Advertisement

Archives of Pharmacal Research

, Volume 38, Issue 4, pp 470–479 | Cite as

Synthesis and biological evaluation of novel fluconazole analogues bearing 1,3,4-oxadiazole moiety as potent antifungal agents

  • Jun Liao
  • Fan Yang
  • Lei Zhang
  • Xiaoyun Chai
  • Qingjie Zhao
  • Shichong Yu
  • Yan Zou
  • Qingguo MengEmail author
  • Qiuye WuEmail author
Research Article

Abstract

A novel series of fluconazole based mimics incorporating 1,3,4-oxadiazole moiety were designed and synthesized. All the title compounds were characterized by 1H-NMR, 13C-NMR, and Q-TOF-MS. Preliminary results revealed that most of analogues exhibited significant antifungal activity against seven pathogenic fungi. Compounds 9g and 9k (MIC80 ≤ 0.125 μg/mL, respectively) were found more potent than the positive controls itraconazole and fluconazole as broad-spectrum antifungal agents. The observed docking results showed that the 1,3,4-oxadiazole moiety enhanced the affinity binding to the cytochrome P450 14α-demethylase (CYP51).

Keywords

Synthesis Fluconazole Antifungal activity 1,3,4-Oxadiazole 

Notes

Acknowledgment

This work was supported by the National Natural Science Foundation of China (No. 20772153) and Science & Technology Commission of Shanghai Municipality (09dZ1976700).

Supplementary material

12272_2014_378_MOESM1_ESM.doc (20.9 mb)
Supplementary material 1 (DOC 21422 kb)

References

  1. Akhter, M., A. Husain, B. Azad, and M. Ajmal. 2009. Aroylpropionic acid based 2,5-disubstituted-1,3,4-oxadiazoles: Synthesis and their anti-inflammatory and analgesic activities. European Journal of Medicinal Chemistry 44: 2372–2378.CrossRefPubMedGoogle Scholar
  2. Casalinuovo, I.A., P. Di Francesco, and E. Garaci. 2004. Fluconazole resistance in Candida albicans: A review of mechanisms. European Review for Medical and Pharmacological Sciences 8: 69–77.PubMedGoogle Scholar
  3. Cha, R., and J.D. Sobel. 2004. Fluconazole for the treatment of candidiasis: 15 years’ experience. Expert Review of Anticancer Therapy 2: 357–366.CrossRefGoogle Scholar
  4. Chai, X.Y., J. Zhang, H.G. Hu, S.C. Yu, Q.Y. Sun, D.Z. Zhang, and Q.Y. Wu. 2009. Design, synthesis, and biological evaluation of novel triazole derivatives as inhibitors of cytochrome P450 14alpha-demethylase. European Journal of Medicinal Chemistry 44: 1913–1920.CrossRefPubMedGoogle Scholar
  5. Chakrabarti, A. 2005. Microbiology of systemic fungal infections. Journal of Postgraduate Medicine 51: S16–S20.PubMedGoogle Scholar
  6. Chandrakantha, B., P. Shetty, V. Nambiyar, N. Isloor, and A.M. Isloor. 2010. Synthesis, characterization and biological activity of some new 1,3,4-oxadiazole bearing 2-flouro-4-methoxy phenyl moiety. European Journal of Medicinal Chemistry 45: 1206–1210.CrossRefPubMedGoogle Scholar
  7. De Pauw, B.E., and F. Meunier. 1999. The challenge of invasive fungal infection. Chemotherapy 45: 1–14.CrossRefPubMedGoogle Scholar
  8. Ducharme, Y., M. Blouin, C. Brideau, A. Chateauneuf, and Y. Gareau. 2010. The discovery of setileuton, a potent and selective 5-lipoxygenase inhibitor. ACS Medicinal Chemistry Letters 1: 170–174.CrossRefPubMedCentralPubMedGoogle Scholar
  9. Gaonkar, S.L., K.M.L. Rai, and B. Prabhuswamy. 2006. Synthesis and antimicrobial studies of a new series of 2-(4-(2-(5-ethylpyridin-2-yl)ethoxy)phenyl)-5-substituted-1,3,4-oxadiazoles. European Journal of Medicinal Chemistry 41: 841–846.CrossRefPubMedGoogle Scholar
  10. James, N.D., and J.W. Growcott. 2009. Zibotentan. Drugs Future 34: 624.CrossRefGoogle Scholar
  11. Ji, H.T., W.N. Zhang, Y. Zhou, M. Zhang, J. Zhu, Y.L. Song, and J. Lü. 2000. A three-dimensional model of lanosterol 14alpha-demethylase of Candida albicans and its interaction with azole antifungals. Journal of Medicinal Chemistry 43: 2493–2505.CrossRefPubMedGoogle Scholar
  12. Karyotakis, N.C., and E.J. Anaissie. 1994. The new antifungal azoles: Fluconazole and itraconazole. Current Opinion in Infectious Diseases 7: 658–666.CrossRefGoogle Scholar
  13. Kauffman, C.A., and P.L. Carver. 1997. Antifungal agents in the 1990s: Current status and future developments. Drugs 53: 539–549.CrossRefPubMedGoogle Scholar
  14. Kumar, D., S. Sundaree, and E.Q. Shah. 2009. An efficient synthesis and biological study of novel indolyl-1,3,4-oxadiazoles as potent anticancer agents. Bioorganic & Medicinal Chemistry Letters 19: 4492–4494.CrossRefGoogle Scholar
  15. Liu, F., X.Q. Luo, B.A. Song, P.S. Bhadury, Y. Song, L.H. Jin, and D.Y. Yu. 2008. Synthesis and antifungal activity of novel sulfoxide derivatives containing trimethoxyphenyl substituted 1,3,4-thiadiazole and 1,3,4-oxadiazole moiety. Bioorganic & Medicinal Chemistry Letters 16: 3632–3640.CrossRefGoogle Scholar
  16. Maertens, J., G. Egerer, W.S. Shin, D. Reichert, M. Stek, S. Chandwani, M. Shivaprakash, and C. Viscoli. 2010. Caspofungin use in daily clinical practice for treatment of invasive aspergillosis: Results of a prospective observational registry. BMC Infectious Diseases 10: 182–188.CrossRefPubMedCentralPubMedGoogle Scholar
  17. National Committee for Clinical Laboratory Standards, Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts Approved Standard. 2002. Document M27-A2, National Committee for Clinical Laboratory Standards, Wayne, PA.Google Scholar
  18. Ogata, M., H. Atobe, H. Kushida, and K.J. Yamamoto. 1971. Furamizole. Antibiot 24: 443–451.CrossRefGoogle Scholar
  19. Ohmoto, K., T. Yamamoto, T. Horiuchi, H. Imanishi, and Y. Odagaki. 2000. Design and synthesis of new orally active nonpeptidic inhibitors of human neutrophil elastase. Journal of Medicinal Chemistry 43: 4927–4929.CrossRefPubMedGoogle Scholar
  20. Ostrosky-Zeichner, L.K., A. Marr, J.H. Rex, and S.H. Cohen. 2003. Amphotericin B: Time for a new “gold standard”. Clinical Infectious Diseases 37: 415–425.CrossRefPubMedGoogle Scholar
  21. Prakash, O., M. Kumar, R. Kumar, C. Sharma, and K.R. Aneja. 2010. Hypervalent iodine(III) mediated synthesis of novel unsymmetrical 2,5-disubstituted 1,3,4-oxadiazoles as antibacterial and antifungal agents. European Journal of Medicinal Chemistry 45: 4252–5742.CrossRefPubMedGoogle Scholar
  22. Rai, G., V. Kenyon, A. Jadhav, L. Schultz, M. Armstrong, J.B. Jameson, E. Hoobler, W. Leister, A. Simeonov, T.R. Holman, and D.J. Maloney. 2010. Discovery of potent and selective inhibitors of human reticulocyte 15-lipoxygenase-1. Journal of Medicinal Chemistry 53: 7392–7404.CrossRefPubMedCentralPubMedGoogle Scholar
  23. Schlecker, R., and P.C. Thieme. 1998. The synthesis of antihypertensive 3-(1,3,4-oxadiazol-2-yl) phenoxypropanolahines. Tetrahedron 44: 3289–3294.CrossRefGoogle Scholar
  24. Shear, N.H., V.V. Villars, and C. Marsolais. 1991. Terbinafine: An oral and topical antifungal agent. Clinics in Dermatology 9: 487–495.CrossRefPubMedGoogle Scholar
  25. Sheehan, D.J., C.A. Hitchcock, and C.M. Sibley. 1999. Current and emerging azole antifungal agents. Clinical Microbiology Reviews 12: 40–79.PubMedCentralPubMedGoogle Scholar
  26. Sheng, C.Q., W.N. Zhang, H.T. Ji, M. Zhang, Y.L. Song, and H. Xu. 2006. Structure-based optimization of azole antifungal agents by CoMFA, CoMSIA, and molecular docking. Journal of Medicinal Chemistry 49: 2512–2525.CrossRefPubMedGoogle Scholar
  27. Suresh-Kumar, G.V., Y. Rajendraprasad, B.P. Mallikarjuna, S.M. Chandrashekar, and C. Kistayya. 2010. Synthesis of some novel 2-substituted-5-[isopropylthiazole] clubbed 1,2,4-triazole and 1,3,4-oxadiazoles as potential antimicrobial and antitubercular agents. European Journal of Medicinal Chemistry 45: 2063–2074.CrossRefPubMedGoogle Scholar
  28. Tan, T.M., Y. Chen, K.H. Kong, J. Bai, Y. Li, S.G. Lim, T.H. Ang, and Y. Lam. 2006. Synthesis and the biological evaluation of 2-benzenesulfonylalkyl-5-substituted-sulfanyl-[1,3,4]-oxadiazoles as potential anti-hepatitis B virus agents. Antiviral Research 7: 7–14.CrossRefGoogle Scholar
  29. Temesgen, Z., and D.S. Siraj. 2008. Raltegravir: First in class HIV integrase inhibitor. Therapeutics and Clinical Risk Management 4: 493–500.PubMedCentralPubMedGoogle Scholar
  30. Vardan, S., S. Mookherjee, H. Smulyan, and R. Eich. 1983. Effects of tiodazosin, a new antihypertensive, hemodynamics and clinical variables. Clinical Pharmacology & Therapeutics 34: 290–296.CrossRefGoogle Scholar
  31. Xu, W.M., F.F. Han, M. He, D.Y. Hu, J. He, Y. Song, and B.A. Song. 2012. Inhibition of tobacco bacterial wilt with sulfone derivatives containing an 1,3,4-oxadiazole moiety. Journal of Agriculture and Food Chemistry 60: 1036–1041.CrossRefGoogle Scholar
  32. Yu, S.C., X.Y. Chai, N. Wang, H. Cui, Q.J. Zhao, and Q.Y. Wu. 2013. Synthesis and antifungal activity of the novel triazole compounds. Medicinal Chemistry Communications 4: 704–708.CrossRefGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2014

Authors and Affiliations

  • Jun Liao
    • 1
  • Fan Yang
    • 2
  • Lei Zhang
    • 2
  • Xiaoyun Chai
    • 1
  • Qingjie Zhao
    • 1
  • Shichong Yu
    • 1
  • Yan Zou
    • 1
  • Qingguo Meng
    • 2
    Email author
  • Qiuye Wu
    • 1
    Email author
  1. 1.Department of Organic Chemistry, College of PharmacySecond Military Medical UniversityShanghaiPeople’s Republic of China
  2. 2.College of PharmacyYantai UniversityYantaiPeople’s Republic of China

Personalised recommendations