Generic placeholder image

Current Organic Synthesis


ISSN (Print): 1570-1794
ISSN (Online): 1875-6271

Research Article

Synthesis of Novel Fluorine Compounds Substituted-4-thiazolidinones Derived from Rhodanine Drug as Highly Bioactive Probes

Author(s): Mohammad S.T. Makki, Reda M. Abdel-Rahman and Nawaa A.H. Alshammari*

Volume 16, Issue 3, 2019

Page: [413 - 422] Pages: 10

DOI: 10.2174/1570179416666190312150046

open access plus


Aim and Objective: It is known that rhodanine drug has various biocidal activities. The aim of this work was to improve the structure of rhodanine drug via alkylation at N, S, and O- centers in addition to the introduction of fluorine atoms. The new fluorinated modified rhodanines 2-16 were evaluated as enzymatic probes for cellobiase activity produced by fungi and as CDK2 inhibitors of tumor cells.

Materials and Methods: Novel fluorine substituted N-alkyl, S-alkyl and amino-rhodanines were obtained via Hydroxy methylation, Mannich reactions, chlorination and amination of 5-(4'-fluorophenylene)-2-thioxothiazolidin- 4-one, and the enzymatic effects of cellobiase produced by fungi and /or CDK2 inhibition of tumor cells were evaluated.

Results: Most of the targets were obtained in high yield and in the form of very pure crystals with characteristic colors. Only compounds 5, 8, 10, 13, and 14 exhibited a higher activity as cellobiase while compounds 2 and 5 showed a highly enzymatic effect on tumor cells. In addition, compounds 2 and 10 can be used as Olomoucine (standard referees).

Conclusion: Various N, S and O-alkyl derivatives of fluorine-substituted rhodanines were prepared via a simple method and used as enzymatic probes for cellobiase activity produced by fungi and CDK2 inhibitors for tumor cells. The more bioactive compounds had rich fluorine atoms as p-fluorophenyl and p-fluorobenzoyl bearing N, S, O-alkyl rhodanine. The highly active compounds may be used as enzymatic materials for various biological transformations in the future.

Keywords: Synthesis, fluorine substituted rhodanine, cellobiase activity of fungi, CDK2 inhibitors, bioactive probes, tumor cells.

Graphical Abstract
Abdel-Rahman, R.M. Chemoselective heterocyclization and pharmacological activities of new heterocycles-a review. Part V-Synthesis of biocidal 4-thiazolidinones derivatives. Boll. Chim. Farm., 2001, 140(6), 401-410.
Liu, X-F.; Zheng, C-J.; Sun, L-P.; Liu, X-K.; Piao, H-R. Synthesis of new chalcone derivatives bearing 2,4-thiazolidinedione and benzoic acid moieties as potential anti-bacterial agents. Eur. J. Med. Chem., 2011, 46(8), 3469-3473.
Liesen, A.P.; de Aquino, T.M.; Carvalho, C.S.; Lima, V.T.; de Araújo, J.M.; de Lima, J.G.; de Faria, A.R.; de Melo, E.J.T.; Alves, A.J.; Alves, E.W.; Alves, A.Q.; Góes, A.J.S. Synthesis and evaluation of anti-Toxoplasma gondii and antimicrobial activities of thiosemicarbazides, 4-thiazolidinones and 1,3,4-thiadiazoles. Eur. J. Med. Chem., 2010, 45(9), 3685-3691.
Aridoss, G.; Amirthaganesan, S.; Kim, M.; Kim, J.; Jeong, Y.T. Synthesis, spectral and biological evaluation of some new thiazolidinones and thiazoles based on t-3-alkyl-r-2,c-6-diarylpiperidin-4-ones. Eur. J. Med. Chem., 2009, 44(10), 4199-4210.
Havrylyuk, D.; Kovach, N.; Zimenkovsky, B.; Vasylenko, O.; Lesyk, R. Synthesis and anticancer activity of isatin-based pyrazolines and thiazolidines conjugates. Arch. Pharm. Chem. Life Sci., 2011, 344(8), 514.
5A2m2i.n, K.; Kamel, M.; Anwar, M.; Khedr, M.; Syam, Y. Synthesis, biological evaluation and molecular docking of novel series of spiro [(2H, 3H) quinazoline-2, 1′-cyclohexan]-4(1H)-one derivatives as anti-inflammatory and analgesic agents. Eur. J. Med. Chem., 2010, 45(6), 2117-2131.
Geronikaki, A.A.; Lagunin, A.A.; Hadjipavlou-Litina, D.I.; Eleftheriou, P.T.; Filimonov, D.A.; Poroikov, V.V.; Alam, I.; Saxena, A.K. Computer-aided discovery of anti-inflammatory thiazolidinones with dual cyclooxygenase/ lipoxygenase inhibition. J. Med. Chem., 2008, 51(6), 1601-1609.
Kaur, H.; Kumar, S.; Vishwakarma, P.; Sharma, M.; Saxena, K.; Kumar, A. Synthesis and antipsychotic and anticonvulsant activity of some new substituted oxa/ thiadiazolylazetidinonyl/ thiazolidinonylcarbazoles. Eur. J. Med. Chem., 2010, 45(7), 2777-2783.
Akula, G.; Srinivas, B.; Vidyasagar, M.; Kandikonda, S. Synthesis of 3-(1H-benzimidazol-2-yl amino) 2-phenyl-1, 3-thiazolidin-4-one as potential CNS depressant. Int. J. Pharm. Tech. Res., 2011, 3, 360-364.
Ravichandran, V.; Jain, A.; Kumar, K.S.; Rajak, H.; Agrawal, R.K. Design, synthesis, and evaluation of thiazolidinone derivatives as antimicrobial and anti-viral agents. Chem. Biol. Drug Des., 2011, 78(3), 464-470.
Kini, D.; Ghate, M. Synthesis and oral hypoglycemic activity of 3-[5′-methyl-2′-aryl-3′-(thiazol-2˝-yl amino) thiazolidin-4′-one] coumarin derivatives. E-J. Chem., 2011, 8(1), 386-390.
Sadashiva, C.; Chandra, J.N.S.; Kavitha, C.; Thimmegowda, A.; Subhash, M.; Rangappa, K.S. Synthesis and pharmacological evaluation of novel N-alkyl/aryl substituted thiazolidinone arecoline analogs as muscarinic receptor 1 agonist in Alzheimer’s dementia models. Eur. J. Med. Chem., 2009, 44(12), 4848-4854.
Arey, B.J.; Yanofsky, S.D.; Pérez, M.C.; Holmes, C.P.; Wrobel, J.; Gopalsamy, A.; Stevis, P.E.; López, F.J.; Winneker, R.C. Differing pharmacological activities of thiazolidinone analogs at the FSH receptor. Biochem. Biophys. Res. Commun., 2008, 368(3), 723-728.
Kouznetsov, V.; Rodríguez, W.; Stashenko, E.; Ochoa, C.; Vega, C.; Rolon, M.; Pereira, D.M.; Escario, J.A.; Barrio, A.G. Transformation of Schiff bases derived from alpha-naphthaldehyde. Synthesis, spectral data and biological activity of new-3-aryl-2-(α-naphthyl)-4-thiazolidinones and N-aryl-N-[1-(α-naphthyl)but-3-enyl] amines. J. Hetero. Chem., 2004, 41(6), 995-999.
Bhandari, S.V.; Bothara, K.G.; Patil, A.A.; Chitre, T.S.; Sarkate, A.P.; Gore, S.T.; Dangre, S.C.; Khachane, C.V. Design, synthesis and pharmacological screening of novel antihypertensive agents using hybrid approach. Bioorg. Med. Chem., 2009, 17(1), 390-400.
Jain, A.K.; Vaidya, A.; Ravichandran, V.; Kashaw, S.K.; Agrawal, R.K. Recent developments and biological activities of thiazolidinone derivatives: A review. Bioorg. Med. Chem., 2012, 20(11), 3378-3395.
Makki, M.S.; Abdel-Rahman, R.M.; Alharbi, A.S. Synthetic approach for novel fluorine substituted α-aminophosphonic acids containing 1,2,4-triazin-5-one moiety as antioxidant agents. Inter. J. Org. Chem., 2018, 8(01), 1-15.
Makki, M.; Bakhotmah, D.A.; Abdel-Rahman, R.M.; Aqlan, F.M. New route to synthesize fluorine substituted lamotrigine drug analogues as an anti-inflammatory agent. Curr. Org. Synth., 2018, 15(1), 116-125.
Ali, T.E.; Abdel-Rahman, R.M. Synthesis and antioxidant activities of some novel fluorinated spiro[oxindole-thiazolidine] fused with sulfur and phosphorus heterocycles. J. Sulfur Chem., 2014, 35(4), 399-411.
Makki, M.; Alfooty, K.; Abdel-Rahman, R.; El-Shahawi, M. Synthesis, voltammetric and analytical applications of some fluorine substituted spirosteroidalthiazolidin-4-one derivatives of sulfa drugs. J. Chinese. Chem. Soc., 2016, 63(2), 189-198.
Alegaon, S.G.; Alagawadi, K.R.; Vinod, D.; Unger, B.; Khatib, N. Synthesis, pharmacophore modeling, and cytotoxic activity of 2-thioxothiazolidin-4-one derivatives. Med. Chem. Res., 2014, 23(12), 5160-5173.
Ono, M.; Hayashi, S.; Matsumura, K.; Kimura, H.; Okamoto, Y.; Ihara, M.; Takahashi, R.; Mori, H.; Saji, H. Rhodanine and thiohydantoin derivatives for detecting tau pathology in Alzheimer’s brains. Am. Chem. Soc., 2011, 2(5), 269-275.
Cutshall, N.S.; O’Day, C.; Prezhdo, M. Rhodanine derivatives as inhibitors of JSP-1. Bioorg. Med. Chem. Lett., 2005, 15(14), 3374-3379.
Russell, A.J.; Westwood, I.M.; Crawford, M.H.J.; Robinson, J.; Kawamura, A.; Redfield, C.; Laurieri, N.; Lowe, E.D.; Davies, S.G.; Sim, E. Selective small molecule inhibitors of the potential breast cancer marker, human arylamine N-acetyltransferase 1, and its murine homologue, mouse arylamine N-acetyltransferase 2. Bioorg. Med. Chem., 2009, 17(2), 905-918.
Barry, A. The Antimicrobial Suseptabalitytest: Principale and Practices; Lea and Febiger: Philadelphia, PA, USA, 1976.
Mandels, M.; Reese, E. Inhibition of cellulases and ß-glucosidases; Adv. Enzy. Hydrol. Cell Relat. Mater, 1963, pp. 58-115.
Somogyi, M. A new reagent for the determination of sugars. J. Biol. Chem., 1945, 160(1), 61-68.
Chandrappa, S.; Kavitha, C.V.; Shahabuddin, M.S.; Vinaya, K.; Ananda Kumar, C.S.; Ranganatha, S.R.; Raghavan, S.C.; Rangappa, K.S. Synthesis of 2-(5-((5-(4-chlorophenyl)furan-2-yl)methylene)-4-oxo-2-thioxothiazoli-din-3-yl)acetic acid derivatives and evaluation of their cytotoxicity and induction of apoptosis in human leukemia cells. Bioorg. Med. Chem., 2009, 17(6), 2576-2584.
Satyanarayana, A.; Kaldis, P. A dual role of Cdk2 in DNA damage response. Cell Div., 2009, 4(1), 9.
O’Connor, P.M. Mammalian G1, and G2 phase checkpoints. Cancer Surv., 1997, 29, 151-182.
Vaziri, H.; Benchimol, S. From telomere loss to p53 induction and activation of a DNA-damage pathway at senescence: The telomere loss/DNA damage model of cell aging. Exp. Gerontol., 1996, 31(1), 295-301.
Makki, M.S.; Abdel-Rahman, R.M.; Khan, K.A. Fluorine substituted 1,2,4-triazinones as potential anti-HIV-1 and CDK2 inhibitors. J. Chem., 2014, 2014, Article ID 430573.
Gucký, T.; Řezníčková, E.; Džubák, P.; Hajdúch, M.; Kryštof, V. Synthesis and anticancer activity of some 1, 5-diaryl-3-(3,4,5-trihydroxyphenyl)-1H-pyrazolo[4,3-e][1,2,4]triazines. Monatsh. Chem., 2010, 141(6), 709-714.

© 2022 Bentham Science Publishers | Privacy Policy