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Design, synthesis, and biological activities of novel azole-bonded \(\upbeta \)-hydroxypropyl oxime O-ethers

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Abstract

The synthesis and biological effects of 15 novel azole-bonded \(\upbeta \)-hydroxypropyl oxime \(O\)-ethers have been described. In this synthesis, the oximation of aromatic ketones followed by an \(O\)-alkylation reaction with epichlorohydrin and/or epibromohydrin led to the corresponding \(O\)-oxime ether adducts. Subsequently, the attained \(O\)-oxime ether adducts were used to synthesize the target molecules after treating them with the appropriate azole derivatives. The in vitro antifungal and antibacterial activities of title compounds were obtained against several pathogenic fungi, Gram-positive and/or Gram-negative bacteria. Benzophenone \(O\)-2-hydroxy-3-(2-phenyl-1\(H\)-imidazol-1-yl) propyl oxime and 9\(H\)-fluoren-9-one \(O\)-2-hydroxy-3-(2-phenyl-1\(H\)-imidazol-1-yl)propyl oxime proved to have considerable antifungal activity against Candida albicans, Candida krusei, Aspergillus niger, and Trichophyton rubrum. These two compounds demonstrated comparable antifungal activity to clotrimazole and fluconazole (standard drugs). All compounds were also tested against Escherichia coli and Staphylococcus aureus as Gram-negative and Gram-positive bacteria, respectively, and their activities were compared to gentamycin and ampicillin (reference drugs). In general, marginal antibacterial activity against tested bacteria was observed for the title compounds. A molecular docking study is also discussed for the two most potent compounds against fungi. The docking study reveals a considerable interaction between the two most potent compounds and the active site of Mycobacterium P450DM. Moreover, these two compounds are much strongly bound to the active site of Mycobacterium P450DM compared to fluconazole.

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References

  1. Kathiravan MK, Salake AB, Chothe AS, Dudhe PB, Watode RP, Mukta MS, Gadhwe S (2012) The biology and chemistry of antifungal agents: a review. Bioorg Med Chem 20:5678–5698. doi:10.1016/j.bmc.2012.04.045

    Article  PubMed  CAS  Google Scholar 

  2. Kontoyannis D, Mantadakis E, Samonis G (2003) Systemic mycoses in the immunocompromised host: an update in antifungal therapy. J Hosp Infect 53:243–258. doi:10.1053/jhin.2002.1278

    Article  Google Scholar 

  3. Rüping MJ, Vehreschild JJ, Cornely OA (2008) Patients at high risk of invasive fungal infections. Drugs 68:1941–1962. doi:10.2165/00003495-200868140-00002

    Article  PubMed  Google Scholar 

  4. Sorbera LA, Aravamudan J, Rosa E (2011) Therapeutic targets for candidiasis. Drugs Future 36:627–630. doi:10.1358/dof.2011.36.8.1686467

    Article  CAS  Google Scholar 

  5. Jain A, Jain S, Rawat S (2010) Emerging fungal infections among children: a review on its clinical manifestations, diagnosis, and prevention. J Pharm Bioallied Sci 2:314–320. doi:10.4103/0975-7406.72131

    Article  PubMed  PubMed Central  Google Scholar 

  6. Kleeman A, Engel J, Kutscher B, Reichert D (1999) Pharmaceutical substances, 3rd edn. Thieme, Stuttgart

    Google Scholar 

  7. Johnson DS, Li JJ (2007) The art of drug synthesis. Wiley, Hoboken

    Book  Google Scholar 

  8. Balkovec JM (1998) In: Bristol JA (ed) Annual reports in medicinal chemistry, vol 33. Academic Press, New York, pp 173–182

    Google Scholar 

  9. Watkins WJ, Renau TE (1999) In: Dohery AM (ed) Annual reports in medicinal chemistry, vol 35. Academic Press, New York, pp 157–166

    Google Scholar 

  10. Xu Y, Sheng C, Wang W, Che X, Cao Y, Dong G, Wang S, Ji H, Miao Z, Yao J, Zhang W (2010) Structure-based rational design, synthesis and antifungal activity of oxime-containing azole derivatives. Bioorg Med Chem Let 20:2942–2945. doi:10.1016/j.bmcl.2010.03.014

    Article  CAS  Google Scholar 

  11. Kunzler A, Neuenfeldt PD, das Neves AM, Pereira CMP, Marques GH, Nascente PS, Fernandes MHV, Hübner SO (2013) Synthesis, antifungal and cytotoxic activities of 2-aryl-3-((piperidin-1-yl)ethyl)thiazolidinones. Eur J Med Chem 64:74–80. doi:10.1016/j.ejmech.2013.03.030

    Article  PubMed  CAS  Google Scholar 

  12. Lovey RG, Elliott AJ, Kaminski JJ, Loebenberg D, Parmegiani RM, Rane DF, Girijavallabhan VM, Pike RE, Guzik H, Antonacci B, Tomaine TY (1992) Isobenzofurans as conformationally constrained miconazole analogs with improved antifungal potency. J Med Chem 35:4221–4229. doi:10.1021/jm00100a030

    Article  PubMed  CAS  Google Scholar 

  13. Bodey GP (1992) Azole antifungal agents. Clin Infect Dis 14:S161–S169. doi:10.1093/clinids/14.Supplement-1.S161

    Article  PubMed  Google Scholar 

  14. Strushkevich N, Usanov SA (2010) Structural basis of human CYP51 inhibition by antifungal azoles. J Mol Biol 397:1067–1078. doi:10.1016/j.jmb.2010.01.075

    Article  PubMed  CAS  Google Scholar 

  15. Odds F, Brown AJP, Gow NAR (2003) Antifungal agents: mechanisms of action. Trends Microbiol 11:272–279. doi:10.1016/S0966-842X(03)00117-3

    Article  PubMed  CAS  Google Scholar 

  16. Gao S, Tao X, Sun L, Sheng C, Zhang W, Yun Y, Li J, Miao H, Chen W (2009) An liquid chromatography-tandem mass spectrometry assay for determination of trace amount of new antifungal drug iodiconazole in human plasma. J Chromatogr B 877:382–386. doi:10.1016/j.jchromb.2008.12.034

    Article  CAS  Google Scholar 

  17. Sun N, Wen J, Lu G, Hong Z, Fan G, Wu Y, Sheng C, Zhang W (2010) An ultra-fast LC method for the determination of iodiconazole in microdialysis samples and its application in the calibration of laboratory-made linear probes. J Pharm Biomed Anal 51:248–251. doi:10.1016/j.jpba.2009.07.016

    Article  PubMed  CAS  Google Scholar 

  18. Jones G, Willett P, Glen RC, Leach AR, Taylor R (1997) Development and validation of a genetic algorithm for flexible docking. J Mol Biol 267:727–748. doi:10.1006/jmbi.1996.0897

    Article  PubMed  CAS  Google Scholar 

  19. Capilla J, Yustes C, Mayayo E, Fernandez B, Ortoneda M, Pastor FJ, Guarro J (2003) Efficacy of albaconazole (UR-9825) in treatment of disseminated scedosporium prolificans infection in rabbits. Antimicrob Agents Chemother 47:1948–1951. doi:10.1128/AAC.47.6.1948-1951.2003

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  20. Fromtling RA, Castañer J (1999) Syn-2869: antifungal. Drugs Future 24:30–37. doi:10.1358/dof.1999.024.01.483809

    Article  CAS  Google Scholar 

  21. Arikan S, Rex JH (2002) Ravuconazole (Eisai/Bristol-Myers Squibb). Curr Opin Investig Drugs 3:555–561

    PubMed  CAS  Google Scholar 

  22. Cao XF, Chu WJ, Cao YB, Yang YS (2013) Design and synthesis of novel antifungal triazole derivatives with good activity and water solubility. Chin Chem Lett 24:303–306. doi:10.1016/j.cclet.2013.01.047

    Article  CAS  Google Scholar 

  23. Fang B, Zhou CH, Rao XC (2010) Synthesis and biological activities of novel amine-derived bis-azoles as potential antibacterial and antifungal agents. Eur J Med Chem 45:4388–4398. doi:10.1016/j.ejmech.2010.06.012

    Article  PubMed  CAS  Google Scholar 

  24. Wang S, Jin G, Wang W, Zhu L, Zhang Y, Dong G, Liu Y, Zhuang C, Miao Z, Yao J, Zhang W, Sheng C (2012) Design, synthesis and structure-activity relationships of new triazole derivatives containing N-substituted phenoxypropylamino side chains. Eur J Med Chem 53:292–299. doi:10.1016/j.ejmech.2012.04.013

    Article  PubMed  CAS  Google Scholar 

  25. Jiang Z, Wang Y, Wang W, Wang S, Xu B, Fan G, Dong G, Liu Y, Yao J, Miao Z, Zhang W, Sheng C (2013) Discovery of highly potent triazole antifungal derivatives by heterocycle-benzene bioisosteric replacement. Eur J Med Chem 64:16–22. doi:10.1016/j.ejmech.2013.04.025

    Article  PubMed  CAS  Google Scholar 

  26. Emami S, Falahati M, Banifatemi A, Amanlou M, Shafiee A (2004) (E)- and (Z)-1,2,4-Triazolylchromanone oxime ethers as conformationally constrained antifungals. Bioorg Med Chem 12:3971–3976. doi:10.1016/j.bmc.2004.06.010

    Article  PubMed  CAS  Google Scholar 

  27. Emami S, Falahati M, Banifatemi A, Moshiri K, Shafiee A (2002) Stereoselective synthesis and in vitro antifungal evaluation of (E)- and (Z)-imidazolylchromanone oxime ethers. Arch Pharm 335:318–324. doi:10.1002/1521-4184(200209)335

    Article  CAS  Google Scholar 

  28. Emami S, Falahati M, Banifatemi A, Shafiee A (2004) Stereoselective synthesis and antifungal activity of (Z)-trans-3-azolyl-2-methylchromanone oxime ethers. Bioorg Med Chem 12:5881–5889. doi:10.1016/j.bmc.2004.08.030

    Article  PubMed  CAS  Google Scholar 

  29. Rossello A, Bertini S, Lapucci A, Macchia M, Martinelli A, Rapposelli S, Herreros E, Macchia B (2002) Synthesis, antifungal activity, and molecular modeling studies of new inverted oxime ethers of oxiconazole. J Med Chem 45:4903–4912. doi:10.1021/jm020980t

    Article  PubMed  CAS  Google Scholar 

  30. Mamolo MG, Zampieri D, Falagiani V, Vio L, Fermeglia M, Ferrone M, Pricl S, Banfi E, Scialinoc G (2004) Antifungal and antimycobacterial activity of new N1-[1-aryl-2-(1H-imidazol-1-yl and 1H–1,2,4-triazol-1-yl)-ethylidene]-pyridine-2-carboxamidrazone derivatives: a combined experimental and computational approach. ARKIVOC v, pp. 231–250, doi:10.3998/ark.5550190.0005.521.

  31. Dyer RL, Ellames GJ, Hamill BJ, Manley PW, Pope AMS (1983) Synthesis of (E)-1-(5-chlorothien-2-yl)-2-(1H-imidazol-1-yl)ethanone 2,6-dichlorophenylhydrazone hydro-chloride, a novel, orally active antifungal agent. J Med Chem 26:442–445. doi:10.1021/jm00357a023

    Article  PubMed  CAS  Google Scholar 

  32. Ayati A, Falahati M, Irannejad H, Emami S (2012) Synthesis, in vitro antifungal evaluation and in silico study of 3-azolyl-4-chromanone phenylhydrazones. DARU J Pharm Sci 20(46):1–7. doi:10.1186/2008-2231-20-46

    Google Scholar 

  33. Soltani Rad MN, Khalafi-Nezhad A, Behrouz S (2009) Design and synthesis of some novel oxiconazole-like carboacyclic nucleoside analogues, as potential chemotherapeutic agents. Helv Chim Acta 92:1760–1774. doi:10.1002/hlca.200900051

    Article  CAS  Google Scholar 

  34. Soltani Rad MN, Khalafi-Nezhad A, Behrouz S (2010) Synthesis of some novel hydrazono acyclic nucleoside analogues. Beilstein J Org Chem 6(49):1–8. doi:10.3762/bjoc.6.49

    Google Scholar 

  35. Soltani Rad MN, Asrari Z, Behrouz S, Hakimelahi GH, Khalafi-Nezhad A (2011) ‘Click synthesis’ of 1H–1,2,3-triazolyl-based oxiconazole (=(1Z)-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanone O-[(2,4-dichlorophenyl)methyl]oxime) analogs. Helv Chim Acta 94:2194–2206. doi:10.1002/hlca.201100189

    Article  CAS  Google Scholar 

  36. Soltani Rad MN, Behrouz S, Nekoei AR, Faghih Z, Khalafi-Nezhad A (2011) Three-component synthesis of some novel N-heterocycle methyl-O-oxime ethers. Synthesis 24:4068–4076. doi:10.1055/s-0031-1289599

  37. Soltani Rad MN, Behrouz S, Karimitabar F, Khalafi-Nezhad A (2012) ‘Click synthesis’ of some novel O-substituted oximes containing 1,2,3-triazole-1,4-diyl residues as new analogs of \(\beta \)-adrenoceptor antagonists. Helv Chim Acta 95:491–501. doi: 10.1002/hlca.201100324

    Article  Google Scholar 

  38. Soltani Rad MN, Behrouz S, Movahedian A, Doroodmand MM, Ghasemi Y, Rasoul-Amini S, Rezaie R (2013) Doped nano-sized copper(I) oxide (Cu\(_{2}\)O) on melamineformaldehyde resin: a highly efficient heterogeneous nano catalyst for ‘click’ synthesis of some novel 1H–1,2,3-triazole derivatives having antibacterial activity. Helv Chim Acta 96:688–701. doi: 10.1002/hlca.201200224

    Article  Google Scholar 

  39. Soltani Rad MN, Behrouz S, Dianat M (2008) Aqueous-mediated ring opening of epoxides with oximes: a rapid entry into \(\beta \)-hydroxy oxime O-ethers as potential \(\beta \)-adrenergic blocking agents. Synthesis 13:2055–2064. doi: 10.1055/s-2008-1067122

    Article  Google Scholar 

  40. Smith PAS, Robertson JE (1962) Some factors affecting the site of alkylation of oxime salts. J Am Chem Soc 84:1197–1204. doi:10.1021/ja00866a027

    Article  CAS  Google Scholar 

  41. Buehler E (1967) Alkylation of syn- and anti-benzaldoximes. J Org Chem 32:261–265. doi:10.1021/jo01288a002

    Article  CAS  Google Scholar 

  42. Smith SG, Milligan DV (1968) Effect of ion pairing on the rate and site of alkylation of oxime salts. J Am Chem Soc 90:2393–2398. doi:10.1021/ja01011a032

    Article  CAS  Google Scholar 

  43. Liu ZZ, Chen HC, Cao SL, Li RT (1993) Solid-liquid phase-transfer catalytic method for N-alkylation of nitroimidazole. Synth Commun 23:2611–2615. doi:10.1080/00397919308012596

    Article  CAS  Google Scholar 

  44. Zhu J, Bienyamé H (2005) Multicomponent reactions. Wiley-VCH, Weinheim

    Book  Google Scholar 

  45. Podust LM, Poulos TL, Waterman MR (2001) Crystal structure of cytochrome P450 14\(\alpha \)-sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors. Proc Natl Acad Sci USA 98:3068–3073. doi: 10.1073/pnas.061562898

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  46. Marcou G, Rognan D (2007) Optimizing fragment and scaffold docking by use of molecular interaction fingerprints. J Chem Inf Model 47:195–207. doi:10.1021/ci600342e

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors wish to thank Shiraz University of Technology research council for partial support of this work.

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Authors and Affiliations

  1. Department of Chemistry, Shiraz University of Technology, 71555-313 , Shiraz, Iran

    Somayeh Behrouz, Mohammad Navid Soltani Rad, Saeid Rostami, Marzieh Behrouz & Elham Zarehnezhad

  2. Fasa University of Medical Sciences, Fasa, Iran

    Ali Zarehnezhad

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  1. Somayeh Behrouz
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  2. Mohammad Navid Soltani Rad
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  3. Saeid Rostami
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  4. Marzieh Behrouz
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  5. Elham Zarehnezhad
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Correspondence to Somayeh Behrouz or Mohammad Navid Soltani Rad.

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Behrouz, S., Rad, M.N.S., Rostami, S. et al. Design, synthesis, and biological activities of novel azole-bonded \(\upbeta \)-hydroxypropyl oxime O-ethers. Mol Divers 18, 797–808 (2014). https://doi.org/10.1007/s11030-014-9539-1

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