Synthesis, characterization and biological evaluation of thioureas, acylthioureas and 4-thiazolidinones as anticancer and antiviral agents

Abstract

In this study, thiourea derivatives [1-4] were synthesized

by using 2-amino-4-substituted pyridine compounds and

these compounds have been used as the starting materials for

synthesis of 2-imino-1,3-thiazolidin-4-one ring [5, 6]. Two

different procedures for 4-thiazolidinone ring closure and

synthesis method were optimized. The synthesized compounds

were identified by the help of elemental analysis, IR, 1H-NMR,

13C-NMR and mass spectral data while the purities of them were

proved with TLC. Synthesized compounds were evaluated for

their antiviral and anticancer activity. Antiviral activity against

Murine norovirus, Yellow fever, Enterovirus and Chikungunya

strains of the test compounds were investigated and EC50 values

of these compounds were determined higher than 0,3 μM.

Cytotoxicity of test compounds was examined on NIH3T3

cell line. When the anticancer activity of test compounds was

examined against PC-3, A549, HeLa, HT-29, MCF-7, SJSA1

and K562 cell lines, the percent proliferation values of these

compounds were observed over 61% for all cell lines.

Keywords

• Acylthioureas,anticancer,antiviral,tautomerism,thiourea,2-amino-1,3-thiazol-4-one,2-imino-1,3-thiazolidin- 4-one

Tiyoüreler, açiltiyoüreler ve 4-tiyazolidinonların sentezi, karakterizasyonu ve antikanser ve antiviral etkilerinin değerlendirilmesi

Abstract

Bu çalışma kapsamında 2-amino-4-sübstitüe piridin

bileşiklerinden hareketle sentezlenen tiyoüre türevleri [1-

4], 2-imino-1,3-tiyazolidin-4-on halkalarının [5, 6] sentez

başlangıç maddelerini oluşturmaktadır. 4-Tiyazolidinon halka

kapaması ve sentezi için iki farklı yöntem optimize edilmiştir.

Sentezlenen bileşiklerin yapıları elementel analiz, IR, 1H-NMR,

13C-NMR ve kütle spektrumu ile kanıtlanmış, saflıkları ise

İTK ile kontrol edilmiştir. Elde edilen bileşikler antiviral ve

antikanser etkinlikleri açısından değerlendirilmiştir. Murine

norovirus, Yellow fever, Enterovirus ve Chikungunya suşlarına

karşı antiviral etkileri incelenen bileşiklerin 0,3 μM’dan yüksek

EC50 değerine sahip oldukları tespit edilmiştir. Sitotoksisiteleri

NIH3T3 hücre hattı üzerinde incelenen bileşiklerin antikanser

etkileri PC-3, A549, HeLa, HT-29, MCF-7, SJSA1 ve K562

hücre hatlarına karşı incelenmiş %61’in üzerinde proliferasyon

değerine sahip oldukları gözlemlenmiştir.

Keywords

• Açiltiyoüre; antikanser; antiviral; tautomerizm; tiyoüre; 2-amino-1,3-tiyazol-4-on; 2-imino-1,3- tiyazolidin-4-on

References

1. 1. Kamel MM, Megally Abdo NY. Synthesis of novel1,2,4-triazoles, triazolothiadiazines and triazolothiadiazolesas potential anticancer agents. Eur J Med Chem 2014; 86: 75-80.
2. 2. Kulabaş N, Tatar E, Bingol Ozakpınar O, Ozsavcı D,Pannecouque C, De Clercq E, Kucukguzel İ. Synthesis andantiproliferative evaluation of novel 2-(4H-1,2,4-triazole-3-ylthio)acetamide derivatives as inducers of apoptosis in cancercells. Eur J Med Chem 2016; 121: 58-70.
3. 3. Karakuş S, Guniz Kucukguzel Ş, Kucukguzel İ, De Clercq E,Pannecouque C, Andrei G, Pannecouque C, Andrei G, SnoeckR, Sahin F, Bayrak OF. Synthesis, antiviral and anticanceractivity of some novel thioureas derived from N-(4-nitro-2-phenoxyphenyl)-methanesulfonamide. Eur J Med Chem2009; 44: 3591-5.
4. 4. Kucukguzel İ, Tatar E, Kucukguzel ŞG, Rollas S, De Clercq E.Synthesis of some novel thiourea derivatives obtained from5-[(4-aminophenoxy)methyl]-4-alkyl/aryl-2,4-dihydro-3H-1,2,4-triazole-3-thiones and evaluation as antiviral/anti-HIVand anti-tuberculosis agents. Eur J Med Chem 2008; 43: 381-92.
5. 5. Liav A, Angala SK, Brennan PJ, Jackson M. N-DAldopentofuranosyl-N’-[p-(isoamyloxy)phenyl]-thioureaderivatives: Potential anti-TB therapeutic agents. Bioorg MedChem Lett 2008; 18: 2649-51.
6. 6. Vega-Perez JM, Perinan I, Argandona M, Vega-Holm M, Palo-Nieto C, Burgos-Moron E, Lopez-Lazaro M, Vargas C, NietoJJ, Iglesias-Guerra F. Isoprenyl-thiourea and urea derivativesas new farnesyl diphosphate analogues: Synthesis and in vitroantimicrobial and cytotoxic activities. Eur J Med Chem 2012;58: 591-612.
7. 7. Tatar E, Karakuş S, Kucukguzel ŞG, Oktem Okullu S,Unubol N, Kocagoz T, De Clercq E, Andrei G, Snoeck R,Pannecouque C, Kalaycı S, Şahin F, Sriram D, Yogeeswari P,Kucukguzel İ. Design, Synthesis, and Molecular DockingStudies of a Conjugated Thiadiazole–Thiourea Scaffold asAntituberculosis Agents. Biol Pharm Bull 2016; 39: 502-15.
8. 8. Kucukguzel İ, Kucukguzel ŞG, Rollas S, Kiraz M. Some3-thioxo/alkylthio-1,2,4-triazoles with a substituted thioureamoiety as possible antimycobacterials. Bioorg Med Chem Lett2001; 11: 1703-7.

9. 9. Zhao F, Xiao JH, Wang Y, Li S. Synthesis of thiourea derivativesas CCR4 antagonists. Chin Chem Lett 2009; 20: 296-9.
10. 10. Ghorab MM, Alsaid MS, Al-Dosary MS, Nissan YM, AttiaSM. Design, synthesis and anticancer activity of some novelthioureido‑benzenesulfonamides incorporated biologicallyactive moieties. Chem Cent J 2016; 10: 1-13.
11. 11. Manjula SN, Malleshappa Noolvi N, Vipan Parihar K,Manohara Reddy SA, Ramani V, Gadad AK, Singh G, GopalanKutty N, Mallikarjuna Rao C. Synthesis and antitumor activityof optically active thiourea and their 2-aminobenzothiazolederivatives: a novel class of anticancer agents. Eur J Med Chem2009; 44: 2923-9.
12. 12. Sunduru N, Srivastava K, Rajakumar S, Puri SK, Saxena JK,Chauhan PM. Synthesis of novel thiourea, thiazolidinedioneand thioparabanic acid derivatives of 4-aminoquinoline aspotent antimalarials. Bioorg Med Chem Lett 2009; 19: 2570-3.
13. 13. McCarthy AR, Pirrie L, Hollick JJ, Ronseaux S, CampbellJ, Higgins M, Staples OD, Tran F, Slawin AMZ, Lain S,Westwood NJ. Synthesis and biological characterisation ofsirtuin inhibitors based on the tenovins. Bioorg Med Chem2012; 20: 1779-93.
14. 14. Koca İ, Ozgur A, Acikalin Coşkun K, Tutar Y. Synthesis andanticancer activity of acyl thioureas bearing pyrazole moiety.Bioorg Med Chem 2013; 21: 3859-65.
15. 15. Agola JO, Hong L, Surviladze Z, Ursu O, Waller A, StrouseJJ, Simpson DS, Schroeder CE, Oprea TI, Golden JE, AubeJ, Buranda T, Sklar LA, Wandinger-Ness A. A CompetitiveNucleotide Binding Inhibitor: In Vitro Characterization ofRab7 GTPase Inhibition. Chem Biol 2012; 7: 1095-108.
16. 16. Thanigaimalai P, Le Hoang TA, Lee KC, Bang SC, SharmaVK, Yun CY, Roh E, Hwang BY, Kim Y, Jung SH. Structuralrequirement(s) of N-phenylthioureas and benzaldehydethiosemicarbazones as inhibitors of melanogenesis inmelanoma B 16 cells. Bioorg Med Chem Lett 2010; 20: 2991-3.
17. 17. Thanigaimalai P, Lee KC, Sharma VK, Joo C, Cho WJ, RohE, Kim Y, Jung SH. Structural requirement of phenylthioureaanalogs for their inhibitory activity of melanogenesis andtyrosinase. Bioorg Med Chem Lett 2011; 21: 6824-8.tautomerizm; tiyoure; 2-amino-1,3-tiyazol-4-on; 2-imino-1,3-tiyazolidin-4-on.
18. 18. Kaminskyy D, Den Hartog GJM, Wojtyra M, Lelyukh M,Gzella A, Bast A, Lesky R. Antifibrotic and anticancer actionof 5-ene amino/iminothiazolidinones. Eur J Med Chem 2016;112: 180-95.
19. 19. Zarghi A, Najafnia L, Daraee B, Dadrass OG, Hedeyati M.Synthesis of 2,3-diaryl-1,3-thiazolidine-4-one derivatives asselective cyclooxygenase (COX-2) inhibitors. Bioorg MedChem Lett 2007; 17: 5634-7.
20. 20. Look GC, Schullek JR, Holmes CP, Chinn JP, Gordon EM,Gallop MA. The identification of cyclooxygenase-I inhibitorsfrom 4-thiazolidinone combinatorial libraries. Bioorg MedChem Lett 1996; 6: 707-12.
21. 21. Kocabalkanlı A, Ateş O, Otuk G. Synthesis of Mannich Basesof some 2,5-disubstituted 4-thiazolidinones and evaluation oftheir antimicrobial activities. Arch Pharm Pharm Med Chem2001; 334: 35-9.
22. 22. Andres CJ, Bronson JJ, D’Andrea SV, Deshpande MS, Falk PJ,Grant-Young KA, Harte WE, Ho HT, Misco PF, RobertsonJG, Stock D, Sun Y, Walsh AW. 4-Thiazolidinones: Novelinhibitors of the bacterial enzyme MurB. . Bioorg Med ChemLett 2000; 10: 715-7.
23. 23. Sarkanj B, Molnar M, Cacic M, Gille L. 4-Methyl-7-hydroxycoumarin antifungal and antioxidant activityenhancement by substitution with thiosemicarbazide andthiazolidinone moieties. Food Chem 2013; 139: 488-95.
24. 24. Ergenc N, Capan G. Synthesis and anticonvulsant activity ofnew 4-thiazolidone and 4-thiazoline derivatives. Farmaco1994; 49: 133-5.
25. 25. Tatar E, Kucukguzel İ, De Clercq E, Krishnan R, Kaushik-BasuN. Synthesis and characterization and antiviral evaluation of1,3-Thiazolidine-4-one derivatives bearing L-Valine sidechain. Marmara Pharm J 2012; 16: 181-93.
26. 26. Ateş O, Altıntaş H, Otuk G. Synthesis and antimicrobial avtivityof 4-Carbethoxymethyl-2-[(α-haloacyl)amino]thiazoles and5-Nonsubstitued/substitued 2-[(4-Carbethoxymethylthiazol-2-yl)imino]-4-thiazolidinones. Arzneim-Forsch/Drug Res2000; 50: 569-75.
27. 27. Kunzler A, Neuenfeldt PD, Neves AM, Pereira CMP, MarquesHG, Nascente PS, Fernandes MHV, Hubner SO, Cunico W.Synthesis, antifungal and cytotoxic activities of 2-aryl-3-((piperidin-1-yl)ethyl)thiazolidinones. Eur J Med Chem 2013;64: 74-80.
28. 28. Loscher W, Von Hodenberg A, Nolting B, FassbenderCP, Taylor C. Ralitoline: A reevaluation of anticonvulsantprofile and determination of active plasma concentrationsin comparison with prototype antiepileptic drugs in mice.Epilepsia 1991; 32: 560-8.
29. 29. Prabhakar YS, Solomon VR, Gupta MK, Kati SB. QSARstudies on thiazolidines a biologically privileged scaffold. TopHeterocycl Chem 2006; 4: 161-249.
30. 30. Dzambaski Z, Markovic R, Kleinpeter E, Baranac-StojanovicM. 2-Alkylidene-4-oxothiazolidine S-oxides: synthesis andstereochemistry. Tetrahedron 2013; 69: 6436-47.
31. 31. Jain AK, Vaidya A, Ravichandran V, Kashaw SK, AgrawalRK. Recent developments and biological activities ofthiazolidinone derivatives: a review. Bioorg Med Chem 2012;20: 3378-95.
32. 32. Kucukguzel İ, Satılmış G, Gurukumar KR, Basu A, Tatar E,Nichols DB, Talele TT, Kaushik-Basu N. 2-Heteroarylimino-5-arylidene-4-thiazolidinones as a new class of non-nucleosideinhibitors of HCV NS5B polymerase. Eur J Med Chem 2013;69: 931-41.
33. 33. Cakır G, Kucukguzel İ, Guhamazumder R, Tatar E, ManvarD, Basu A, Patel BA, Zia J, Talele TT, Kaushik-Basu N. Novel4-Thiazolidinones as Non-Nucleoside Inhibitors of HepatitisC Virus NS5B RNA-Dependent RNA Polymerase. ArchPharm Chem Life Sci 2015; 348: 10-22.
34. 34. St. Laurent DR, Gao Q, Wu D, Serrano-Wu MH. Regioselectivesynthesis of 3-(heteroaryl)-iminothiazolidin-4-ones.Tetrahedron Lett 2004; 45: 1907-10.
35. 35. Urbano M, Guerrero M, Velaparthi S, Crisp M, Chase P,Hodder P, Schaeffer MT, Brown S, Rosen H, Roberts E.Discovery, synthesis and SAR analysis of novel selective smallmolecule S1P4-R agonists based on a (2Z,5Z)-5-((pyrrol-3-yl)methylene)-3-alkyl-2-(alkylimino)thiazolidin-4-onechemotype. Bioorg Med Chem Lett 2011; 21: 6739-45.
36. 36. Nowaczyk A, Kowiel M, Gzella A, Fijałkowski Ł, HorishnyV, Lesyk R. Conformational space and vibrational spectra of2-[(2,4-dimethoxyphenyl)amino]-1,3-thiazolidin-4-one. JMol Model 2014; 20: 2366-74.
37. 37. Richter SB, Stach LJ. Acaricidal compositions ofphosphoramidate esters. US 3996352A, 1975.
38. 38. Kucukguzel ŞG, Oruc EE, Rollas S, Şahin F, Ozbek A.Synthesis, characterisation and biological activity of novel4-thiazolidinones, 1,3,4-oxadiazoles and some relatedcompounds. Eur J Med Chem 2002; 37: 197-206.
39. 39. Cıkla P, Tatar E, Kucukguzel İ, Şahin F, Yurdakul D, Basu A,Krishnan R, Nichols DB, Kaushik-Basu N, Kucukguzel ŞG.Synthesis and characterization of flurbiprofen hydrazidederivatives as potential anti-HCV, anticancer and antimicrobialagents. Med Chem Res 2013; 22: 5685-99.
40. 40. Havrylyuk D, Mosula L, Zimenkovsky B, Vasylenko O, GzellaA, Lesyk R. Synthesis and anticancer activity evaluation of4-thiazolidinones containing benzothiazole moiety. Eur J MedChem 2010; 45: 5012-21.
41. 41. Vicini P, Geronikaki A, Incerti M, Zani F, Dearden J, HewittM. 2-Heteroarylimino-5-benzylidene-4-thiazolidinonesanalogues of 2-thiazolylimino-5-benzylidene-4-thiazolidinones with antimicrobial activity: synthesis andstructure-activity relationship. Bioorg Med Chem 2008; 16:3714-24.
42. 42. Anderluh M, Jukič M, Petrič R. Three-component one-potsynthetic route to 2-amino-5-alkylidene-thiazol-4-ones.Tetrahedron 2009; 65: 344-50.
43. 43. Koca İ, Ozgur A, Er M, Gumuş M, Acikalin Coşkun K, TutarY. Design and synthesis of pyrimidinyl acyl thioureas as novelHsp90 inhibitors in invasive ductal breast cancer and its bonemetastasis. Eur J Med Chem 2016; 122: 280-90.
44. 44. Shen W, Fang Y, Tong A, Zhu Q. Synthesis and structure–activity relationship of acylthiourea derivatives as inhibitorsof microsomal epoxide hydrolase. Med Chem Res 2012; 21:4214-8.
45. 45. Mahdavi M, Shirazi MS, Taherkhani R, Saeedi M, Alipour E,Moghadam FH, Moradi A, Nadri H, Emami S, FiroozpourL, Shafiee A, Foroumadi A. Synthesis, biological evaluationand docking study of 3-aroyl-1-(4-sulfamoylphenyl)thioureaderivatives as 15-lipoxygenase inhibitors. Eur J Med Chem2014; 82: 308-13.
46. 46. Katritzky AR, Kirichenko N, Rogovoy BV, Kister J, Tao H.Synthesis of Mono- and N,N-Disubstituted Thioureas andN-Acylthioureas. Synthesis 2004; 11: 1799-805.
47. 47. Khan SA, Asiri AM, Yusuf M. Synthesis and biologicalevaluation of some thiazolidinone derivatives of steroid asantibacterial agents. Eur J Med Chem 2009; 44: 2597-600.
48. 48. Ottana R, Maccari R, Ciurleo R, Paoli P, Jacomelli M, Manao G,Camici G, Laggner C, Langer T. 5-Arylidene-2-phenylimino-4-thiazolidinones as PTP1B and LMW-PTP inhibitors. BioorgMed Chem 2009; 17: 1928-37.
49. 49. Hou T, Xu X. Recent development and application of virtualscreening in drug discovery: an overview. Curr Pharm Des2004; 10: 1011-33.
50. 50. Van de Waterbeemd H, Gifford E. ADMET in silico modelling:towards prediction paradise? Nat Rev Drug Discov 2003; 2:192-204.
51. 51. Hou T, Wang J, Zhang W, Xu X. ADME evaluation in drugdiscovery. 6. Can oral bioavailability in humans be effectivelypredicted by simple molecular property-based rules? J ChemInf Model 2007; 47: 460-3.
52. 52. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ.Experimental and computational approaches to estimatesolubility and permeability in drug discovery and developmentsettings. Adv Drug Deliv Rev 2001; 46: 3-26.
53. 53. Bratislava Slovak Republic. “Molinspiration Cheminformatics”.,[Accessed: 27 September, 2016].
54. 54. Zhao YH, Abraham MH, Le J, Hersey A, Luscombe CN, BeckG, Sherborne B, Cooper I. Rate-limited steps of human oralabsorption and QSAR studies. Pharm Res 2002; 19: 1446-57.
55. 55. Ertl P, Rohde B, Selzer P. Fast calculation of molecular polarsurface area as a sum of fragment-based contributions and itsapplication to the prediction of drug transport properties. JMed Chem 2000; 43: 3714-7.
56. 56. Sarkis GY, Faisal ED. Synthesis and spectroscopic properties ofsome new N,N’-disubstituted thioureas of potential biologicalinterest. J Heterocyclic Chem 1985; 22: 137-40.
57. 57. Golardo-Godoy A, Gever J, Fife KL, Silber BM, Prusiner SB,Renslo AR. 2-Aminothiazoles as therapeutic leads for priondiseases. J Med Chem 2011; 54: 1010-21.