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Medicinal Chemistry Research

, Volume 26, Issue 12, pp 3136–3148 | Cite as

Synthesis, biological evaluation and in silico study of bis-thiourea derivatives as anticancer, antimalarial and antimicrobial agents

  • Ratchanok Pingaew
  • Nujarin Sinthupoom
  • Prasit Mandi
  • Veda Prachayasittikul
  • Rungrot Cherdtrakulkiat
  • Supaluk Prachayasittikul
  • Somsak Ruchirawat
  • Virapong Prachayasittikul
Original Research

Abstract

Two sets of bis-thioureas including a para series (814) and a meta series (4, 5, 1519), were synthesized and evaluated for their anticancer, antimalarial and antimicrobial activities. Most of the synthesized bis-thioureas, except for analogs 811, displayed cytotoxicity against MOLT-3 cell line (IC50 = 1.55–32.32 µM). Derivatives 5, 14, 18 and 19 showed a broad spectrum of anticancer activity. Analogs (4, 5, 8, 13, 14, 18 and 19) exhibited higher inhibitory efficacy in HepG2 cells than the control drug, etoposide. Significantly, bis-trifluoromethyl analog 19 was the promising potent cytotoxic agent (IC50 = 1.50–18.82 µM) with the best safety index (1.64–20.60). Antimalarial activity results showed that trifluoromethyl derivative 18 was the most potent compound (IC50 = 1.92 µM, selective index = 6.86). Antimicrobial activity revealed that bis-thioureas 12, 18 and 19 exhibited selective activity against Gram-positive bacteria and fungi. Promisingly, the bis-trifluoromethyl derivative 19 was the most potent compound in the series and displayed higher potency, against most of the Gram-positive bacteria and fungi, than that of ampicillin, the reference drug. Among the tested strains of microorganisms, compound 19 inhibited the growth of Staphylococcus epidermidis ATCC 12228 and Micrococcus luteus ATCC 10240 with the lowest MIC of 1.47 µM. The findings demonstrated that trifluoromethyl group plays a crucial role in their biological activities. Furthermore, the molecular docking was performed to reveal possible binding modes of the compounds against target proteins.

Keywords

Thiourea Trifluoromethyl group Anticancer activity Antimalarial activity Antimicrobial activity Molecular docking 

Notes

Acknowledgements

This project is financially supported by Srinakharinwirot University (grant no. 497/2559). Great supports from the office of the Higher Education Commission and Mahidol University under the National Research Universities Initiative are appreciated. We are also indebted to Chulabhorn Research Institute for recording mass spectra and bioactivity testing.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

44_2017_2008_MOESM1_ESM.doc (19 mb)
Supplementary Information

References

  1. Azam MA, Thathan J, Jubie S (2015) Dual targeting DNA gyrase B (GyrB) and topoisomerse IV (ParE) inhibitors: a review. Bioorg Chem 62:41–63CrossRefPubMedGoogle Scholar
  2. Basarab GS, Manchester JI, Bist S, Boriack-Sjodin PA, Dangel B, Illingworth R, Sherer BA, Sriram S, Uria-Nickelsen M, Eakin AE (2013) Fragment-to-hit-to-lead discovery of a novel pyridylurea scaffold of ATP competitive dual targeting type II topoisomerase inhibiting antibacterial agents. J Med Chem 56:8712–8735CrossRefPubMedGoogle Scholar
  3. Bielenica A, Stefańska J, Stępień K, Napiórkowska A, Augustynowicz-Kopeć E, Sanna G, Madeddu S, Boi S, Giliberti G, Wrzosek M, Struga M (2015) Synthesis, cytotoxicity and antimicrobial activity of thiourea derivatives incorporating 3-(trifluoromethyl)phenyl moiety. Eur J Med Chem 101:111–125CrossRefPubMedGoogle Scholar
  4. BioVia (2017) Discovery Studio Visualizer version 16.1.0.15350, San Diego, CAGoogle Scholar
  5. Böhm H-J, Banner D, Bendels S, Kansy M, Kuhn B, Müller K, Obst-Sander U, Stahl M (2004) Fluorine in medicinal chemistry. Chembiochem 5:637–643CrossRefPubMedGoogle Scholar
  6. Carmichael J, DeGraff WG, Gazdar AF, Minna JD, Mitchell JB (1987) Evaluation of a tetrazolium-based semiautomated colorimetrie assay: assessment of radiosensitivity. Cancer Res 47:943–946PubMedGoogle Scholar
  7. Charifson PS, Grillot A-L, Grossman TH, Parsons JD, Badia M, Bellon S, Deininger DD, Drumm JE, Gross CH, Le Tiran A, Liao Y, Mani N, Nicolau DP, Perola E, Ronkin S, Shannon D, Swenson LL, Tang Q, Tessier PR, Tian S-K, Trudeau M, Wang T, Wei Y, Zhang H, Stamos D (2008) Novel dual-targeting benzimidazole urea inhibitors of DNA gyrase and topoisomerase IV possessing potent antibacterial activity: intelligent design and evolution through the judicious use of structure-guided design and stucture-activity relationships. J Med Chem 51:5243–5263CrossRefPubMedGoogle Scholar
  8. ChemAxon (2013) MarvinSketch Version 6.0, Budapest, Hungary. https://www.chemaxon.com/
  9. Cunha S, MacEdo Jr FC, Costa GAN, Rodrigues Jr MT, Verde RBV, De Souza Neta LC, Vencato I, Lariucci C, Sá FP (2007) Antimicrobial activity and structural study of disubstituted thiourea derivatives. Monatsh Chem 138:511–516CrossRefGoogle Scholar
  10. Dallakyan S (2013) PyRx Version 0.8. http://pyrx.scripps.eduGoogle Scholar
  11. Delano W (2002) PyMOL Release 0.99. DeLano Scientific LLC, Pala Alto, CAGoogle Scholar
  12. Desjardins RE, Canfield CJ, Haynes JD, Chulay JD (1979) Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique. Antimicrob Agents Chemother 16:710–718CrossRefPubMedPubMedCentralGoogle Scholar
  13. Doyle A, Griffiths JB (1997) Mammalian cell culture: essential techniques. Wiley, Chichester, UKGoogle Scholar
  14. Ehmann DE, Lahiti SD (2014) Novel compounds targeting bacterial DNA topoisomerase/DNA gyrase. Curr Opin Pharmacol 18:76–83CrossRefPubMedGoogle Scholar
  15. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T. Montgomery JA Jr, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross, J.B., Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski V.G, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian 09, Gaussian Inc., Wallingford, CTGoogle Scholar
  16. Grillot A-L, Le Tiran A, Shannon D, Krueger E, Liao Y, O’Dowd H, Tang Q, Ronkin S, Wang T, Waal N, Li P, Lauffer D, Sizensky E, Tanoury J, Perola E, Grossman TH, Doyle T, Hanzelka B, Jones S, Dixit V, Ewing N, Liao S, Boucher B, Jacobs M, Bennani Y, Charifson PS (2014) Second-generation antibacterial benzimidazole ureas: discovery of a preclinical candidate with reduced metabolic liability. J Med Chem 57:8792–8816CrossRefPubMedGoogle Scholar
  17. Gulgas CG, Reineke TM (2008) Macrocyclic Eu3+ chelates show selective luminescence responses to anions. Inorg Chem 47:1548–1559CrossRefPubMedGoogle Scholar
  18. Hunt L, Jordan M, De Jesus M, Wurm FM (1999) GFP-expressing mammalian cells for fast, sensitive, noninvasive cell growth assessment in a kinetic mode. Biotechnol Bioeng 65:201–205CrossRefPubMedGoogle Scholar
  19. Jones CES, Turega SM, Clarke ML, Philp D (2008) A rationally designed cocatalyst for the Morita-Baylis-Hillman reaction. Tetrahedron Lett 49:4666–4669CrossRefGoogle Scholar
  20. Kumar V, Chimni SS (2015) Recent developments on thiourea based anticancer chemotherapeutics. Anticancer Agents Med Chem 15:163–175CrossRefPubMedGoogle Scholar
  21. Li H-Q, Lv P-C, Yan T, Zhu H-L (2009) Urea derivatives as anticancer agents. Anticancer Agents Med Chem 9:471–480CrossRefPubMedGoogle Scholar
  22. Liu S, Louie MC, Rajagopalan V, Zhou G, Ponce E, Nguyen T, Green L (2015) Synthesis and evaluation of the diarylthiourea analogs as novel anti-cancer agents. Bioorg Med Chem Lett 25:1301–1305CrossRefPubMedGoogle Scholar
  23. Mishra A, Batra S (2013) Thiourea and Guanidine derivatives as antimalarial and antimicrobial agents. Curr Top Med Chem 13:2011–2025CrossRefPubMedGoogle Scholar
  24. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30:2785–2791CrossRefPubMedPubMedCentralGoogle Scholar
  25. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63CrossRefPubMedGoogle Scholar
  26. Müller K, Faeh C, Diederich F (2007) Fluorine in pharmaceuticals: looking beyond intuition. Science 317:1881–1886CrossRefPubMedGoogle Scholar
  27. Nowotarski SL, Pachaiyappan B, Holshouser SL, Kutz CJ, Li Y, Huang Y, Sharma SK, Casero Jr RA, Woster PM (2015) Structure-activity study for (bis)ureidopropyl- and (bis)thioureidopropyldiamine LSD1 inhibitors with 3-5-3 and 3-6-3 carbon backbone architectures. Bioorg Med Chem 23:1601–1612CrossRefPubMedPubMedCentralGoogle Scholar
  28. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) UCSF Chimera-a visualization system for exploratory research and analysis. J Comput Chem 25:1605–1612CrossRefPubMedGoogle Scholar
  29. Pingaew R, Tongraung P, Worachartcheewan A, Nantasenamat C, Prachayasittikul S, Ruchirawat S, Prachayasittikul V (2013) Cytotoxicity and QSAR study of (thio)ureas derived from phenylalkylamines and pyridylalkylamines. Med Chem Res 22:4016–4029CrossRefGoogle Scholar
  30. Prachayasittikul S, Worachartcheewan A, Nantasenamat C, Chinworrungsee M, Sornsongkhram N, Ruchirawat S, Prachayasittikul V (2011) Synthesis and structure-activity relationship of 2-thiopyrimidine-4-one analogs as antimicrobial and anticancer agents. Eur J Med Chem 46:738–742CrossRefPubMedGoogle Scholar
  31. Purser S, Moore PR, Swallow S, Gouverneur V (2008) Fluorine in medicinal chemistry. Chem Soc Rev 37:320–330CrossRefPubMedGoogle Scholar
  32. Saeed A, Shaheen U, Hameed A, Naqvi SZH (2009) Synthesis, characterization and antimicrobial activity of some new 1-(fluorobenzoyl)-3-(fluorophenyl)thioureas. J Fluor Chem 130:1028–1034CrossRefGoogle Scholar
  33. Sanner MF (1999) Python: a programming language for software integration and development. J Mol Graph Mod 17:57–61Google Scholar
  34. Sharma SK, Wu Y, Steinbergs N, Crowley ML, Hanson AS, Casero Jr RA, Woster PM (2010) (Bis)urea and (bis)thiourea inhibitors of lysine-specific demethylase 1 as epigenetic modulators. J Med Chem 53:5197–5212CrossRefPubMedPubMedCentralGoogle Scholar
  35. Shing JC, Choi JW, Chapman R, Schroeder MA, Sarkaria JN, Fauq A, Bram RJ (2014) A novel synthetic 1,3-phenyl bis-thiourea compound targets microtubule polymerization to cause cancer cell death. Cancer Biol Ther 15:895–905CrossRefPubMedPubMedCentralGoogle Scholar
  36. Smart BE (2001) Fluorine substituent effects (on bioactivity). J Fluor Chem 109:3–11CrossRefGoogle Scholar
  37. Stefanska J, Nowicka G, Struga M, Szulczyk D, Koziol AE, Augustynowicz-Kopec E, Napiorkowska A, Bielenica A, Filipowski W, Filipowska A, Drzewiecka A, Giliberti G, Madeddu S, Boi S, Colla PL, Sanna G (2015) Antimicrobial and anti-biofilm activity of thiourea derivatives incorporating a 2-aminothiazole scaffold. Chem Pharm Bull 63:225–236CrossRefPubMedGoogle Scholar
  38. Suresha GP, Suhas R, Kapfo W, Gowda DC (2011) Urea/thiourea derivatives of quinazolinone-lysine conjugates: Synthesis and structure-activity relationships of a new series of antimicrobials. Eur J Med Chem 46:2530–2540CrossRefPubMedGoogle Scholar
  39. Tahir S, Badshah A, Hussain RA, Tahir MN, Tabassum S, Patujo JA, Rauf MK (2015) DNA-binding studies and biological activities of new nitrosubstituted acyl thioureas. J Mol Struct 1099:215–225CrossRefGoogle Scholar
  40. Trager W, Jensen JB (1976) Human malaria parasites in continuous culture. Science 193:673–675CrossRefPubMedGoogle Scholar
  41. Vega-Pérez JM, Periñán I, Argandoña M, Vega-Holm M, Palo-Nieto C, Burgos-Morón E, López-Lázaro M, Vargas C, Nieto JJ, Iglesias-Guerra F (2012) Isoprenyl-thiourea and urea derivatives as new farnesyldiphosphate analogues: Synthesis and in vitro antimicrobial and cytotoxic activities. Eur J Med Chem 58:591–612CrossRefPubMedGoogle Scholar
  42. Verlinden BK, de Beer M, Pachaiyappan B, Besaans E, Andayi WA, Reader J, Niemand J, van Biljon R, Guy K, Egan T, Woster PM, Birkholtz L (2015) Interrogating alkyl and arylalkylpolyamino (bis)urea and (bis)thioureaisosteres as potent antimalarial chemotypes against multiple lifecycle forms of Plasmodium falciparum parasites. Bioorg Med Chem 23:5131–5143CrossRefPubMedPubMedCentralGoogle Scholar
  43. Verlinden BK, Niemand J, Snyman J, Sharma SK, Beattie RJ, Woster PM, Birkholtz L (2011) Discovery of novel alkylated (bis)urea and (bis)thiourea polyamine analogues with potent antimalarial activities. J Med Chem 54:6624–6633CrossRefPubMedPubMedCentralGoogle Scholar
  44. Vriend G (1990) WHAT IF: a molecular modeling and drug design program. J Mol Graph 8:52–56CrossRefPubMedGoogle Scholar
  45. Wang J, Sánchez-Roselló M, Aceña JL, del Pozo C, Sorochinsky AE, Fustero S, Soloshonok VA, Liu H (2014) Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade (2001−2011). Chem Rev 114:2432–2506CrossRefPubMedGoogle Scholar
  46. Zhu W, Wang J, Wang S, Gu Z, Aceña JL, Izawa K, Liu H, Soloshonok VA (2014) Recent advances in the trifluoromethylation methodology and new CF3-containing drugs. J Fluor Chem 167:37–54CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Ratchanok Pingaew
    • 1
  • Nujarin Sinthupoom
    • 2
  • Prasit Mandi
    • 3
  • Veda Prachayasittikul
    • 4
  • Rungrot Cherdtrakulkiat
    • 2
  • Supaluk Prachayasittikul
    • 4
  • Somsak Ruchirawat
    • 5
    • 6
    • 7
  • Virapong Prachayasittikul
    • 2
  1. 1.Department of Chemistry, Faculty of ScienceSrinakharinwirot UniversityBangkokThailand
  2. 2.Department of Clinical Microbiology and Applied Technology, Faculty of Medical TechnologyMahidol UniversityBangkokThailand
  3. 3.Department of Community Medical Technology, Faculty of Medical TechnologyMahidol UniversityBangkokThailand
  4. 4.Center of Data Mining and Biomedical Informatics, Faculty of Medical TechnologyMahidol UniversityBangkokThailand
  5. 5.Chulabhorn Research InstituteBangkokThailand
  6. 6.Program in Chemical BiologyChulabhorn Graduate InstituteBangkokThailand
  7. 7.Center of Excellence on Environmental Health and Toxicology (EHT), CHEMinistry of EducationBangkokThailand

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