Skip to main content
SpringerLink
Log in

Investigation of tautomerism of 1,3,5-triazine derivative, stability, and acidity of its tautomers from density functional theory

  • Original Paper
  • Published:
Journal of Molecular Modeling Aims and scope Submit manuscript

Abstract

Recent studies have identified N2,N4-bis(4-fluorophenethyl)-N6-(3-(dimethylamino)propyl)-1,3,5-triazine-2,4,6-triamine (1TZ(7,8,9)) as a potent, pure antagonist that inhibits thermosensory transient receptor potential vanilloid 1 channel (TRPV1) channel activity. This study provides theoretical data on the stability and acidity of the tautomers of this molecule. We show that this triazine can exist as three predominant tautomers (2TZ(5,7,8), 4TZ(3,7,9), 7TZ(1,8,9)). In the aqueous phase, equilibrium constants calculations show that only the tautomeric equilibria between 1TZ(7,8,9) and the three most stable triazines can be present which suggests that these three tautomeric equilibria would be the basis of 1TZ(7,8,9)’s biological activity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data availability

N/A

References

  1. Shao X, Zuo M, Zhao C et al (2020) Solubility of 2,4-diamino-6-(4-pyridyl)-1,3,5-triazine in tetrahydrofuran and alcohols between 288.15 K and 318.15 K. J Mol Liq 309:113170. https://doi.org/10.1016/j.molliq.2020.113170

    Article  CAS  Google Scholar 

  2. Ni-Komatsu L, Leung JK, Williams D et al (2005) Triazine-based tyrosinase inhibitors identified by chemical genetic screening. Pigment Cell Res 18:447–453. https://doi.org/10.1111/j.1600-0749.2005.00273.x

    Article  CAS  PubMed  Google Scholar 

  3. Chen C, Chen Q, Kang J et al (2020) Hydrophilic triazine-based dendron for copper and lead adsorption in aqueous systems: performance and mechanism. J Mol Liq 298:112031. https://doi.org/10.1016/j.molliq.2019.112031

    Article  CAS  Google Scholar 

  4. Ghasemian M, Kakanejadifard A, Azarbani F et al (2014) The triazine-based azo–azomethine dyes; spectroscopy, solvatochromism and biological properties of 2,2′-((2,2′-(6-methoxy-1,3,5-triazine-2,4-diyl) bis(oxy)bis(2,1-phenylene))bis(azan-1-yl-1-ylidene)bis(methan-1-yl-1-ylidene))bis(4-phenyldiazenyl)phenol. J Mol Liq 195:35–39. https://doi.org/10.1016/j.molliq.2014.01.011

    Article  CAS  Google Scholar 

  5. Baryshnikov GV, Bondarchuk SV, Minaeva VA et al (2017) Solvatochromic effect in absorption and emission spectra of star-shaped bipolar derivatives of 1,3,5-triazine and carbazole. A time-dependent density functional study. J Mol Model 23:55. https://doi.org/10.1007/s00894-017-3234-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Martins EPS, de Lima EO, Martins FT et al (2019) Synthesis, spectroscopic characterization, DFT studies, and preliminary antimicrobial evaluation of new antimony(III) and bismuth(III) complexes derived from 1,3,5-triazine. J Mol Struct 1183:373–383. https://doi.org/10.1016/j.molstruc.2019.01.096

    Article  CAS  Google Scholar 

  7. Tomašić T, Kovač A, Klebe G et al (2012) Virtual screening for potential inhibitors of bacterial MurC and MurD ligases. J Mol Model 18:1063–1072. https://doi.org/10.1007/s00894-011-1139-8

    Article  CAS  PubMed  Google Scholar 

  8. Chen M, Hu D, Li X et al (2015) Antiviral activity and interaction mechanisms study of novel glucopyranoside derivatives. Bioorg Med Chem Lett 25:3840–3844. https://doi.org/10.1016/j.bmcl.2015.07.068

    Article  CAS  PubMed  Google Scholar 

  9. Marín-Ocampo L, Veloza LA, Abonia R, Sepúlveda-Arias JC (2019) Anti-inflammatory activity of triazine derivatives: a systematic review. Eur J Med Chem 162:435–447. https://doi.org/10.1016/j.ejmech.2018.11.027

    Article  CAS  PubMed  Google Scholar 

  10. Bhat HR, Singh UP, Thakur A et al (2015) Synthesis, antimalarial activity and molecular docking of hybrid 4-aminoquinoline-1,3,5-triazine derivatives. Exp Parasitol 157:59–67. https://doi.org/10.1016/j.exppara.2015.06.016

    Article  CAS  PubMed  Google Scholar 

  11. Cascioferro S, Parrino B, Spanò V et al (2017) 1,3,5-Triazines: a promising scaffold for anticancer drugs development. Eur J Med Chem 142:523–549. https://doi.org/10.1016/j.ejmech.2017.09.035

    Article  CAS  PubMed  Google Scholar 

  12. Zhang C-L, Liu Y-X, Zhang X-M et al (2018) Synthesis, characterization, DNA/HSA interactions and in vitro cytotoxic activities of two novel water-soluble copper(II) complexes with 1,3,5-triazine derivative ligand and amino acids. Mater Sci Eng C 91:414–425. https://doi.org/10.1016/j.msec.2018.05.065

    Article  CAS  Google Scholar 

  13. Ismail AM, Abou El Maaty WM, Jean-Claude BJ, Mostafa SI (2019) Synthesis, characterization and anticancer activity of new Zn(II) and MoO22+ complexes of 2-amino-4,6-mercaptotriazine. Inorg Chem Commun 106:217–223. https://doi.org/10.1016/j.inoche.2019.04.024

    Article  CAS  Google Scholar 

  14. Kala RS, Tharmaraj P, Sheela CD (2014) Synthesis, spectral studies, NLO, and biological studies on metal(II) complexes of s-triazine-based ligand. Synth React Inorg Metal-Orga Nano-Metal Chem 44:1487–1496. https://doi.org/10.1080/15533174.2013.818018

    Article  CAS  Google Scholar 

  15. Demeshko S, Leibeling G, Dechert S, Meyer F (2004) 1,3,5-Triazine-based tricopper(II) complexes: structure and magnetic properties of threefold-symmetric building blocks. Dalton Trans:3782–3787. https://doi.org/10.1039/B407598F

  16. Burton SJ, Vivian Stead C, Ansell RJ, Lowe CR (1996) An artificial redox coenzyme based on a triazine dye template. Enzym Microb Technol 18:570–580. https://doi.org/10.1016/0141-0229(96)00136-6

    Article  CAS  Google Scholar 

  17. Puthiaraj P, Lee Y-R, Zhang S, Ahn W-S (2016) Triazine-based covalent organic polymers: design, synthesis and applications in heterogeneous catalysis. J Mater Chem A 4:16288–16311. https://doi.org/10.1039/C6TA06089G

    Article  CAS  Google Scholar 

  18. Mellor IR, Ogilvie J, Pluteanu F et al (2004) Methoctramine analogues inhibit responses to capsaicin and protons in rat dorsal root ganglion neurons. Eur J Pharmacol 505:37–50. https://doi.org/10.1016/j.ejphar.2004.10.005

    Article  CAS  PubMed  Google Scholar 

  19. Kitaguchi T, Swartz KJ (2005) An inhibitor of TRPV1 channels isolated from funnel web spider venom. Biochemistry 44:15544–15549. https://doi.org/10.1021/bi051494l

    Article  CAS  PubMed  Google Scholar 

  20. Vidal-Mosquera M, Fernández-Carvajal A, Moure A et al (2011) Triazine-based vanilloid 1 receptor open channel blockers: design, synthesis, evaluation, and SAR analysis. J Med Chem 54:7441–7452. https://doi.org/10.1021/jm200981s

    Article  CAS  PubMed  Google Scholar 

  21. De Petrocellis L, Schiano Moriello A, Byun JS et al (2015) Inhibitory effect of positively charged triazine antagonists of prokineticin receptors on the transient receptor vanilloid type-1 (TRPV1) channel. Pharmacol Res 99:362–369. https://doi.org/10.1016/j.phrs.2015.07.009

    Article  CAS  PubMed  Google Scholar 

  22. Harris VH, Smith CL, Jonathan Cummins W et al (2003) The effect of Tautomeric constant on the specificity of nucleotide incorporation during DNA replication: support for the rare tautomer hypothesis of substitution mutagenesis. J Mol Biol 326:1389–1401. https://doi.org/10.1016/S0022-2836(03)00051-2

    Article  CAS  PubMed  Google Scholar 

  23. Katritzky AR, Hall CD, El-Gendy BE-DM, Draghici B (2010) Tautomerism in drug discovery. J Comput Aided Mol Des 24:475–484. https://doi.org/10.1007/s10822-010-9359-z

    Article  CAS  PubMed  Google Scholar 

  24. Martin YC (2009) Let’s not forget tautomers. J Comput Aided Mol Des 23:693. https://doi.org/10.1007/s10822-009-9303-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kasetti Y, Bharatam PV (2012) Tautomerism in drugs with benzimidazole carbamate moiety: an electronic structure analysis. Theor Chem Accounts 131:1160. https://doi.org/10.1007/s00214-012-1160-8

    Article  CAS  Google Scholar 

  26. Bartolini B, Corniello C, Sella A et al (2003) The enol tautomer of indole-3-pyruvic acid as a biological switch in stress responses. In: Allegri G, Costa CVL, Ragazzi E et al (eds) Developments in tryptophan and serotonin metabolism. Springer US, Boston, MA, pp 601–608

    Chapter  Google Scholar 

  27. Srinivas K, Sitha S, Sridhar B et al (2006) Tautomerism of bis(2,4-benzyloxy)-6-(5H)-one-1,3,5-triazine: a combined crystallographic and quantum-chemical investigation. Struct Chem 17:561–568. https://doi.org/10.1007/s11224-006-9058-5

    Article  CAS  Google Scholar 

  28. Becke AD (1993) Density-functional thermochemistry. III. The role of exact exchange. J Chem Phys 98:5648–5652. https://doi.org/10.1063/1.464913

    Article  CAS  Google Scholar 

  29. Stephens PJ, Devlin FJ, Chabalowski CF, Frisch MJ (1994) Ab initio calculation of vibrational absorption and circular dichroism spectra using density functional force fields. J Phys Chem 98:11623–11627. https://doi.org/10.1021/j100096a001

    Article  CAS  Google Scholar 

  30. McLean AD, Chandler GS (1980) Contracted Gaussian basis sets for molecular calculations. I. Second row atoms, Z=11–18. J Chem Phys 72:5639–5648. https://doi.org/10.1063/1.438980

    Article  CAS  Google Scholar 

  31. Krishnan R, Binkley JS, Seeger R, Pople JA (1980) Self-consistent molecular orbital methods. XX. A basis set for correlated wave functions. J Chem Phys 72:650–654. https://doi.org/10.1063/1.438955

    Article  CAS  Google Scholar 

  32. Anandan K, Kolandaivel P, Kumaresan R (2004) Ab initio and DFT studies on tautomerism of indazole in gaseous and aqueous phases. J Mol Struct THEOCHEM 686:83–89. https://doi.org/10.1016/j.theochem.2004.08.014

    Article  CAS  Google Scholar 

  33. Karthika M, Senthilkumar L, Kanakaraju R (2014) Hydrogen-bond interactions in hydrated 6-selenoguanine tautomers: a theoretical study. Struct Chem 25:197–213. https://doi.org/10.1007/s11224-013-0239-8

    Article  CAS  Google Scholar 

  34. Senthilkumar L, Kolandaivel P (2003) Post Hartree–Fock and density functional theory studies on tautomerism of 6-thioxanthine in gas phase and in solution. J Mol Struct THEOCHEM 638:69–78. https://doi.org/10.1016/S0166-1280(03)00546-3

    Article  CAS  Google Scholar 

  35. Umadevi V, Mano Priya A, Senthilkumar L (2015) DFT study on the tautomerism of organic linker 1H-imidazole-4,5-tetrazole (HIT). Comput Theor Chem 1068:149–159. https://doi.org/10.1016/j.comptc.2015.06.022

    Article  CAS  Google Scholar 

  36. Semmeq A, Ouaskit S, Monari A, Badawi M (2019) Ionization and fragmentation of uracil upon microhydration. Phys Chem Chem Phys 21:4810–4821. https://doi.org/10.1039/C8CP07452F

    Article  CAS  PubMed  Google Scholar 

  37. Semmeq A, Monari A, Badawi M, Ouaskit S (2019) Ab initio study of the stepwise versus concerted fragmentation pathways in microhydrated thymine radical Cations. Chem Eur J 25:15525–15534. https://doi.org/10.1002/chem.201902462

    Article  CAS  PubMed  Google Scholar 

  38. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani J, 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 Jr. JA, Peralta JE, Ogliaro F, Bearpark MJ, Heyd J, Brothers EN, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell AP, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam NJ, Klene M, Knox JE, Cross JB, 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, VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian 09, in, Gaussian, Inc., Wallingford

  39. Barone V, Cossi M (1998) Quantum calculation of molecular energies and energy gradients in solution by a conductor solvent model. J Phys Chem A 102:1995–2001. https://doi.org/10.1021/jp9716997

    Article  CAS  Google Scholar 

  40. Mezey PG, Ladik JJ (1979) A non-empirical molecular orbital study on the relative stabilities of adenine and guanine tautomers. Theoret Chim Acta 52:129–145. https://doi.org/10.1007/BF00634788

    Article  CAS  Google Scholar 

  41. Mezey PG, Ladik JJ, Barry M (1979) Non-empirical SCF MO studies on the protonation of biopolymer constituents. Theoret Chim Acta 54:251–258. https://doi.org/10.1007/BF00578344

    Article  Google Scholar 

  42. Elguero J (2013) Tautomerism. In: Maloy S, Hughes K (eds) Brenner’s encyclopedia of genetics2nd edn. Academic Press, San Diego, pp 18–22

    Chapter  Google Scholar 

  43. Remko M (2003) Theoretical study of molecular structure and gas-phase acidity of some biologically active sulfonamides. J Phys Chem A 107:720–725. https://doi.org/10.1021/jp026980m

    Article  CAS  Google Scholar 

  44. Rogstad KN, Jang YH, Sowers LC, Goddard WA (2003) First principles calculations of the pKa values and tautomers of isoguanine and xanthine. Chem Res Toxicol 16:1455–1462. https://doi.org/10.1021/tx034068e

    Article  CAS  PubMed  Google Scholar 

  45. Jang YH, Goddard WA, Noyes KT et al (2003) pKa values of guanine in water: density functional theory calculations combined with Poisson−Boltzmann continuum−solvation model. J Phys Chem B 107:344–357. https://doi.org/10.1021/jp020774x

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the PMMS (Pôle Messin de Modélisation et de Simulation) and the LPCT high-performance computing resources for providing us with computer time. We also thank the colleagues of Constitution and Reaction of Matter Laboratory of University Felix Houphouët Boigny for their useful advices.

Code availability

N/A

Author information

Authors and Affiliations

  1. Laboratoire de Constitution et Réaction de la Matière (LCRM), Université Felix Houphouët-Boigny, 22 BP 582, Abidjan 22, Côte d’Ivoire

    Lucie Affoue Bede, Alain Kouassi Koffi & Fred-Lawson Ekozias Digre Beke

  2. Laboratoire de Physique et Chimie Théoriques UMR 7019, CNRS et Université de Lorraine, BP239, Boulevard des Aiguillettes, 54 506, Vandoeuvre-lès- Nancy-Cedex, France

    Abderrahmane Semmeq & Michael Badawi

Authors
  1. Lucie Affoue Bede
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alain Kouassi Koffi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fred-Lawson Ekozias Digre Beke
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Abderrahmane Semmeq
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michael Badawi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Lucie Affoue Bede: performing the actual study, writing the first draft.

Alain Kouassi Koffi: writing the first draft.

Fred-Lawson Ekozias Digre Beke: writing the first draft.

Abderrahmane Semmeq: performing the actual study, Correcting the draft to final form.

Michael Badawi: Reviewing, assessing, and correcting the draft to final form.

Corresponding authors

Correspondence to Lucie Affoue Bede or Michael Badawi.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bede, L.A., Koffi, A.K., Beke, FL.E.D. et al. Investigation of tautomerism of 1,3,5-triazine derivative, stability, and acidity of its tautomers from density functional theory. J Mol Model 27, 147 (2021). https://doi.org/10.1007/s00894-021-04774-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00894-021-04774-5

Keywords

Search

Navigation