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Design, synthesis, molecular docking and cytotoxic activity of novel urea derivatives of 2-amino-3-carbomethoxythiophene

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Abstract

An efficient feasible route for the one-pot synthesis of novel series of urea derivatives (2a–2j) from 2-amino-3-carbomethoxythiophene (1) via in situ isocyanate has been developed, and their corresponding anticancer activities were accomplished. The series of urea derivatives were characterized by using 1H, 13C nuclear magnetic resonance and mass spectroscopic analysis. The cytotoxic activities were evaluated against human cervical (HeLa) and human lung (NCI-H23) cancer cell lines. These studies revealed satisfactory activity for some of the compounds, which could potentially serve as lead compounds for drug discovery and development. Furthermore, molecular docking studies supported in identifying the potential binding sites between the urea derivatives and eukaryotic ribonucleotidereductase (RR). High ambiguity driven docking (HADDOCK) modelling was specifically employed to determine the model complex of RR and urea derivatives. The proposed model has provided a deep insight into the molecular level interactions of RR-urea model complexes in understanding the exact pharmacophore for designing highly potent RR inhibitors. Overall, the present work has shed light in developing a feasible and robust approach for the synthesis of novel urea derivatives of 2-amino-3-carbomethoxythiophene and identified a part of molecular structure that is responsible for a specific biological interaction leading to potential anticancer activities.

Graphic abstract

We report herein, the experimental design, synthesis and characterization of a novel series of urea derivatives of 2-amino-3carbomethoxythiophene with pyrimidine amine and benzyl amine analogues as both derivatives which exhibited potential antitumor activity via one pot synthesis and subsequently studied the structure activity relationships (SAR), and anticancer activities. The docking studies identified a part of molecularstructure that is responsible for a specific biological interaction leading to the destruction of cancer cells.

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References

  1. Xu H, Faber C, Uchiki T, Racca J and Dealwis C 2006 Structures of eukaryotic ribonucleotide reductase I define gemcitabine diphosphate binding and subunit assembly PNAS 103 4028

    Article  CAS  Google Scholar 

  2. Van der Donk W A, Yu G, Silva D J, Stubbe J, McCarthy J R, Jarvi E T, Matthews D P, Resvick R J and Wagner E 1996 Inactivation of ribonucleotide reductase by (E)-2’-Fluoromethylene-2’-deoxycytidine 5’-diphosphate:  A paradigm for nucleotide mechanism-based inhibitors Biochemistry 35 8381

  3. Mayhew C N, Phillips J D, Greenberg R N, Birch N J, Elford H L and Gallicchio V S 1999 In vivo and in vitro comparison of the short-term hematopoietic toxicity between hydroxyurea and trimidox or didox, novel ribonucleotide reductase inhibitors with potential anti-hiv-1 activity Stem Cells 17 345

  4. Szekeres T, Fritzer-Szekeres M, Elford H L and Jayaram H M 1997 The enzyme ribonucleotide reductase: Target for antitumor and anti-HIV therapy Crit. Rev. Clin. Lab. Sci. 34 503

    Article  CAS  Google Scholar 

  5. Karp J E, Giles F J, Gojo I, Morris L, Greer J, Johnson B, Thein M, Sznol M and Low J 2008 A phase I study of the novel ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine®) in combination with the nucleoside analog fludarabine for patients with refractory acute leukemias and aggressive myeloproliferative disorders Leuk Res. 32 71

  6. Xu H, Fairman J W, Wijerathna S R, Kreischer N R, Macchia J, Helmbrecht E, Cooperman B S and Dealwis C 2008 The structural basis for peptidomimetic inhibition of eukaryotic ribonucleotide reductase: A conformationally flexible pharmacophore J. Med. Chem. 51 4653

    Article  CAS  Google Scholar 

  7. Ren F, Zhong Y, Mai X, Liao Y J, Liu C, Feng L H, Sun W, Zen W B, Liu W M, Liu J and Jin N 2014 Synthesis and anticancer evaluation of benzyloxyurea derivatives Chem. Pharm. Bull. 62 898

    Article  CAS  Google Scholar 

  8. Moorthy N S H N, Cerqueira N M F S A, Ramos M J and Fernandes P A 2013 Development of ribonucleotide reductase inhibitor: A review on structure activity relationships Mini Rev. Med. Chem. 13 1389

  9. Hardjono S, Siswodihardjo S, Pramono P and Darmanto W 2016 Quantative structure cytotoxic activity relation 1-(Benzyoloxy)urea and its derivatives Curr. Drug Discov. Technol. 13 101

    Article  CAS  Google Scholar 

  10. Aversa C, Leone F, Zucchini G, Serini G, Geuna E, Milani A, Valdembri D, Martinello R and Montemurro F 2015 Linifanib: current status and future potential in cancer therapy Exp. Rev. Anticancer Ther. 15 677

    Article  CAS  Google Scholar 

  11. Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith R A, Schwartz B, Simantov R and Kelley S 2006 Discovery and development of sorafenib: A multikinase inhibitor for treating cancer Nat. Rev. Drug Discov. 5 835

    Article  CAS  Google Scholar 

  12. Kan R C, Farrell A T, Saber H, Tang S, Williams G, Jee J M, Liang C, Booth B, Chidambaram N, Morse D et al 2006 Sorafenib for the treatment of advanced renal cell carcinoma Clin. Cancer Res. 12 7271

    Article  Google Scholar 

  13. Keating G M and Santoro A 2009 Sorafenib Drugs 69 223

  14. Ferrari S M, Politti U, Spisni R, Materazzi G, Baldini E, Ulisse S, Miccoli P, Antonelli A and Fallahi P Sorafenib in the treatment of thyroid cancer Exp. Rev. Anticancer Ther. 15 863

  15. Capozzi M, De Divitiis C, Ottaiano A, von Arx C, Scala S, Tatangelo F, Delrio P and Tafuto S 2019 Lenvatinib, a molecule with versatile application: from preclinical evidence to future development in anti-cancer treatment Cancer Manag. Res. 11 3847

    Article  CAS  Google Scholar 

  16. Shimshomi J A, Bialer M, Wloderczyk B, Finnell R H and Yagen B 2007 Potent anticonvulsant urea derivatives of constitutional isomers of valproic acid J. Med. Chem. 50 6419

    Article  Google Scholar 

  17. Kumar M and Hosur M V 2003 Adaptability and flexibility of HIV-1 protease Eur. J. Biochem. 270 1231

    Article  CAS  Google Scholar 

  18. Zheng Q Z, Cheng K, Zhang X M, Liu K, Jiao Q C and Zhu H L 2010 Synthesis of some N-alkyl substituted urea derivatives as antibacterial and antifungal agents Eur. J. Med. Chem. 45 3207

    Article  CAS  Google Scholar 

  19. Watson R J, Daniel Allen R, Birch H L, Chapman G A, Galvin F C, Jopling L A, Knight R L, Meier D, Oliver K, Meissner J, David W G, Owen Elizabeth A, Thomas J, Tremayne N and Williams S C 2008 Development of CXCR3 antagonists. Part 3: Tropenyl and homotropenyl-piperidine urea derivatives. Bioorg. Med. Chem. Lett. 18 147

  20. Viana G M, Aguiara L C, Ferrao J A, Simas A B C and Vasconcelos M G 2013 The use of aqueous potassium dichloroiodate for the synthesis of ureas Tetrahedron Lett. 54 936

    Article  CAS  Google Scholar 

  21. Gewald K, Schinke E and Bottcher H 1966 Heterocyclen aus CH-aciden Nitrilen, VIII. 2-Amino-thiophene aus methylenaktiven Nitrilen, Carbonylverbindungen und Schwefel Chem. Ber. 99 94

  22. Bozorov K, FeiNie L, Zhao J and Haji A 2017 2-Aminothiophene scaffolds: Diverse biological and pharmacological attributes in medicinal chemistry Eur. J. Med. Chem. 140 465

    Article  CAS  Google Scholar 

  23. Aly H M, Saleh N M and Elhady H A 2011 Design and synthesis of some new thiophene, thienopyrimidine and thienothiadiazine derivatives of antipyrine as potential antimicrobial agents Eur. J. Med. Chem. 46 4566

    Article  CAS  Google Scholar 

  24. Massari S, Nannetti G, Goracci L, Sancineto L, Muratore G, Sabatini S, Manfroni G, Mercorelli B, Cecchetti V, Facchini M., Palù G, Cruciani G, Loregian A and Tabarrini O 2013 Structural investigation of cycloheptathiophene-3-carboxamide derivatives targeting influenza virus polymerase assembly J. Med. Chem. 56 10118

    Article  CAS  Google Scholar 

  25. Lu X, Wan B, Franzblau S G and You Q 2011 Design, synthesis and anti-tubercular evaluation of new 2-acylated and 2-alkylated amino-5-(4-(benzyloxy)phenyl)thiophene-3-carboxylic acid derivatives Eur. J. Med. Chem. 46 3551

    Article  CAS  Google Scholar 

  26. Aguiar A C V, Moura R O, Mendonça-Junior J F B, Oliveira Rocha H A D, Gomes R B, Amara C and Schiavon M D S C 2016 Evaluation of the antiproliferative activity of 2-amino thiophene derivatives against human cancer cells lines Biomed. Pharmacother. 84 403

    Article  Google Scholar 

  27. Romagnoli R, Baraldi P G, Cruz-Lopez O, Tolomeo M, Cristina A D, Pipitone R M, Grimaudo S, Balzarini J, Brancale A and Hame E 2011 Synthesis of novel antimitotic agents based on 2-amino-3-aroyl-5(hetero)arylethynyl thiophene derivatives Bioorg. Med. Chem. Lett. 21 2746

    Article  CAS  Google Scholar 

  28. Romagnoli R, Baraldi P G, Lopez-Cara C, Salvador M K, Preti D, Tabrizi M A, Balzarini J, Nussbaumer P, Bassetto M, Brancale A, Fu X-H, Yang G, Li J, Zhang S Z, Hamel E, Bortolozzi R, Basso G and Viola G 2014 Design, synthesis and biological evaluation of 3,5-disubstituted 2-amino thiophene derivatives as a novel class of antitumor agents Bioorg. Med. Chem. 22 5097

    Article  CAS  Google Scholar 

  29. Bozorov K, Zhao J Y, Fei Nie L, Ma H R, Bobakulov K, Hu R, Rustamova N, Huang G, Thomas E and Haji A A 2017 Synthesis and in vitro biological evaluation of novel diaminothiophene scaffolds as antitumor and anti-influenza virus agents RSC Adv. 7 31417

  30. Balzarini J, Thomas J, Liekens S, Noppen S, Dehaen W and Romagnoli R 2014 2-aminothiophene-3-carboxylic acid ester derivatives as novel highly selective cytostatic agents Invest. New Drugs 32 200

    Article  CAS  Google Scholar 

  31. Véras of Aguiar AC, of Moura RO, Bezerra Mendonça J F Junior, de Oliveira Rocha H A, Gomes Câmara R B and Dos Santos Carvalho Schiavon M 2016 Evaluation of the antiproliferative activity of 2-amino thiophene derivatives against human cancer cells lines Biomed. Pharmacother. 84 403

  32. Kaur R, Kaur P, Sharma S, Singh G, Mehndiratta S, Bedi P M S and Nepali K 2015 Anti-cancer pyrimidines in diverse scaffolds: a review of patent literature Recent Pat. Anticancer Drug Discov. 10 23

    Article  CAS  Google Scholar 

  33. Al-Issa S A 2013 Synthesis and anticancer activity of some fused pyrimidines and related heterocycles Saudi Pharm. J. 21 305

  34. Hackenberg F and Tacke M 2014 Benzyl-substituted metallocarbene antibiotics and anticancer drugs Dalton Trans. 43 8144

    Article  CAS  Google Scholar 

  35. Lebedev A V, Lebedeva A B, Sheludyakov V D et al 2006 Organosilicon synthesis of isocyanates: I. Synthesis of isocyanates of the furan, thiophene, and mono-and polyfluorophenyl series Russ. J. Gen. Chem 76 110

  36. Charalambides Y C and Moratti S C 2007 Comparison of base promoted and self catalyzed conditions in the synthesis of isocyanates from amines using triphosgene Synth. Commun. 37 1037

    Article  CAS  Google Scholar 

  37. Hempel J E, Cadar A G and Hong C C 2016 Development of thieno- and benzopyrimidinone inhibitors of the Hedgehog signaling pathway reveals PDE4-dependent and PDE4-independent mechanisms of action Bioorg. Med. Chem. Lett. 26 1947

    Article  CAS  Google Scholar 

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Acknowledgements

The docking studies were supported by grants from the National Institutes of Health (NIH): 1R01GM126833-01

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Authors and Affiliations

  1. Department of Chemistry, GITAM University, Rushikonda, Visakhapatnam, India

    Venugopalarao Vikram

  2. Department of Chemistry, Case Western Reserve University, Cleveland, OH, USA

    Srinivasa R Penumutchu

  3. Department of Bioscience and Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur, India

    Raviraj Vankayala

  4. Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan

    Suresh Thangudu

  5. Department of Chemistry, Gayatri Vidya Parishad College for Degree and PG Courses (A), Rushikonda, Visakhapatnam, India

    Karteek Rao Amperayani & Umadevi Parimi

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  1. Venugopalarao Vikram
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  2. Srinivasa R Penumutchu
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  3. Raviraj Vankayala
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  4. Suresh Thangudu
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Correspondence to Umadevi Parimi.

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Supplementary Information (SI)

1H NMR and 13C NMR data is available at www.ias.ac.in/chemsci.

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Vikram, V., Penumutchu, S.R., Vankayala, R. et al. Design, synthesis, molecular docking and cytotoxic activity of novel urea derivatives of 2-amino-3-carbomethoxythiophene. J Chem Sci 132, 126 (2020). https://doi.org/10.1007/s12039-020-01834-w

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  • DOI: https://doi.org/10.1007/s12039-020-01834-w

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