Medicinal Chemistry Research

, Volume 26, Issue 11, pp 2699–2706 | Cite as

Towards the design of 3-aminopyrazole pharmacophore of pyrazolopyridine derivatives as novel antioxidants

  • Apilak Worachartcheewan
  • Chanin Nantasenamat
  • Supaluk Prachayasittikul
  • Anyaporn Aiemsaard
  • Virapong Prachayasittikul
Original Research
  • 173 Downloads

Abstract

Free radicals and oxidants can cause oxidative damage to physiologically important biomolecules that subsequently leads to the development of a wide range of chronic and degenerative diseases such as aging, cancer, cardiovascular and neurodegenerative diseases. Antioxidants have been shown to be instrumental in counteracting the deleterious effects of these reactive oxygen species. Herein, a series of 20 pyrazolopyridine derivatives with antioxidant activity were utilized for constructing a quantitative structure–activity relationship model as to unravel the origins of the antioxidant activity. Quantum chemical and molecular descriptors were used to quantitate the physicochemical properties of investigated compounds. Significant descriptors as identified by stepwise regression analysis consisted of Mor11m, Mor25v, JGI5, H8p, GATS5p, and GVWAI-50. Statistical parameters suggested that the constructed quantitative structure–activity relationship models were robust with Q2 = 0.9370 and root mean square error  = 4.7414 as evaluated via leave-one-out cross-validation. The mechanistic basis of the antioxidant activity as deduced from significant descriptors was rationalized. Particularly, compounds with the highest antioxidant activity required compounds to have the highest mean topological charge index of order 5 (JGI5) and Geary autocorrelation–lag 5/weighted by atomic polarizabilities (GATS5p) but necessitated low 3D-MoRSE-signal 25/weighted by atomic van der Waals volumes (Mor25v). Such properties are well corroborated by the 3-aminopyrazole pharmacophore from investigated compounds. Molecular insights unraveled herein is anticipated to be useful as guidelines for further rational design of novel pyrazole analogs with potent antioxidant activity.

Keywords

Pyrazolopyridine Antioxidant activity Oxidative stress QSAR Multiple linear regression Data mining 

Notes

Acknowledgements

We gratefully acknowledge the support from the Office of the Higher Education Commission, Mahidol University under the National Research Universities Initiative as well as partial support from the Annual Government Grant under Mahidol University (B.E. 2556–2558). AW gratefully acknowledges the research grant supported by the Thailand Research Fund (Grant No. TRG5880143).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

References

  1. Abdel-Hamid MK, Abdel-Hafez AA, El-Koussi NA, Mahfouz NM (2009) Quantitative structure–activity relationship (QSAR) studies on a series of 1,3,4-thiadiazole-2-thione derivatives as tumor-associated carbonic anhydrase IX inhibitors. J Enzyme Inhib Med Chem 24:722–729CrossRefPubMedGoogle Scholar
  2. Abu-Melha S (2013) Synthesis and antimicrobial activity of some new heterocycles incorporating the pyrazolopyridine moiety. Arch Pharm Chem Life Sci 346:912–921CrossRefGoogle Scholar
  3. Alam MS, Ahmed JU, Lee DU (2014) Synthesis, antibacterial, antioxidant activity and QSAR studies of novel 2-arylidenehydrazinyl-4-arylthiazole analogues. Chem Pharm Bull 62:1259–1268CrossRefPubMedGoogle Scholar
  4. Al-Omar MA, Youssef KM, El-Sherbeny MA, Awadalla SA, El-Subbagh HI (2005) Synthesis and in vitro antioxidant activity of some new fused pyridine analogs. Arch Pharm Chem Life Sci 338:175–180CrossRefGoogle Scholar
  5. Amić D, Davidović-Amić D, Beslo D, Rastija V, Lucić B, Trinajstić N (2007) SAR and QSAR of the antioxidant activity of flavonoids. Curr Med Chem 14:827–845CrossRefPubMedGoogle Scholar
  6. Amr AG, Mohamed AM, Mohamed SF, Abdel-Hafez NA, Hammam Ael-F (2006) Anticancer activities of some newly synthesized pyridine, pyrane, and pyrimidine derivatives. Bioorg Med Chem 14:5481–5488CrossRefPubMedGoogle Scholar
  7. Branham ML, Ross EA, Govender T (2012) Predictive models for maximum recommended therapeutic dose of antiretroviral drugs. Comput Math Methods Med 2012:469769CrossRefGoogle Scholar
  8. Cai J, Liu L, Chen J, Cao M, Ji M (2013) Design, synthesis, and bioactivity of pyrazole acid derivatives as endothelin receptor antagonists. Med Chem 9:1113–1122CrossRefPubMedGoogle Scholar
  9. Deng X, Gray NS (2012) Pyrazolopyridines as inhibitors of the kinase LRRK2: a patent evaluation (WO2011141756). Expert Opin Ther Pat 22:709–713CrossRefPubMedGoogle Scholar
  10. Dennington II R, Keith T, Millam J, Eppinnett K, Hovell WL, Gilliland R (2003) GaussView, Version 3.09. Semichem, Inc., Shawnee Mission, KS, USAGoogle Scholar
  11. Deodhar MN, Khopade PL, Varat MG (2013) Sulfonamide based β-carbonic anhydrase inhibitors: 2D QSAR study. ISRN Med Chem 2013:1–8CrossRefGoogle Scholar
  12. Eriksson L, Johansson E (1996) Multivariate design and modeling in QSAR. Chemom Intell Lab Syst 34:1–19CrossRefGoogle Scholar
  13. 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 JA, 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 Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian 09, Revision A.02. Gaussian, Inc., Wallingford, CT, USAGoogle Scholar
  14. Gouda MA (2012) Synthesis and antioxidant evaluation of some new pyrazolopyridine derivatives. Arch Pharm Chem Life Sci 345:155–162CrossRefGoogle Scholar
  15. Gudmundsson KS, Johns BA, Allen SH (2008) Pyrazolopyridines with potent activity against herpesviruses: effects of C5 substituents on antiviral activity. Bioorg Med Chem Lett 18:1157–1161CrossRefPubMedGoogle Scholar
  16. Hanna MM (2012) New pyrimido[5,4-e]pyrrolo[1,2-c]pyrimidines: synthesis, 2D-QSAR, anti-inflammatory, analgesic and ulcerogenicity studies. Eur J Med Chem 55:12–22CrossRefPubMedGoogle Scholar
  17. Kaiser JP, Feng Y, Bollag JM (1996) Microbial metabolism of pyridine, quinoline, acridine, and their derivatives under aerobic and anaerobic conditions. Microbiol Rev 60:483–498PubMedPubMedCentralGoogle Scholar
  18. Kumar H, Saini D, Jain S, Jain N (2013) Pyrazole scaffold: a remarkable tool in the development of anticancer agents. Eur J Med Chem 70:248–258CrossRefPubMedGoogle Scholar
  19. Nantasenamat C, Isarankura-Na-Ayudhya C, Prachayasittikul V (2010) Advances in computational methods to predict the biological activity of compounds. Expert Opin Drug Discov 5:633–654CrossRefPubMedGoogle Scholar
  20. Nantasenamat C, Prachayasittikul V (2015) Maximizing computational tools for successful drug discovery. Expert Opin Drug Discov 10:321–329CrossRefPubMedGoogle Scholar
  21. Prachayasittikul S, Pingaew R, Worachartcheewan A, Sinthupoom N, Prachayasittikul V, Ruchirawat S, Prachayasittikul V (2017) Roles of pyridine and pyrimidine derivatives as privileged scaffolds in anticancer agents. Mini Rev Med Chem 17:869–901Google Scholar
  22. Prachayasittikul V, Pingaew R, Worachartcheewan A, Nantasenamat C, Prachayasittikul S, Ruchirawat S, Prachayasittikul V (2014) Synthesis, anticancer activity and QSAR study of 1,4-naphthoquinone derivatives. Eur J Med Chem 84:247–263CrossRefPubMedGoogle Scholar
  23. Prachayasittikul V, Worachartcheewan A, Shoombuatong W, Songtawee N, Simeon S, Prachayasittikul V, Nantasenamat C (2015) Computer-aided drug design of bioactive natural products. Curr Top Med Chem 15:1780–1800CrossRefPubMedGoogle Scholar
  24. Talete srl (2007) DRAGON for Windows (Software for molecular descriptor calculations), version 5.5. Milano, ItalyGoogle Scholar
  25. Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39:44–84CrossRefPubMedGoogle Scholar
  26. Witten IH, Frank E, Hall MA (2011) Data mining: practical machine learning tools and techniques, 3rd edn. Morgan Kaufmann, San Francisco, USAGoogle Scholar
  27. Worachartcheewan A, Nantasenamat C, Isarankura-Na-Ayudhya C, Prachayasittikul S, Prachayasittikul V (2011) Predicting the free radical scavenging activity of curcumin derivatives. Chemom Intell Lab Syst 109:207–216CrossRefGoogle Scholar
  28. Worachartcheewan A, Nantasenamat C, Owasirikul W, Monnor T, Naruepantawart O, Janyapaisarn S, Prachaysittikul S, Prachayasittikul V (2014) Insights into antioxidant activity of 1-adamantylthiopyridine analogs using multiple linear regression. Eur J Med Chem 73:258–264CrossRefPubMedGoogle Scholar
  29. Worachartcheewan A, Prachayasittikul S, Pingaew R, Nantasenamat C, Tantimongcolwat T, Ruchirawat S, Prachayasittikul V (2012) Antioxidant, cytotoxicity and QSAR study of 1-adamantylthio derivatives of 3-picoline and phenylpyridines. Med Chem Res 21:3514–3522CrossRefGoogle Scholar
  30. Wu J, Shi Q, Chen Z, He M, Jin L, Hu D (2012) Synthesis and bioactivity of pyrazole acyl thiourea derivatives. Molecules 17:5139–5150CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Apilak Worachartcheewan
    • 1
    • 2
    • 3
  • Chanin Nantasenamat
    • 3
  • Supaluk Prachayasittikul
    • 3
  • Anyaporn Aiemsaard
    • 1
  • Virapong Prachayasittikul
    • 4
  1. 1.Department of Community Medical Technology, Faculty of Medical TechnologyMahidol UniversityBangkokThailand
  2. 2.Department of Clinical Chemistry, Faculty of Medical TechnologyMahidol UniversityBangkokThailand
  3. 3.Center of Data Mining and Biomedical Informatics, Faculty of Medical TechnologyMahidol UniversityBangkokThailand
  4. 4.Department of Clinical Microbiology and Applied Technology, Faculty of Medical TechnologyMahidol UniversityBangkokThailand

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