Skip to main content

Advertisement

SpringerLink
Log in

Importance of substituents in ring opening: a DFT study on a model reaction of thiazole to thioamide

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

Abstract

Thiazole ring is an important active molecular skeleton of drugs. Thiazole in natural products and drugs are usually harmlessly eliminated. However, hepatotoxic reactions may occur due to the biological activation of thiazole to produce reactive thioamide. A typical example is hepatotoxic sudoxicam and safety meloxicam. The only structural difference between them is a methyl group on C5 position of thiazole in meloxicam. The molecular basis for the difference remains unknown and the bioactivation mechanism of the thiazole ring is still obscure. Quantum chemical calculations were performed to elucidate the activation mechanism of the thiazole ring under P450 catalysis, and the influence of the substituents on the activation pathways of thiazole ring was also studied. The calculated results show that the activation of thiazole is closely related to the substituents on the thiazole and spin state of Cpd I. The thiazole and substituted thiazole directly open the ring when catalyzed by doublet spin state Cpd I that catalyzed by the quartet spin state Cpd I can open the ring directly or indirectly, which is related to the substituents. Thiazoles modified with electron-donating substituents mainly undergo direct ring opening, while thiazoles modified with electron-withdrawing groups or weak electron-donating groups mainly undergo indirect ring-opening process accompanied by intermediate formation. The research results laid the foundation for the design of thiazole ring drugs, and also laid a theoretical foundation for the study of reducing the toxicity of thiazole ring drugs.

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
Fig. 6
Fig. 7

Similar content being viewed by others

Data availability

All the relevant research data are provided in the Supporting information.

References

  1. Ayati A, Emami S, Asadipour A, Shafiee A, Foroumadi A (2015) Recent applications of 1,3-thiazole core structure in the identification of new lead compounds and drug discovery. Eur. J. Med. Chem. 97:699–718. https://doi.org/10.1016/j.ejmech.2015.04.015

    Article  CAS  PubMed  Google Scholar 

  2. de Siqueira LRP, de Moraes Gomes PAT, de Lima Ferreira LP, de Melo Rêgo MJB, Leite ACL (2019) Multi-target compounds acting in cancer progression: focus on thiosemicarbazone, thiazole and thiazolidinone analogues. Eur. J. Med. Chem. 170:237–260. https://doi.org/10.1016/j.ejmech.2019.03.024

    Article  CAS  PubMed  Google Scholar 

  3. Das J, Chen P, Norris D, Padmanabha R, Lin J, Moquin RV, Shen Z, Cook LS, Doweyko AM, Pitt S, Pang S, Shen DR, Fang Q, de Fex HF, McIntyre KW, Shuster DJ, Gillooly KM, Behnia K, Schieven GL, Wityak J, Barrish JC (2006) 2-Aminothiazole as a novel kinase inhibitor template. Structure−activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor. J. Med. Chem. 49 (23):6819–6832. doi:https://doi.org/10.1021/jm060727j

  4. Walmsley S, Bernstein B, King M, Arribas J, Beall G, Ruane P, Johnson M, Johnson D, Lalonde R, Japour A, Brun S, Sun E (2002) Lopinavir–ritonavir versus nelfinavir for the initial treatment of HIV infection. N. Engl. J. Med. 346(26):2039–2046. https://doi.org/10.1056/NEJMoa012354

    Article  CAS  PubMed  Google Scholar 

  5. Pasqualotto AC, Thiele K, Goldani L (2010) Novel triazole antifungal drugs: focus on isavuconazole, ravuconazole and albaconazole. Curr. Opin. Investig. Drugs 11(2):165–174

    CAS  PubMed  Google Scholar 

  6. Fox LM, Saravolatz LD (2005) Nitazoxanide: a new thiazolide antiparasitic agent. Clin. Infect. Dis. 40(8):1173–1180. https://doi.org/10.1086/428839

    Article  CAS  PubMed  Google Scholar 

  7. Obach RS, Kalgutkar AS, Ryder TF, Walker GS (2008) In vitro metabolism and covalent binding of enol-carboxamide derivatives and anti-inflammatory agents sudoxicam and meloxicam: insights into the hepatotoxicity of sudoxicam. Chem. Res. Toxicol. 21:1890. https://doi.org/10.1021/tx800185b

    Article  CAS  PubMed  Google Scholar 

  8. Maienfisch P, Angst M, Brandl F, Fischer W, Hofer D, Kayser H, Kobel W, Rindlisbacher A, Senn R, Steinemann A, Widmer H (2001) Chemistry and biology of thiamethoxam: a second generation neonicotinoid. Pest Manag. Sci. 57(10):906–913. https://doi.org/10.1002/ps.365

    Article  CAS  PubMed  Google Scholar 

  9. Vitaku E, Smith DT, Njardarson JT (2014) Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals. J. Med. Chem. 57(24):10257–10274. https://doi.org/10.1021/jm501100b

    Article  CAS  PubMed  Google Scholar 

  10. Dalvie DK, Kalgutkar AS, Khojasteh-Bakht SC, Obach RS, O’Donnell JP (2002) Biotransformation reactions of five-membered aromatic heterocyclic rings. Chem. Res. Toxicol. 15(3):269–299. https://doi.org/10.1021/tx015574b

    Article  CAS  PubMed  Google Scholar 

  11. Hobbs DC, Twomey TM (1977) Metabolism of sudoxicam by the rat, dog, and monkey. Drug Metabolism and Disposition 5 (1):75 doi:10.1.1.1070.5457

  12. Roth SH (2001) Arthritis therapy: a better time, a better day. Rheumatology 40(6):603–606. https://doi.org/10.1093/rheumatology/40.6.603

    Article  CAS  PubMed  Google Scholar 

  13. Schmid J, Busch U, Trummlitz G, Prox A, Kaschke S, Wachsmuth H (1995) Meloxicam: metabolic profile and biotransformation products in the rat. Xenobiotica 25(11):1219–1236. https://doi.org/10.3109/00498259509046678

    Article  CAS  PubMed  Google Scholar 

  14. Uetrecht J, Naisbitt DJ (2013) Idiosyncratic adverse drug reactions: current concepts. Pharmacol. Rev. 65(2):779. https://doi.org/10.1124/pr.113.007450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Barnette DA, Schleiff MA, Osborn LR, Flynn N, Matlock M, Swamidass SJ, Miller GP (2020) Dual mechanisms suppress meloxicam bioactivation relative to sudoxicam. Toxicology 440:152478. https://doi.org/10.1016/j.tox.2020.152478

    Article  CAS  PubMed  Google Scholar 

  16. Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M (2018) DrugBank 5.0: A major update to the DrugBank database for 2018. Nucleic Acids Res. 46 (D1):D1074-D1082. doi:https://doi.org/10.1093/nar/gkx1037

  17. Shaik S, Hirao H, Kumar D (2007) Reactivity patterns of cytochrome P450 enzymes: multifunctionality of the active species, and the two states-two oxidants conundrum. Nat. Prod. Rep. 24(3):533–552. https://doi.org/10.1039/B604192M

    Article  CAS  PubMed  Google Scholar 

  18. Li C, Wu W, Cho K-B, Shaik S (2009) Oxidation of tertiary amines by cytochrome P450—kinetic isotope effect as a spin-state reactivity probe. Chemistry – A European Journal 15 (34):8492–8503. doi:doi:https://doi.org/10.1002/chem.200802215

  19. Taxak N, Desai PV, Patel B, Mohutsky M, Klimkowski VJ, Gombar V, Bharatam PV (2012) Metabolic-intermediate complex formation with cytochrome P450: theoretical studies in elucidating the reaction pathway for the generation of reactive nitroso intermediate. J. Comput. Chem. 33(21):1740–1747. https://doi.org/10.1002/jcc.23008

    Article  CAS  PubMed  Google Scholar 

  20. Li X-X, Wang Y, Zheng Q-C, Zhang H-X (2016) Detoxification of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by cytochrome P450 enzymes: a theoretical investigation. J. Inorg. Biochem. 154(154):21–28. https://doi.org/10.1016/j.jinorgbio.2015.10.009

    Article  CAS  PubMed  Google Scholar 

  21. Özkılıç Y, Tüzün NŞ (2019) Mechanism of kynurenine 3-monooxygenase-catalyzed hydroxylation reaction: a quantum cluster approach. J. Phys. Chem. A 123(14):3149–3159. https://doi.org/10.1021/acs.jpca.8b11831

    Article  CAS  PubMed  Google Scholar 

  22. Sono M, Roach MP, Coulter ED, Dawson JH (1996) Heme-containing oxygenases. Chem. Rev. 96(7):2841–2888. https://doi.org/10.1021/cr9500500

    Article  CAS  PubMed  Google Scholar 

  23. Shaik S, Cohen S, Wang Y, Chen H, Kumar D, Thiel W (2010) P450 enzymes: their structure, reactivity, and selectivity—modeled by QM/MM calculations. Chem. Rev. 110(2):949–1017. https://doi.org/10.1021/cr900121s

    Article  CAS  PubMed  Google Scholar 

  24. Woolf TF, Radulovic LL (1989) Oxicams: metabolic disposition in man and animals. Drug Metab. Rev. 21(2):255–276. https://doi.org/10.3109/03602538909029942

    Article  CAS  PubMed  Google Scholar 

  25. Mizutani T, Yoshida K, Kawazoe S (1994) Formation of toxic metabolites from thiabendazole and other thiazoles in mice. Identification of thioamides as ring cleavage products. Drug Metabolism and Disposition 22 (5):750 doi:https://doi.org/10.1080/004982598239704

  26. Chesne C, Guyomard C, Guillouzo A, Schmid J, Ludwig E, Sauter T (1998) Metabolism of Meloxicam in human liver involves cytochromes P4502C9 and 3A4. Xenobiotica 28(1):1–13. https://doi.org/10.1080/004982598239704

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work is based on research supported by the Meritocracy Research Funds of China West Normal University (17YC037).

Author information

Authors and Affiliations

  1. Chemical Synthesis and Pollution Control Key Laboratory of Sichuan Province, China West Normal University, Nanchong, 637009, Sichuan, People’s Republic of China

    Xue Bai, Dan Qin & Lijun Yang

  2. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, Sichuan, People’s Republic of China

    Lijun Yang

Authors
  1. Xue Bai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dan Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lijun Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Xue Bai performed the theoretical calculation and wrote the article, Lijun Yang interpreted the results and modified the article, and Dan Qin did the proof reading.

Corresponding author

Correspondence to Lijun Yang.

Ethics declarations

Consent to participate

All the authors give their consent.

Consent for publication

All the authors give their consent.

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.

Supplementary information

ESM 1

(DOCX 112 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bai, X., Qin, D. & Yang, L. Importance of substituents in ring opening: a DFT study on a model reaction of thiazole to thioamide. J Mol Model 27, 89 (2021). https://doi.org/10.1007/s00894-021-04704-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00894-021-04704-5

Keywords

Search

Navigation