Drug design: 4-thiazolidinones applications. Part 1. Synthetic routes to the drug-like molecules





Structure-based drug design, 5-Ene-4-thiazolidinones, Thiopyrano[2,3-d]thiazoles, biological activity, SAR analysis, Michael acceptors


4-Thiazolidinones, as examples of privileged scaffolds, have been the focus of medicinal chemistry since 60th. Among them, 5-substituted thiazolidinones with a C5 exocyclic bond (5-ene derivatives) are of special interest due to chemical characteristics and pharmacological profiles, possessing anticancer, antimicrobial, and antiviral properties, as well as being high-affinity ligands to a number of biological targets. A new medicinal chemistry trend claims that the aforementioned compounds are frequent hitters or pan assay interference compounds, which are useless because of the possible low selectivity. This is argued by the Michael acceptor property of 5-ene-4-thiazolidinones, which is actively discussed in the literature and requires further investigation. Based on SAR analysis, the main vectors for the design of 5-ene-4-thiazolidinone-based molecules were proposed: complication of C5 fragment; introduction of the substituents in the N3 position; synthesis of isosteric heterocycles; combination with other pharmacologically attractive fragments; annealing of thiazolidinone core; utilisation of 5-ene-thiazolidinones in synthesis of other compounds. The affinity of 5-ene-4-thiazolidinones toward various targets can be regarded as an advantage in polypharmacological approaches. Michael acceptors are considered as the “new old tool” for new drug creation, especially anticancer agents. One of the possible solutions within privileged substructure-based diversity-oriented synthesis is the fixation of 5-ene-4-thiazolidinone fragment in the fused heterocycles, for example, thiopyrano[2,3-d]thiazoles obtained from 5-ene-thiazolidinones.


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Lesyk R, Zimenkovsky B. 4-Thiazolidones: Centenarian History, Current Status and Perspectives for Modern Organic and Medicinal Chemistry. Current Organic Chemistry. 2004 Nov 1;8(16):1547-1577. https://doi.org/10.2174/1385272043369773

Havrylyuk D, Zimenkovsky B, Lesyk R. Synthesis, Biological Activity of Thiazolidinones Bearing Indoline Moiety and Isatin Based Hybrids. Mini-Reviews in Organic Chemistry. 2014 Dec 24;12(1):66-87. https://doi.org/10.2174/1570193x11666141028231910

Havrylyuk D, Roman O, Lesyk R. Synthetic approaches, structure activity relationship and biological applications for pharmacologically attractive pyrazole/pyrazoline–thiazolidine-based hybrids. European Journal of Medicinal Chemistry. 2016 May;113:145-166. https://doi.org/10.1016/j.ejmech.2016.02.030

Tripathi AC, Gupta SJ, Fatima GN, Sonar PK, Verma A, Saraf SK. 4-Thiazolidinones: The advances continue…. European Journal of Medicinal Chemistry. 2014 Jan;72:52-77. https://doi.org/10.1016/j.ejmech.2013.11.017

Tomasic T, Masic L. Rhodanine as a Privileged Scaffold in Drug Discovery. Current Medicinal Chemistry. 2009 May 1;16(13):1596-1629. https://doi.org/10.2174/092986709788186200

Verma A, Saraf SK. 4-Thiazolidinone – A biologically active scaffold. European Journal of Medicinal Chemistry. 2008 May;43(5):897-905. https://doi.org/10.1016/j.ejmech.2007.07.017

Tomašić T, Peterlin Mašič L. Rhodanine as a scaffold in drug discovery: a critical review of its biological activities and mechanisms of target modulation. Expert Opinion on Drug Discovery. 2012 May 19;7(7):549-560. https://doi.org/10.1517/17460441.2012.688743

Mendgen T, Steuer C, Klein CD. Privileged Scaffolds or Promiscuous Binders: A Comparative Study on Rhodanines and Related Heterocycles in Medicinal Chemistry. Journal of Medicinal Chemistry. 2012 Jan 11;55(2):743-753. https://doi.org/10.1021/jm201243p

Baell JB. Observations on screening-based research and some concerning trends in the literature. Future Medicinal Chemistry. 2010 Oct;2(10):1529-1546. https://doi.org/10.4155/fmc.10.237

Baell JB, Holloway GA. New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays. Journal of Medicinal Chemistry. 2010 Apr 8;53(7):2719-2740. https://doi.org/10.1021/jm901137j

Baell J, Walters MA. Chemistry: Chemical con artists foil drug discovery. Nature. 2014 Sep;513(7519):481-483. https://doi.org/10.1038/513481a

Kaminskyy D, Kryshchyshyn A, Lesyk R. 5-Ene-4-thiazolidinones – An efficient tool in medicinal chemistry. European Journal of Medicinal Chemistry. 2017 Nov;140:542-594. https://doi.org/10.1016/j.ejmech.2017.09.031

Kaminskyy D, Kryshchyshyn A, Lesyk R. Recent developments with rhodanine as a scaffold for drug discovery. Expert Opinion on Drug Discovery. 2017 Oct 11;12(12):1233-1252. https://doi.org/10.1080/17460441.2017.1388370

Lesyk RB, Zimenkovsky BS, Kaminskyy DV, Kryshchyshyn AP, Havryluk DY, Atamanyuk DV, Subtel'na IY, Khyluk DV. Thiazolidinone motif in anticancer drug discovery. Experience of DH LNMU medicinal chemistry scientific group. Biopolymers and Cell. 2011 Mar 20;27(2):107-117. https://doi.org/10.7124/bc.000089

Kryshchyshyn A, Roman O, Lozynskyi A, Lesyk R. Thiopyrano[2,3-d]Thiazoles as New Efficient Scaffolds in Medicinal Chemistry. Scientia Pharmaceutica. 2018 Jun 14;86(2):26. https://doi.org/10.3390/scipharm86020026

Mosula L, Zimenkovsky B, Havrylyuk D, Missir A, Chiriţă I, Lesyk R. Synthesis and antitumor activity of novel 2-thioxo-4-thiazolidinones with benzothiazole moieties. Farmacia. 2009;57(3):321-30.

Havrylyuk D, Mosula L, Zimenkovsky B, Vasylenko O, Gzella A, Lesyk R. Synthesis and anticancer activity evaluation of 4-thiazolidinones containing benzothiazole moiety. European Journal of Medicinal Chemistry. 2010 Nov;45(11):5012-5021. https://doi.org/10.1016/j.ejmech.2010.08.008

Kaminskyy D, den Hartog GJ, Wojtyra M, Lelyukh M, Gzella A, Bast A, Lesyk R. Antifibrotic and anticancer action of 5-ene amino/iminothiazolidinones. European Journal of Medicinal Chemistry. 2016 Apr;112:180-195. https://doi.org/10.1016/j.ejmech.2016.02.011

Senkiv J, Finiuk N, Kaminskyy D, Havrylyuk D, Wojtyra M, Kril I, Gzella A, Stoika R, Lesyk R. 5-Ene-4-thiazolidinones induce apoptosis in mammalian leukemia cells. European Journal of Medicinal Chemistry. 2016 Jul;117:33-46. https://doi.org/10.1016/j.ejmech.2016.03.089

Wojtyra MN, Lesyk RB. СИНТЕЗ 3-ПІРИДИЛЗАМІЩЕНИХ 4-ТІАЗОЛІДИНОНІВ ЯК ПОТЕНЦІЙНИХ БІОЛОГІЧНО АКТИВНИХ СПОЛУК. Фармацевтичний часопис. 2017 Mar 24;(1). https://doi.org/10.11603/2312-0967.2017.1.7533

Wojtyra M, Lesyk R, Zimenkovsky B, Grellier P. (Z)-(5-[5-(3,5-diaryl-4,5-dihydropyrazol-1-yl-methylidene)-3-(pyridine-3-yl)-2-thioxothiazolidin-4-ones exhibiting antitrypanosomal action. 2017 Oct 10; UA 119822 (Ukraine).

Holota S, Kryshchyshyn A, Derkach H, Trufin Y, Demchuk I, Gzella A, Grellier P, Lesyk R. Synthesis of 5-enamine-4-thiazolidinone derivatives with trypanocidal and anticancer activity. Bioorganic Chemistry. 2019 May;86:126-136. https://doi.org/10.1016/j.bioorg.2019.01.045

Lelyukh M, Havrylyuk D, Lesyk R. Synthesis and Anticancer Activity of Isatin, Oxadiazole and 4-Thiazolidinone Based Conjugates. Chemistry & Chemical Technology. 2015 Mar 15;9(1):29-36. https://doi.org/10.23939/chcht09.01.029

Kaminskyy D. A Facile Synthesis and Anticancer Activity Evaluation of Spiro[Thiazolidinone-Isatin] Conjugates. Scientia Pharmaceutica. 2011;79(4):763-777. https://doi.org/10.3797/scipharm.1109-14

Havrylyuk D, Zimenkovsky B, Vasylenko O, Zaprutko L, Gzella A, Lesyk R. Synthesis of novel thiazolone-based compounds containing pyrazoline moiety and evaluation of their anticancer activity. European Journal of Medicinal Chemistry. 2009 Apr;44(4):1396-1404. https://doi.org/10.1016/j.ejmech.2008.09.032

Ouyang G, Cai X, Chen Z, Song B, Bhadury PS, Yang S, Jin L, Xue W, Hu D, Zeng S. Synthesis and Antiviral Activities of Pyrazole Derivatives Containing an Oxime Moiety. Journal of Agricultural and Food Chemistry. 2008 Nov 12;56(21):10160-10167. https://doi.org/10.1021/jf802489e

Havrylyuk D, Zimenkovsky B, Vasylenko O, Gzella A, Lesyk R. Synthesis of New 4-Thiazolidinone-, Pyrazoline-, and Isatin-Based Conjugates with Promising Antitumor Activity. Journal of Medicinal Chemistry. 2012 Oct 9;55(20):8630-8641. https://doi.org/10.1021/jm300789g

Kryshchyshyn A, Kaminskyy D, Karpenko O, Gzella A, Grellier P, Lesyk R. Thiazolidinone/thiazole based hybrids – New class of antitrypanosomal agents. European Journal of Medicinal Chemistry. 2019 Jul;174:292-308. https://doi.org/10.1016/j.ejmech.2019.04.052

Kaminskyy D, Bednarczyk-Cwynar B, Vasylenko O, Kazakova O, Zimenkovsky B, Zaprutko L, Lesyk R. Synthesis of new potential anticancer agents based on 4-thiazolidinone and oleanane scaffolds. Medicinal Chemistry Research. 2011 Nov 25;21(11):3568-3580. https://doi.org/10.1007/s00044-011-9893-9

Komarista I. Synthesis, transformations and biological activity of some azolidones and their condensed derivatives. Moscow, USSR: I.M. Sechenov First State Medical Institute; 1989.

Komaritsa ID, Baranov SN, Grishuk AP. 4-Thiazolidines, derivatives and analogs. Chemistry of Heterocyclic Compounds. 1967 Jul;3(2):533-534. https://doi.org/10.1007/bf00481594

Plevachuk NE, Komaritsa ID. A study of azolidones and their derivatives. Chemistry of Heterocyclic Compounds. 1970 Feb;6(2):144-145. https://doi.org/10.1007/bf00474983

Grischuk AP, Komaritsa ID, Baranov SN. 4-Thionazolidones, derivatives and analogs. Chemistry of Heterocyclic Compounds. 1968;2(5):541-543. https://doi.org/10.1007/bf00477515

Lozynskyi A, Zimenkovsky B, Lesyk R. Synthesis and Anticancer Activity of New Thiopyrano[2,3-d]thiazoles Based on Cinnamic Acid Amides. Scientia Pharmaceutica. 2014;82(4):723-733. https://doi.org/10.3797/scipharm.1408-05

Lozynskyi A, Zasidko V, Atamanyuk D, Kaminskyy D, Derkach H, Karpenko O, Ogurtsov V, Kutsyk R, Lesyk R. Synthesis, antioxidant and antimicrobial activities of novel thiopyrano[2,3-d]thiazoles based on aroylacrylic acids. Molecular Diversity. 2017 Apr 19;21(2):427-436. https://doi.org/10.1007/s11030-017-9737-8

Lozynskyi A, Zimenkovsky B, Nektegayev I, Lesyk R. Arylidene pyruvic acids motif in the synthesis of new thiopyrano[2,3-d]thiazoles as potential biologically active compounds. Heterocyclic Communications. 2015 Jan 1;21(1). https://doi.org/10.1515/hc-2014-0204

Zelisko N, Atamanyuk D, Ostapiuk Y, Bryhas A, Matiychuk V, Gzella A, Lesyk R. Synthesis of fused thiopyrano[2,3-d][1,3]thiazoles via hetero-Diels–Alder reaction related tandem and domino processes. Tetrahedron. 2015 Dec;71(50):9501-9508. https://doi.org/10.1016/j.tet.2015.10.019

Zelisko N, Atamanyuk D, Vasylenko O, Bryhas A, Matiychuk V, Gzella A, Lesyk R. Crotonic, cynnamic, and propiolic acids motifs in the synthesis of thiopyrano[2,3-d][1,3]thiazoles via hetero-Diels–Alder reaction and related tandem processes. Tetrahedron. 2014 Jan;70(3):720-729. https://doi.org/10.1016/j.tet.2013.11.083

Lozynskyi A, Golota S, Zimenkovsky B, Atamanyuk D, Gzella A, Lesyk R. Synthesis, anticancer and antiviral activities of novel thiopyrano[2,3-d]thiazole-6-carbaldehydes. Phosphorus, Sulfur, and Silicon and the Related Elements. 2016 Mar 30;191(9):1245-1249. https://doi.org/10.1080/10426507.2016.1166108

Kryshchyshyn AP, Atamanyuk DV, Kaminskyy DV, Grellier P, Lesyk RB. Investigation of anticancer and anti-parasitic activity of thiopyrano[2,3-d]thiazoles bearing norbornane moiety. Biopolymers and Cell. 2017 Jun 30;33(3):183-205. https://doi.org/10.7124/bc.00094f

Lesyk R, Zimenkovsky B, Atamanyuk D, Jensen F, Kieć-Kononowicz K, Gzella A. Anticancer thiopyrano[2,3-d][1,3]thiazol-2-ones with norbornane moiety. Synthesis, cytotoxicity, physico-chemical properties, and computational studies. Bioorganic & Medicinal Chemistry. 2006 Aug;14(15):5230-5240. https://doi.org/10.1016/j.bmc.2006.03.053

Atamanyuk D, Zimenkovsky B, Lesyk R. Synthesis and anticancer activity of novel thiopyrano[2,3-d]thiazole-based compounds containing norbornane moiety. Journal of Sulfur Chemistry. 2008 Apr;29(2):151-162. https://doi.org/10.1080/17415990801911723

Lozynskyi A, Zimenkovsky B, Karkhut A, Polovkovych S, Gzella AK, Lesyk R. Application of the 2(5 H )furanone motif in the synthesis of new thiopyrano[2,3- d ]thiazoles via the hetero-Diels–Alder reaction and related tandem processes. Tetrahedron Letters. 2016 Jul;57(30):3318-3321. https://doi.org/10.1016/j.tetlet.2016.06.060

Zelisko N, Karpenko O, Muzychenko V, Gzella A, Grellier P, Lesyk R. trans -Aconitic acid-based hetero -Diels-Alder reaction in the synthesis of thiopyrano[2,3- d ][1,3]thiazole derivatives. Tetrahedron Letters. 2017 May;58(18):1751-1754. https://doi.org/10.1016/j.tetlet.2017.03.062

Atamanyuk D. Synthesis and Biological Activity of New Thiopyrano[2,3-d]thiazoles Containing a Naphthoquinone Moiety. Scientia Pharmaceutica. 2013;81(2):423-436. https://doi.org/10.3797/scipharm.1301-13

Atamanyuk D, Zimenkovsky B, Atamanyuk V, Lesyk R. 5-Ethoxymethylidene-4-thioxo-2-thiazolidinone as Versatile Building Block for Novel Biorelevant Small Molecules with Thiopyrano[2,3-d][1,3]thiazole Core. Synthetic Communications. 2013 Oct 29;44(2):237-244. https://doi.org/10.1080/00397911.2013.800552

Lesyk R, Kaminskyy D, Vasylenko O, Atamanyuk D, Gzella A. Isorhodanine and Thiorhodanine Motifs in the Synthesis of Fused Thiopyrano[2,3-d][1,3]thiazoles. Synlett. 2011 May 26;2011(10):1385-1388. https://doi.org/10.1055/s-0030-1260765

Zelisko NI, Finiuk NS, Shvets VM, Medvid YO, Stoika RS, Lesyk RB. Screening of spiro-substituted thiopyrano[2,3-d]thiazoles for their cytotoxic action on tumor cells. Biopolymers and Cell. 2017 Aug 31;33(4):282-290. https://doi.org/10.7124/bc.00095a

Zelisko N, Atamanyuk D, Vasylenko O, Grellier P, Lesyk R. Synthesis and antitrypanosomal activity of new 6,6,7-trisubstituted thiopyrano[2,3-d][1,3]thiazoles. Bioorganic & Medicinal Chemistry Letters. 2012 Dec;22(23):7071-7074. https://doi.org/10.1016/j.bmcl.2012.09.091

Lozynskyi A, Zimenkovsky B, Gzella AK, Lesyk R. Arylidene Pyruvic Acids Motif in the Synthesis of New 2H,5H-Chromeno[4′,3′:4,5]thiopyrano[2,3-d]thiazoles via Tandem Hetero-Diels–Alder-Hemiacetal Reaction. Synthetic Communications. 2015 Aug 3;45(19):2266-2270. https://doi.org/10.1080/00397911.2015.1076004

Matiychuk VS, Lesyk RB, Obushak MD, Gzella A, Atamanyuk DV, Ostapiuk YV, Kryshchyshyn AP. A new domino-Knoevenagel–hetero-Diels–Alder reaction. Tetrahedron Letters. 2008 Jul;49(31):4648-4651. https://doi.org/10.1016/j.tetlet.2008.05.062

How to Cite

Lesyk R. Drug design: 4-thiazolidinones applications. Part 1. Synthetic routes to the drug-like molecules. JMS [Internet]. 2020 Mar. 31 [cited 2023 Jun. 4];89(1):e406. Available from: https://jms.ump.edu.pl/index.php/JMS/article/view/406



Review Papers
Received 2020-02-04
Accepted 2020-04-02
Published 2020-03-31