Molecular topology and QSAR multi-target analysis to boost the in silico research for fungicides in agricultural chemistry

  • Riccardo Zanni
  • Maria Galvez-Llompart
  • Inma Garcia-Pereira
  • Jorge Galvez
  • Ramon Garcia-DomenechEmail author
Original Article


The aim of the present study is to show how molecular topology can be a powerful in silico tool for the prediction of the fungicidal activity of several diphenylamine derivatives against three fungal species (cucumber downy mildew, rice blast and cucumber gray mold). A multi-target QSAR model was developed, and two strategies were followed. First is the construction of a virtual library of molecules using DesMol2 program and a subsequent selection of potential active ones. Second is the selection of molecules from the literature on the basis of molecular scaffolds. More than 700 diphenylamine derivatives designed and other 60 fluazinam’s derivatives with structural similarity higher than 80% were studied. Almost twenty percent of the molecules analyzed show potential activity against the three fungal species.


QSAR Molecular topology Drug design Agro-chemistry Fungicides 



Authors acknowledge the MINECO (Spanish Ministry of Economy, Industry and Competitivity) Project: “Desarrollo de nuevas herramientas para el control de oidios” (AGL2016-76216-C2-2-R). I.GP acknowledges the MECD (Spanish Ministry of Education, Culture and Sport) Program: “University teacher formation,” to carry out this study.

Supplementary material

11030_2018_9879_MOESM1_ESM.xlsx (274 kb)
Supplementary material 1 (XLSX 273 kb)


  1. 1.
    Kumar A, Tiwari A, Sharma A (2018) Changing paradigm from one target one ligand towards multi target directed ligand design for key drug targets of Alzheimer disease: an important role of in silico methods in multi target directed ligands design. Curr Neuropharmacol. CrossRefPubMedGoogle Scholar
  2. 2.
    Abeijon P, Garcia-Mera X, Caamano O, Yanez M, Lopez-Castro E, Romero-Duran FJ, Gonzalez-Diaz H (2017) Multi-target mining of alzheimer disease proteome with Hansch’s QSBR-perturbation theory and experimental-theoretic study of new thiophene isosters of rasagiline. Curr Drug Targets 18(5):511–521. CrossRefPubMedGoogle Scholar
  3. 3.
    Zanni R, Galvez-Llompart M, Galvez J, Garcia-Domenech R (2014) QSAR multi-target in drug discovery: a review. Curr Comput Aided Drug Des 10(2):129–136CrossRefGoogle Scholar
  4. 4.
    Garcia-Domenech R, Zanni R, Galvez-Llompart M, Galvez J (2015) Predicting antiprotozoal activity of benzyl phenyl ether diamine derivatives through QSAR multi-target and molecular topology. Mol Divers 19(2):357–366CrossRefGoogle Scholar
  5. 5.
    Tenorio-Borroto E, Garcia-Mera X, Peñuelas-Rivas CG, Vasquez-Chagoyan JC, Prado-Prado FJ, Castañedo N, Gonzalez-Díaz H (2013) Entropy model for multiplex drug-target interaction endpoints of drug immunotoxicity. Curr Top Med Chem 13(14):1636–1649CrossRefGoogle Scholar
  6. 6.
    Zanni R, Galvez-Llompart M, García-Domenech R, Galvez J (2015) Latest advances in molecular topology applications for drug discovery. Expert Opin Drug Discov 10(9):945–957. CrossRefPubMedGoogle Scholar
  7. 7.
    Garcia-Domenech R, Galvez J, de Julian-Ortiz JV, Pogliani L (2008) Some new trends in chemical graph theory. Chem Rev 108(3):1127–1169. CrossRefPubMedGoogle Scholar
  8. 8.
    Zanni R, Galvez-Llompart M, Machuca J, Garcia-Domenech R, Recacha E, Pascual A, Rodriguez-Martinez JM, Galvez J (2017) Molecular topology: a new strategy for antimicrobial resistance control. Eur J Med Chem 8(137):233–246. CrossRefGoogle Scholar
  9. 9.
    Zanni R, Galvez-Llompart M, Morell C, Rodríguez-Henche N, Díaz-Laviada I, Recio-Iglesias MC, Garcia-Domenech R, Galvez J (2015) Novel cancer chemotherapy hits by molecular topology: dual Akt and Beta-catenin inhibitors. PLoS ONE 10(4):e0124244. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Galvez-Llompart M, Recio MC, Garcia-Domenech R, Galvez J (2017) Molecular topology: a strategy to identify novel compounds against ulcerative colitis. Mol Divers 21(1):219–234. CrossRefPubMedGoogle Scholar
  11. 11.
    García-Domenech R, Aguilera J, El Moncef A, Pocovi S, Galvez J (2010) Application of molecular topology to the prediction of mosquito repellents of a group of terpenoid compounds. Mol Divers 14:321–329CrossRefGoogle Scholar
  12. 12.
    Bashir Y, Aslam A, Kamran M, Qureshi MI, Jahangir A, Rafiq M, Bibi N, Muhammad N (2017) On forgotten topological indices of some dendrimers structure. Molecules 22(6):867. CrossRefGoogle Scholar
  13. 13.
    Chen CP, Chen CC, Huang CW, Chang YC (2018) Evaluating molecular properties involved in transport of small molecules in stratum corneum: a quantitative structure-activity relationship for skin permeability. Molecules 23(4):911. CrossRefGoogle Scholar
  14. 14.
    Szczechura W, Staniaszek M, Klosinska U, Kozik EU (2015) Molecular analysis of new sources of resistance to Pseudoperonospora cubensis (Berk. et Curt.) Rostovzev in cucumber. Russ J Genet 51(10):974–979CrossRefGoogle Scholar
  15. 15.
    Gladieux P, Ravel S, Rieux A, Cros-Arteil S, Adreit H, Milazzo J, Thierry M, Fournier E, Terauchi R, Tharreau D (2018) Coexistence of multiple endemic and pandemic lineages of the rice blast pathogen. MBio 9(2):e01806–e01817. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Deng JJ, Huang WQ, Li ZW, Lu DL, Zhang Y, Luo XC (2018) Biocontrol activity of recombinant aspartic protease from Trichoderma harzianum against pathogenic fungi. Enzyme Microb Technol 112:35–42. CrossRefPubMedGoogle Scholar
  17. 17.
    Fernández-Ortuño D, Tores JA, de Vicente A, Pérez-García A (2008) Mechanisms of resistance to QoI fungicides in phytopathogenic fungi. Int Microbiol 11(1):1–9PubMedGoogle Scholar
  18. 18.
    Martinez-Cruz J, Romero D, de Vicente A, Perez-García A (2017) Transformation of the cucurbit powdery mildew pathogen Podosphaera xanthii by Agrobacterium tumefaciens. N Phytol 213(4):1961–1973. CrossRefGoogle Scholar
  19. 19.
    Li H, Guan A, Huang G, Liu CL, Li Z, Xie Y, Lan J (2016) Design, synthesis and structure-activity relationship of novel diphenylamine derivatives. Bioorg Med Chem 24(3):453–461. CrossRefPubMedGoogle Scholar
  20. 20.
    ChemDraw Ultra package (version 10.0) (2009) CambridgeSoftGoogle Scholar
  21. 21.
    Kier LB, Hall LH (1986) Molecular connectivity in structure-activity analysis, 1st edn. Research Studies Press, LetchworthGoogle Scholar
  22. 22.
    Galvez J, Garcia-Domenech R, Salabert MT, Soler R (1994) Charge indexes. New topological descriptors. J Chem Inf Comput Sci 34:520–525CrossRefGoogle Scholar
  23. 23.
    Galvez J, Garcia-Domenech R, de Julian-Ortiz JV, Soler R (1995) Topological approach to drug design. J Chem Inf Comput Sci 35:272CrossRefGoogle Scholar
  24. 24.
    Garcia-Pereira I (2018) Desmol2 software. Department of Physical Chemistry. Faculty of Pharmacy. University of Valencia.
  25. 25.
    Klecka WR (1980) Discriminant analysis. Sage University paper series on quantitative applications in the social sciences, 1st edn. Sage Publications, Beverly HillsGoogle Scholar
  26. 26.
    StatSoft I. Statistica (data analysis software system) (2009) Version 9. Tulsa, USAGoogle Scholar
  27. 27.
    De Maesschalck R, Jouan-Rimbaud D, Massart D (2000) The Mahalanobis distance. Chemom Intell Lab Syst 50(1):1–18CrossRefGoogle Scholar
  28. 28.
    Roderick LJA, Rubin DB (2014) Statistical analysis with missing data, vol 333. Wiley, HobokenGoogle Scholar
  29. 29.
    Speck-Planche A, Kleandrova VV, Luan F, Cordeiro MN (2012) Fragment-based approach for the in silico discovery of multi-target insecticides. Mol BioSyst 8(8):2188–2196CrossRefGoogle Scholar
  30. 30.
    ChemIDplus A TOXNET DATABASE (2018)

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Riccardo Zanni
    • 1
  • Maria Galvez-Llompart
    • 2
  • Inma Garcia-Pereira
    • 3
  • Jorge Galvez
    • 1
  • Ramon Garcia-Domenech
    • 1
    • 4
    Email author
  1. 1.Molecular Topology and Drug Design Unit, Department of Physical ChemistryUniversity of ValenciaValenciaSpain
  2. 2.Microbiology and Plant Pathology-Unit (CSIC Associated), Department of Microbiology, Faculty of SciencesUniversity of MalagaMalagaSpain
  3. 3.Institute of Robotics and Information and Communication Technologies (IRTIC)University of ValenciaValenciaSpain
  4. 4.Department of Physical ChemistryUniversity of ValenciaValenciaSpain

Personalised recommendations