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Reaction of [2-(3-hetaryl-1,2,4-triazol-5-yl)phenyl]amines with ketones: a density functional theory study

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Abstract

The derivatives of 1,2,4- triazole have attracted great attention among medicinal chemists due to their wide range of biological activity, good pharmacodynamic and pharmacokinetic profiles, and low toxicity, that necessitates the development of various synthesis methods and a comprehensive study of their reaction mechanisms. A detailed investigation of possible pathways for formation of new spiro-condensed [1,2,4]triazolo[1,5-c]quinazolines, that combine two structural domains with different biological properties, was performed by computational study at the SMD/B3lyp/6-31+G(d) theory level. The mechanism of interaction between [2-(3-hetaryl-1,2,4-triazol-5-yl)phenyl]amine and cyclohexanone in methanol involves three main processes: formation of carbinolamine by addition of an amine to double bond C=O, elimination of a water molecule, and intramolecular cyclization leading to formation of spiro compounds. Results show increase in reactivity of reactants during acid-catalyzed reaction compared to uncatalyzed one. The nature of the heterocyclic substituent on the triazole ring has little effect on the reaction energy, while the mechanism is unchanged.

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Data availability

The data supporting the findings of this study are available within its supplementary material and from the corresponding author on reasonable request.

References

  1. Kazeminejad Z, Marzi M, Shiroudi A, Kouhpayeh SA, Farjam M, Zarenezhad E (2022) Novel 1, 2, 4-triazoles as antifungal agents. Biomed Res Int 2022:1–39. https://doi.org/10.1155/2022/4584846

    Article  CAS  Google Scholar 

  2. Maddila S, Pagadala R, Jonnalagadda BS (2013) 1, 2, 4-triazoles: a review of synthetic approaches and the biological activity. Lett Org Chem 10:693–714. https://doi.org/10.2174/157017861010131126115448

    Article  CAS  Google Scholar 

  3. Kaur P, Chawla A (2017) 1, 2, 4-triazole: a review of pharmacological activities. Int Res J Pharm 8:10–29. https://doi.org/10.7897/2230-8407.087112

    Article  CAS  Google Scholar 

  4. Kapron B, Luszczki JJ, Plaziska A, Siwek A, Karcz T, Grybos A, Bowak G, Makuch-Kocka A, Walczak K, Langner E, Szalast K, Marciniak S, Paczkowska M, Cielecka J, Ciesla LM, Plech T (2019) Development of the 1, 2, 4-triazole-based anticonvulsant drug candidates acting on the voltage-gated sodium channels. Insights from in-vivo, in-vitro, and in-silico studies. Eur J Pharm Sci 129:42–57. https://doi.org/10.1016/j.ejps.2018.12.018

    Article  CAS  PubMed  Google Scholar 

  5. Gao F, Wang T, Xiao J, Huang G (2019) Antibacterial activity study of 1, 2, 4-triazole derivatives. Eur J Med Chem 173:274–281. https://doi.org/10.1016/j.ejmech.2019.04.043

    Article  CAS  PubMed  Google Scholar 

  6. Othman AA, Kihel M, Amara S (2019) 1, 3, 4-oxadiazole, 1, 3, 4-thiadiazole and 1, 2, 4-triazole derivatives as potential antibacterial agents. Arab J Chem 12:1660–1675. https://doi.org/10.1016/j.arabjc.2014.09.003

    Article  CAS  Google Scholar 

  7. Shahzad SA, Yar M, Khan ZA, Shahzadi L, Naqvi SAR, Mahmood A, Ullah S, Shaikh AJ, Sherazi TA, Bale AT, Kukulowicz J, Bajda M (2019) Identification of 1, 2, 4-triazoles as new thymidine phosphorylase inhibitors: Future anti-tumor drugs. Bioorg Chem 85:209–220. https://doi.org/10.1016/j.bioorg.2019.01.005

    Article  CAS  PubMed  Google Scholar 

  8. El-Sherief HAM, Youssif BGM, Bukhari SNA, Abdelazeem AH, Abdel-Aziz MA-RHM (2018) Synthesis, anticancer activity and molecular modeling studies of 1, 2, 4-triazole derivatives as EGFR inhibitors. Eur J Med Chem 156:774–789. https://doi.org/10.1016/j.ejmech.2018.07.024

    Article  CAS  PubMed  Google Scholar 

  9. Wittine K, Babic MS, Makuc D, Plavec J, Pavelic SK, Sedic M, Pavelic K, Leyssen P, Neyts J, Balzarini J, Nintas M (2012) Novel 1, 2, 4-triazole and imidazole derivatives of L-ascorbic and imino-ascorbic acid: synthesis, anti-HCV and antitumor activity evaluations. Bioorg Med Chem 20:3675–3685. https://doi.org/10.1016/j.bmc.2012.01.054

    Article  CAS  PubMed  Google Scholar 

  10. Zhang S, Xu Z, Gao C, Ren QC, Chang L, Lv ZS, Feng LS (2017) Triazole derivatives and their anti-tubercular activity. Eur J Med Chem 138:501–513. https://doi.org/10.1016/j.ejmech.2017.06.051

    Article  CAS  PubMed  Google Scholar 

  11. Jin RY, Zeng CY, Liang XH, Sun XH, Liu YF, Wang YY, Zhou S (2018) Design, synthesis, biological activities and DFT calculation of novel 1, 2, 4-triazole Schiff base derivatives. Bioorg Chem 80:253–260. https://doi.org/10.1016/j.bioorg.2018.06.030

    Article  CAS  PubMed  Google Scholar 

  12. Xu J, Cao Y, Zhang J, Yu S, Chai X, Wu Q, Zhang D, Jiang Y, Sun Q (2011) Design, synthesis and antifungal activities of novel 1, 2, 4-triazole derivatives. Eur J Med Chem 46:3142–3148. https://doi.org/10.1016/j.ejmech.2011.02.042

    Article  CAS  PubMed  Google Scholar 

  13. Fan YL, Ke X, Li M (2018) Coumarin–triazole hybrids and their biological activities. J Heterocycl Chem 55:791–802. https://doi.org/10.1002/jhet.3112

    Article  CAS  Google Scholar 

  14. Mishra SS, Singh P (2016) Hybrid molecules: the privileged scaffolds for various pharmaceuticals. Eur J Med Chem 124:500–536. https://doi.org/10.1016/j.ejmech.2016.08.039

    Article  CAS  PubMed  Google Scholar 

  15. Hu YQ, Gao C, Zhang S, Xu L, Xu Z, Feng LS, Wu X, Zhao F (2017) Quinoline hybrids and their antiplasmodial and antimalarial activities. Eur J Med Chem 139:22–47. https://doi.org/10.1016/j.ejmech.2017.07.061

    Article  CAS  PubMed  Google Scholar 

  16. Amin KM, Anwar MM, Syam YM, Khedr M, Kamel MM, Kassem EMMA (2013) A novel class of substituted spiro[quinazoline-2,1’-cyclohexane] derivatives as effective ppar-1 inhibitors: molecular modeling, synthesis, cytotoxic and enzyme assay evaluation. Acta Pol Pharm Drug Res 7:687–708

    Google Scholar 

  17. Mustazza C, Borioni A, Sestili I, Sbraccia M, Rodomonte A, Ferretti R, Rosaria Del Giudice M (2006) Synthesis and evaluation as NOP ligands of some spiro[piperidine-4,2’(1’H)-quinazolin]-4’(3’H)-ones and spiro[piperidine-4,5’(6’H)-[1,2,4]triazolo[1,5-c]quinazolines]. Chem Pharm Bull 54:611–622. https://doi.org/10.1248/cpb.54.611

    Article  CAS  Google Scholar 

  18. Antypenko OM, Kholodnyak SV, Schabelnyk KP, Antypenko LM, Kovalenko SI (2017) 2-(Azolyl) anilines: methods of synthesis, cyclocondensations, and biological properties. Chem Heterocycl Comp 53:292–309. https://doi.org/10.1007/s10593-017-2051-7

    Article  CAS  Google Scholar 

  19. Kehler J, Ritzen A, Langgard M, Petersen SL, Farah MM, Bundgaard C, Christoffersen CT, Nielsen J, Kilburn JP (2011) Triazoloquinazolines as a novel class of phosphodiesterase 10A (PDE10A) inhibitors. Bioorg Med Chem Lett 21:3738–3742. https://doi.org/10.1016/j.bmcl.2011.04.067

    Article  CAS  PubMed  Google Scholar 

  20. Antipenko LN, Karpenko AV, Kovalenko SI, Katzev AM, Komarovska-Porokhnyavets EZ (2009) Synthesis, cytotoxicity by bioluminescence inhibition, antibacterial and antifungal activity of ([1,2,4]Triazolo[1,5-c]quinazolin-2-ylthio)carboxylic acid amides. Arch Pharm Chem Life Sci 342:651–662. https://doi.org/10.1002/ardp.200900077

    Article  CAS  Google Scholar 

  21. Wesseler F, Lohmann S, Riege D, Halver J, Roth A, Pichlo C, Weber S, Takamiya M, Muller E, Ketzel J, Flegel J, Gihring A, Rastegar S, Bertrand J, Baumann U, Knippschild U, Peifer C, Sievers S, Waldmann H, Schade D (2022) Phenotypic discovery of Triazolo[1,5-c]quinazolines as a first-in-class bone morphogenetic protein amplifier chemotype. J Med Chem 65:15263–15281. https://doi.org/10.1021/acs.jmedchem.2c01199

    Article  CAS  PubMed  Google Scholar 

  22. Zeydi MM, Montazeri N, Fouladi M (2017) Synthesis and evaluation of novel [1,2,4]Triazolo[1,5-c]quinazoline derivatives as antibacterial agents. J Heterocycl Chem 54:3549–3553. https://doi.org/10.1002/jhet.2979

    Article  CAS  Google Scholar 

  23. Kovalenko SI, Antypenko LM, Bilyi AK, Kholodnyak SV, Karpenko OV, Antypenko OM, Mykhaylova NS, Los TI, Kolomoets OS (2013) Synthesis and anticancer activity of 2-(alkyl-, alkaryl-, aryl-, hetaryl-)-[1, 2, 4] triazolo [1, 5-c] quinazolines. Sci Pharm 81:359–391. https://doi.org/10.3797/scipharm.1211-08

    Article  CAS  PubMed  Google Scholar 

  24. Kholodnyak SV, Schabelnyk KP, Voskoboynik OYu, Antypenko OM, Кovalenko SI, Palchykov VO, Okovyty SI, Shishkina SV (2016) 5,6-dihydro-[1,2,4]triazolo[1,5-c]quinazolines. message 4. Spirocompounds with [1,2,4]triazolo[1,5-c] quinazolines moieties. The synthesis and spectral characteristics. J Org Pharm Chem 14:24–31

    Google Scholar 

  25. Cmikiewicz A, Gordon AJ, Berski S (2018) Characterisation of the reaction mechanism between ammonia and formaldehyde from the topological analysis of ELF and catastrophe theory perspective. Struct Chem 29:243–255. https://doi.org/10.1007/s11224-017-1024-x

    Article  CAS  Google Scholar 

  26. Hall NE, Smith BJ (1998) High-level ab initio molecular orbital calculations of imine formation. J Phys Chem A 102:4930–4938. https://doi.org/10.1021/jp9810825

    Article  CAS  Google Scholar 

  27. Ding Y, Cui Y, Li T (2015) New views on the reaction of primary amine and aldehyde from DFT study. J Phys Chem A 119:4252–4260. https://doi.org/10.1021/acs.jpca.5b02186

    Article  CAS  PubMed  Google Scholar 

  28. Silva PJ (2020) New insights into the mechanism of Schiff base synthesis from aromatic amines in the absence of acid catalyst or polar solvents. PeerJ Org Chem 2:1–4. https://doi.org/10.7717/peerj-ochem.4

    Article  CAS  Google Scholar 

  29. Solís-Calero C, Ortega-Castro J, Hernàndez-Laguna A, Muñoz F (2012) Reaction mechanism of covalent modification of phosphatidylethanolamine lipids by reactive aldehydes 4-hydroxy-2-nonenal and 4-oxo-2-nonenal. Theor Chem Acc 131:1–12. https://doi.org/10.1021/acs.chemrestox.6b00443

    Article  CAS  Google Scholar 

  30. Ortega-Castro J, Adrover M, Frau J, Salvà A, Donoso J, Muñoz F (2010) DFT studies on Schiff base formation of vitamin B6 analogues. Reaction between a pyridoxamine-analogue and carbonyl compounds. J Phys Chem A 114:4634–4640. https://doi.org/10.1021/jp909156m

    Article  CAS  PubMed  Google Scholar 

  31. Qu ZW, Zhu H, Zhukova NA, Katsyuba SA, Mamedov VA, Grimme S (2021) Mechanistic insights for acid-catalyzed rearrangement of quinoxalin-2-one with diamine and enamine. ChemCatChem 13:1503–1508

    Article  CAS  Google Scholar 

  32. 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 JrJA, 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 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 O, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ( 2009) Gaussian 09, Revision A.01. Gaussian Inc., Wallingford

  33. Becke ADJ (1993) Density-functional thermochemistry.3.The role of exact exchange. Chem Phys 98:5648–5652

    CAS  Google Scholar 

  34. Hehre WJ, Radom L, Schleyer PR, Pople JA (1986) Ab initio molecular orbital theory. Wiley, New York

    Google Scholar 

  35. Marenich AV, Cramer CJ, Truhlar DG (2009) Universal solvation model based on solute electron density and on a continuum model of the solvent defined by the bulk dielectric constant and atomic surface tensions. J Phys Chem B 13:6378–6396. https://doi.org/10.1021/jp810292n

    Article  CAS  Google Scholar 

  36. Pylypenko OO, Okovytyy SI, Sviatenko LK, Voronkov EO, Shabelnyk KP, Kovalenko SI (2023) Tautomeric behavior of 1, 2, 4-triazole derivatives: combined spectroscopic and theoretical study. Struct Chem 34:181–192. https://doi.org/10.1007/s11224-022-02057-0

    Article  CAS  Google Scholar 

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The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

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Authors and Affiliations

  1. Department of Physical, Organic and Inorganic Chemistry, Oles Honchar Dnipro National University, Gagarin Av. 72, Dnipro, 49045, Ukraine

    Olena O. Pylypenko & Sergiy I. Okovytyy

  2. Department of Biomedical Disciplines, Donetsk National Medical University, 4A Yuriy Kovalenko Str, Kropyvnytskyi, 25001, Ukraine

    Olena O. Pylypenko

  3. Interdisciplinary Center for Nanotoxicity, Department of Chemistry, Physics & Atmospheric Sciences, Jackson State University, Jackson, MS, 39217, USA

    Liudmyla K. Sviatenko

  4. Department of Pharmaceutical, Organic and Bioorganic Chemistry, Zaporizhzhia State Medical and Pharmaceutical University, 26 Maiakovskoho Ave., Zaporizhzhia, 69035, Ukraine

    Kostyantin P. Shabelnyk

  5. Research Institute of Chemistry and Geology, Oles Honchar Dnipro National University, 22 Kazakova Str, Dnipro, 49000, Ukraine

    Sergiy I. Kovalenko

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  1. Olena O. Pylypenko
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OP calculated and interpreted data and was a contributor in writing the manuscript. LS calculated and interpreted data and was a contributor in writing the manuscript. KS was a contributor in writing the manuscript. SK was a contributor in writing the manuscript. SO interpreted data and was a contributor in writing and editing the manuscript. All authors read and approved the final manuscript.

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Correspondence to Sergiy I. Okovytyy.

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214_2024_3110_MOESM1_ESM.docx

SMD/B3lyp/6-31+G(d) modeled pathways for acid-catalyzed reaction of 2-(3-(thiophen-2-yl)-1,2,4-triazol-5-yl)anilines and 2-(3-(pyrrol-2-yl)-1,2,4-triazol-5-yl)anilines with cyclohexanone in methanol along with the corresponding Gibbs free energy diagram (DOCX 4789 kb)

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Pylypenko, O.O., Sviatenko, L.K., Shabelnyk, K.P. et al. Reaction of [2-(3-hetaryl-1,2,4-triazol-5-yl)phenyl]amines with ketones: a density functional theory study. Theor Chem Acc 143, 35 (2024). https://doi.org/10.1007/s00214-024-03110-3

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