A comprehensive study on crystal structure of a novel sulfonamide-dihydroquinolinone through experimental and theoretical approaches

  • C. A. Moreira
  • J. M. F. CustódioEmail author
  • W. F. Vaz
  • G. D. C. D’Oliveira
  • C. Noda Perez
  • H. B. Napolitano
Original Paper


Quinolinones and sulfonamides are moieties with biological potential that can be linked to form new hybrid compounds with improved potential. However, there are few hybrids of these molecules reported. In this sense, this work presents a structural description of a new sulfonamide-dihydroquinolinone (E)-2-(2-methoxyphenyl)-3-(3-nitrobenzylidene)-1-(phenylsulfonyl)-2,3 dihydroquinolin-4(1H)-one (DHQ). The molecular structure of DHQ was elucidated by X-ray diffraction, nuclear magnetic resonance and infrared spectroscopy, and both molecular packing and intermolecular interactions were analyzed by Hirshfeld surfaces and fingerprint maps. In addition, theoretical calculations on frontier orbitals, molecular electrostatic potential maps, and assignments were performed. The crystal packing of DHQ was found to be stabilized by a dimer through a weak C–H⋯O interaction along the c axis. Moreover, the structure is stabilized mainly by C–H⋯O and C–H⋯π interactions, since the interaction C25–H25⋯π contributes to a chain formation. The Hirshfeld normalized surface shows that the closest interactions are around the atoms linked to the dimer formation. The calculations indicate that DHQ possesses electrophilic sites near O atoms and depleted electrons around the H atoms. There is a band GAP of 3.29 eV between its frontier orbitals, which indicates that DHQ is more reactive than other analogues published.


Quinolinones Hirshfeld surfaces IR assignments 



The authors would like to thank the financial support of Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). This research was developed with support of the High Performance Computing Center of Universidade Estadual de Goiás (UEG).


  1. 1.
    Viegas-Junior C, Danuello A, da Silva Bolzani V et al (2007) Molecular hybridization: a useful tool in the design of new drug prototypes. Curr Med Chem 14:1829–1852. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Walsh J, Bell A (2009) Hybrid drugs for malaria. Curr Pharm Des 15:2970–2985. CrossRefPubMedGoogle Scholar
  3. 3.
    Guantai EM, Ncokazi K, Egan TJ et al (2010) Design, synthesis and in vitro antimalarial evaluation of triazole-linked chalcone and dienone hybrid compounds. Bioorg Med Chem 18:8243–8256. CrossRefPubMedGoogle Scholar
  4. 4.
    Lazar C, Kluczyk A, Kiyota T, Konishi Y (2004) Drug evolution concept in drug design: 1. Hybridization method. J Med Chem.
  5. 5.
    Singh P, Raj R, Kumar V et al (2012) 1,2,3-Triazole tethered β-lactam-Chalcone bifunctional hybrids: synthesis and anticancer evaluation. Eur J Med Chem 47:594–600. CrossRefPubMedGoogle Scholar
  6. 6.
    Lacerda RB, de Lima CKF, da Silva LL et al (2009) Discovery of novel analgesic and anti-inflammatory 3-arylamine-imidazo[1,2-a]pyridine symbiotic prototypes. Bioorg Med Chem 17:74–84. CrossRefPubMedGoogle Scholar
  7. 7.
    Domínguez JN, León C, Rodrigues J et al (2005) Synthesis and antimalarial activity of sulfonamide chalcone derivatives. Farmaco 60:307–311. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Kobkeatthawin T, Chantrapromma S, Chidan Kumar CS, Fun H-K (2015) Synthesis, characterization, and crystal structure of sulfonamide chalcone: (E)-4-methoxy-N-(4-(3-(3,4,5-trimethoxyphenyl)acryloyl)phenyl)-benzenesulfonamide. Crystallogr Rep 60:1058–1064. CrossRefGoogle Scholar
  9. 9.
    Seo WD, Kim JH, Kang JE et al (2005) Sulfonamide chalcone as a new class of α-glucosidase inhibitors. Bioorg Med Chem Lett 15:5514–5516. CrossRefPubMedGoogle Scholar
  10. 10.
    Tashima T (2015) The structural use of carbostyril in physiologically active substances. Bioorg Med Chem Lett 25:3415–3419. CrossRefPubMedGoogle Scholar
  11. 11.
    Charushin VN, Mochulskaya NN, Antipin FV et al (2018) Synthesis and antimycobacterial evaluation of new (2-oxo-2H-chromen-3-yl) substituted fluoroquinolones. J Fluor Chem 208:15–23. CrossRefGoogle Scholar
  12. 12.
    Tashima T, Murata H, Kodama H (2014) Design and synthesis of novel and highly-active pan-histone deacetylase (pan-HDAC) inhibitors. Bioorg Med Chem 22:3720–3731. CrossRefPubMedGoogle Scholar
  13. 13.
    Savanur HM, Pawashe GM, Kim KM, Kalkhambkar RG (2018) Synthesis and molecular modeling studies of Coumarin- and 1-Aza-Coumarin-linked miconazole analogues and their antifungal activity. ChemistrySelect 3:9648–9653. CrossRefGoogle Scholar
  14. 14.
    O’Brien NJ, Brzozowski M, Wilson DJD et al (2014) Synthesis and biological evaluation of substituted 3-anilino-quinolin-2(1H)-ones as PDK1 inhibitors. Bioorg Med Chem 22:3781–3790. CrossRefPubMedGoogle Scholar
  15. 15.
    Kraus JM, Tatipaka HB, McGuffin SA et al (2010) Second generation analogues of the Cancer drug clinical candidate Tipifarnib for anti-Chagas disease drug discovery. J Med Chem 53:3887–3898. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Nqoro X, Tobeka N, Aderibigbe B et al (2017) Quinoline-based hybrid compounds with antimalarial activity. Molecules 22:2268. CrossRefPubMedCentralGoogle Scholar
  17. 17.
    Custodio JMF, Michelini LJ, de Castro MRC et al (2018) Structural insights into a novel anticancer sulfonamide chalcone. New J Chem 42:3426–3434. CrossRefGoogle Scholar
  18. 18.
    Lee B, Kang W, Shon J et al (2014) Potential of 4′-(p-toluenesulfonylamide)-4-hydroxychalcone to inhibit the human cytochrome P450 2J2 isoform. J Korean Soc Appl Biol Chem 57:31–34. CrossRefGoogle Scholar
  19. 19.
    Stoob K, Singer HP, Mueller SR et al (2007) Dissipation and transport of veterinary sulfonamide antibiotics after manure application to grassland in a small catchment. Environ Sci Technol. doi:
  20. 20.
    Beaver KA, Siegmund AC, Spear KL (1996) Application of the sulfonamide functional group as an anchor for solid phase organic synthesis (SPOS). Tetrahedron Lett 37:1145–1148. CrossRefGoogle Scholar
  21. 21.
    Gryzło B, Kulig K (2014) Quinoline – a promising fragment in the search for new Antimalarials. Mini Rev Med Chem 14:332–344. CrossRefPubMedGoogle Scholar
  22. 22.
    Sunduru N, Srivastava K, Rajakumar S et al (2009) Synthesis of novel thiourea, thiazolidinedione and thioparabanic acid derivatives of 4-aminoquinoline as potent antimalarials. Bioorg Med Chem Lett 19:2570–2573. CrossRefPubMedGoogle Scholar
  23. 23.
    Ghorab MM, Ragab FA, Hamed MM (2009) Design, synthesis and anticancer evaluation of novel tetrahydroquinoline derivatives containing sulfonamide moiety. Eur. J Med Chem 44:4211–4217. CrossRefPubMedGoogle Scholar
  24. 24.
    Yurttaş L, Çiftçi GA (2018) New Quinoline based sulfonamide derivatives: cytotoxic and apoptotic activity evaluation against pancreatic Cancer cells. Anti Cancer Agents Med Chem 18:1122–1130. CrossRefGoogle Scholar
  25. 25.
    Alqasoumi SI, Al-Taweel AM, Alafeefy AM et al (2010) Novel quinolines and pyrimido[4,5-b]quinolines bearing biologically active sulfonamide moiety as a new class of antitumor agents. Eur. J Med Chem 45:738–744. CrossRefPubMedGoogle Scholar
  26. 26.
    Zajdel P, Marciniec K, Maślankiewicz A et al (2012) Quinoline- and isoquinoline-sulfonamide derivatives of LCAP as potent CNS multi-receptor—5-HT1A/5-HT2A/5-HT7 and D2/D3/D4—agents: the synthesis and pharmacological evaluation. Bioorg Med Chem 20:1545–1556. CrossRefPubMedGoogle Scholar
  27. 27.
    Kim JH, Ryu HW, Shim JH et al (2009) Development of new and selective Trypanosoma cruzi trans-sialidase inhibitors from sulfonamide chalcones and their derivatives. ChemBioChem 10:2475–2479. CrossRefPubMedGoogle Scholar
  28. 28.
    Ahmed NS, Badahdah KO, Qassar HM (2017) Novel quinoline bearing sulfonamide derivatives and their cytotoxic activity against MCF7 cell line. Med Chem Res 26:1201–1212. CrossRefGoogle Scholar
  29. 29.
    Afzal O, Kumar S, Haider MR et al (2015) A review on anticancer potential of bioactive heterocycle quinoline. Eur. J Med Chem 97:871–910. CrossRefPubMedGoogle Scholar
  30. 30.
    Groom CR, Bruno IJ, Lightfoot MP, Ward SC (2016) The Cambridge structural database. Acta Crystallogr Sect B Struct Sci Cryst Eng Mater 72:171–179. CrossRefGoogle Scholar
  31. 31.
    Wang HM, Zhang L, Liu J et al (2015) Synthesis and anti-cancer activity evaluation of novel prenylated and geranylated chalcone natural products and their analogs. Eur J Med Chem 92:439–448. CrossRefPubMedGoogle Scholar
  32. 32.
    de Castro MRC, Aragão ÂQ, Da Silva CC et al (2016) Conformational variability in sulfonamide chalcone hybrids: crystal structure and cytotoxicity. J Braz Chem Soc 27:884–898. CrossRefGoogle Scholar
  33. 33.
    Custodio JMF, D’Oliveira GDC, Gotardo F et al (2019) Chalcone as potential nonlinear optical material: a combined theoretical, structural, and spectroscopic study. J Phys Chem C 123:5931–5941. CrossRefGoogle Scholar
  34. 34.
    Sheldrick GM (2008) A short history of SHELX. Acta Crystallogr A 64:112–122. CrossRefPubMedGoogle Scholar
  35. 35.
    Turner MJ, McKinnon JJ, Wolff SK et al (2017) CrystalExplorer17. University of Western Australia. http://hirshfeldsurface.netGoogle Scholar
  36. 36.
    McKinnon JJ, Jayatilaka D, Spackman MA (2007) Towards quantitative analysis of intermolecular interactions with Hirshfeld surfaces. Chem Commun 68:3814. CrossRefGoogle Scholar
  37. 37.
    McKinnon JJ, Spackman MA, Mitchell AS (2004) Novel tools for visualizing and exploring intermolecular interactions in molecular crystals. Acta Crystallogr Sect B Struct Sci 60:627–668. CrossRefGoogle Scholar
  38. 38.
    Koenderink JJ, van Doorn AJ (1992) Surface shape and curvature scales. Image Vis Comput 10:557–564. CrossRefGoogle Scholar
  39. 39.
    Spackman MA, McKinnon JJ (2002) Fingerprinting intermolecular interactions in molecular crystals. CrystEngComm 4:378–392. CrossRefGoogle Scholar
  40. 40.
    Becke AD (1993) Density-functional thermochemistry. III. The role of exact exchange. J Chem Phys 98:5648. CrossRefGoogle Scholar
  41. 41.
    Merrick JP, Moran D, Radom L (2007) An evaluation of harmonic vibrational frequency scale factors. J Phys Chem A 111:11683–11700. CrossRefPubMedGoogle Scholar
  42. 42.
    Foresman JB, Frisch AE (1996) Exploring chemistry with electronic structure methods, Segunda. Gaussian, Inc, PittsburghGoogle Scholar
  43. 43.
    Buczek A, Kupka T, Broda MA, Żyła A (2016) Predicting the structure and vibrational frequencies of ethylene using harmonic and anharmonic approaches at the Kohn–sham complete basis set limit. J Mol Model 22:42. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Jamroz MH (2004) Vibrational energy distribution analysis VEDA 4, Warsaw. Scholar
  45. 45.
    Dennington R, Keith T, Millam J (2009) GaussView, Version 5. Semichem Inc., Shawnee MissionGoogle Scholar
  46. 46.
    Bruno IJ, Cole JC, Kessler M et al (2004) Retrieval of Crystallographically-derived molecular geometry information. J Chem Inf Comput Sci 44:2133–2144. CrossRefPubMedGoogle Scholar
  47. 47.
    Macrae CF, Bruno IJ, Chisholm JA et al (2008) Mercury CSD 2.0 – new features for the visualization and investigation of crystal structures. J Appl Crystallogr 41:466–470. CrossRefGoogle Scholar
  48. 48.
    Spek AL (2010) THE PLATON CRYSTALLOGRAPHIC PACKAGE DOCUMENTATION - VERSION 29-09-2010 overview of THE content of this document chapter 0 – general introduction to the PLATON package. Acta Crystallogr D65:148–155Google Scholar
  49. 49.
    Karabacak M, Çınar M, Çoruh A, Kurt M (2009) Theoretical investigation on the molecular structure, infrared, Raman and NMR spectra of Para-halogen benzenesulfonamides, 4-X-C6H4SO2NH2 (X=Cl, Br or F). J Mol Struct 919:26–33. CrossRefGoogle Scholar
  50. 50.
    Pavia DL, Lampman GM, Kriz GS, Vyvyan JA (2015) Introduction to spectroscopy, 5th edn. Cengage learning, MasonGoogle Scholar
  51. 51.
    Panicker CY, Varghese HT, John MA, Harikumar B (2008) IR, Raman and ab-initio calcualtions of 2 , 6-dimethoxyphenol. Orient J Chem 24:973–976Google Scholar
  52. 52.
    Raja B, Balachandran V, Revathi B, Anitha K (2018) Molecular structure, vibrational spectroscopic, natural bond orbital analysis, frontier molecular orbital analysis and thermodynamic properties of N-tert-butoxy carbonyl-L-phenylalanine by DFT methods. Mater Res Innov.
  53. 53.
    Pearson RG (1986) Absolute electronegativity and hardness correlated with molecular orbital theory. Proc Natl Acad Sci U S A 83:8440–8441. CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Oliveira SS, Santin LG, Almeida LR et al (2017) Synthesis, characterization, and computational study of the supramolecular arrangement of a novel cinnamic acid derivative. J Mol Model 23:35. CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • C. A. Moreira
    • 1
  • J. M. F. Custódio
    • 2
    Email author
  • W. F. Vaz
    • 1
  • G. D. C. D’Oliveira
    • 2
  • C. Noda Perez
    • 2
  • H. B. Napolitano
    • 1
    • 3
  1. 1.Grupo de Química Teórica e Estrutural de AnápolisUniversidade Estadual de GoiásAnápolisBrazil
  2. 2.Instituto de QuímicaUniversidade Federal de GoiásGoiâniaBrazil
  3. 3.Laboratorio de Novos MateriaisCentro Universitário de AnápolisAnápolisBrazil

Personalised recommendations