatives which have carboxyalkyl fragment at N-3 position was more effective than the compounds with a substituent containing an amino group at C-5 position. We synthesised a series of rhodanine derivatives with a carboxyalkyl acid radical at N-3 position (acetic, propionic, butyric, caproic). The synthesis of the 3carboxyalkylrhodanine acids (Scheme 1) was conducted according to the modified procedure proposed by Körner (1908) at the beginning of the 20th century. The synthesised compounds underwent Knoevenagel condensation with 4-diethylaminobenzoic, 4-dibutylaminobenzoic aldehydes and 4-diphenylaminobenzoic aldehyde with triethylamine as a catalyst. Quaternary ammonium salts, the intermediates obtained during reactions, were not isolated but transformed to appropriate acids with hydrochloric acid (Scheme 2). Material and methods All reagents for the synthesis of rho (...truncated)


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Waldemar Tejchman, Izabela Korona-Glowniak, Anna Malm, Marek Zylewski, Piotr Suder. Antibacterial properties of 5-substituted derivatives of rhodanine-3-carboxyalkyl acids, Medicinal Chemistry Research, 2017, pp. 1316-1324, Volume 26, Issue 6, DOI: 10.1007/s00044-017-1852-7