Medicinal Chemistry Research

, Volume 27, Issue 2, pp 592–606 | Cite as

Imidazole-thiazole coupled derivatives as novel lanosterol 14-α demethylase inhibitors: ionic liquid mediated synthesis, biological evaluation and molecular docking study

  • Anna Pratima G. Nikalje
  • Shailee V. Tiwari
  • Aniket P. Sarkate
  • Kshipra S. Karnik
Original Research


A novel series of imidazole-thiazole coupled derivatives (7a7q) were synthesized using Green protocol and identified by different spectroscopic techniques. The synthesized derivatives (7a7q) were evaluated for their in vitro antifungal activity against the six fungi strains. The compounds 7j and 7k exhibited the most promising antifungal activity. The compound 7k exhibited extremely high antifungal activity against C. albicans, C. glabrata, F. oxysporum, A. flavus, A. niger, and C. neoformans with MIC80 values of 0.2, 0.2, 20, 35, 40, and 5 µg/ml respectively. The mode of action of the most promising antifungal compounds 7j and 7k was established by ergosterol extraction and quantitation assay. From the ergosterol extraction and quantitation assay it was found that the compounds 7j and 7k act by inhibition of ergosterol biosynthesis in C. albicans. The molecular docking study revealed the high spontaneous binding ability of the tested compounds to the active site of lanosterol 14α-demethylase, which proves that the tested compounds inhibit the synthesis of lanosterol 14α-demethylase. The synthesized compounds were analyzed for ADMET properties to establish oral drug like behavior and shows satisfactory results. To establish the antifungal selectivity and safety, the most active compounds were further tested for cytotoxicity against human cancer cell lines HeLa and K-562 and were found to be non-cytotoxic in nature. The in vivo acute oral toxicity study was performed for the most active compounds and results indicate that the compounds are non-toxic in nature.


Imidazole-thiazole Antifungal activity Ergosterol extraction and quantitation assay Molecular docking Acute oral toxicity 



The authors are thankful to Mrs. Fatima Zakaria, Chairman, Maulana Azad Educational Trust and Dr. Zahid Zaheer, Principal, Y.B. Chavan College of Pharmacy, Dr. Rafiq Zakaria Campus, Aurangabad 431 001 (M.S.), India for providing the laboratory facility.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

44_2017_2085_MOESM1_ESM.docx (1.7 mb)
Supplementary Information


  1. Albataineh MT, Sutton DA, Fothergill AW, Wiederhold NP (2016) Update from the laboratory clinical identification and susceptibility testing of fungi and trends in antifungal resistance. Infect Dis Clin North Am 30:13–35CrossRefPubMedGoogle Scholar
  2. Arthington-Skaggs BA, Warnock DW, Morrison CJ (2000) Quantitation of Candida albicans ergosterol content improves the correlation between in vitro antifungal susceptibility test results and in vivo outcome after fluconazole treatment in murine model of invasive candidiasis. Antimicrob Agents Chemother 44:2081–2085CrossRefPubMedPubMedCentralGoogle Scholar
  3. Brown GD, Denning DW, Gow NAR, Levitz SM, Netea MG, White TC (2012) Hidden killers: human fungal infections. SciTransl Med 4:165–13Google Scholar
  4. Denning DW, Bromley MJ (2015) How to bolster the antifungal pipeline. Science 347:1414–1416CrossRefPubMedGoogle Scholar
  5. Franchetti P, Cappellacci L, Pasqualini M, Petrelli R, Jayaprakasan V, Jayaram HN, Boyd DB, Jain MD, Grifantini M (2005) Synthesis, conformational analysis, and biological activity of new analogues of thiazole-4-carboxamide adenine dinucleotide (TAD) as IMP dehydrogenase inhibitors. Bioorg Med Chem 13:2045–2053CrossRefPubMedGoogle Scholar
  6. Gu XH, Wan XZ, Jiang B (1999) Syntheses and biological activities of bis(3-indolyl)thiazoles, analogues of marine bis(indole) alkaloid nor topsentins. Bioorg Med Chem Lett 9:569–572CrossRefPubMedGoogle Scholar
  7. Kumar PSV, Suresh L, Chandramouli GVP (2015) Ionic liquid catalyzed multi-component synthesis, antifungal activity, docking studies and in-silico ADMET properties of novel fused chromeno-pyrazolo-phthalazine derivatives. J Saudi Chem Soc
  8. 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 20:5678–5698CrossRefPubMedGoogle Scholar
  9. Lamberth C, Dumeunier R, Trah S, Wendeborn S, Godwin J, Schneiter P, Corran A (2013) Synthesis and fungicidal activity of tubulin polymerisation promoters. Part 3: Imidazoles. Bioorg Med Chem 21:127–134CrossRefPubMedGoogle Scholar
  10. Lima IO, De Medeiros Nobrega F, De Oliveira WA, Lima EO, Menezes EA, Cunha F, MeloDiniz AMFF (2012) Anti-candida albicans effectiveness of citral and investigation of mode of action. Pharma Biol 50:1536–1541CrossRefGoogle Scholar
  11. Medime E, Capan G (1994) Synthesis and anticonvulsant activity of new 4-thiazolidone and 4-thiazoline derivatives. II Farmaco 49:449–451Google Scholar
  12. Meunier B (2008) Hybrid molecules with a dual mode of action: dream or reality? Acc Chem Res 41:69–77CrossRefPubMedGoogle Scholar
  13. Nikalje AG, Ghodke MS, Kalam Khan FA, Sangshetti JN (2015) CAN catalyzed one-pot synthesis and docking study of some novel substituted imidazole coupled 1, 2, 4-triazole-5-carboxylic acids as antifungal agents. Chin Chem Lett 26:108–112CrossRefGoogle Scholar
  14. National Committee for Clinical Laboratory Standards (2002) Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts Approved Standard. Document M27-A2. National Committee for Clinical Laboratory Standards, Wayne, PAGoogle Scholar
  15. Pianalto KM, Alspaugh JA (2016) New horizons in antifungal therapy. J Fungi 2:1–24CrossRefGoogle Scholar
  16. Roemer T, Krysan DJ (2014) Antifungal drug development: challenges, unmet clinical needs, and new approaches. Cold Spring Harb Perspect Med 4:a019703CrossRefPubMedPubMedCentralGoogle Scholar
  17. Sangshetti JN, Lokwani DK, Sarkate AP, Shinde DB (2011) Synthesis, antifungal activity, and docking study of some new 1,2,4-triazole analogs. Chem Biol Drug Des 78:800–809CrossRefPubMedGoogle Scholar
  18. Strushkevich N, Usanov SA, Park H (2010) Structural basis of human CYP51 inhibition by antifungal azoles. J Mol Biol 397:1067–1078CrossRefPubMedGoogle Scholar
  19. Shiradkar MR, Murahari KK, Reddy H, Tatikonda S, Chakravarthy AK, Panchal D, Kaur R, Burange P, Ghogare J, Mokalec V, Raut M (2007) Synthesis of new S-derivatives of clubbed triazolylthiazole as anti-Mycobacterium tuberculosis agents. Bioorg Med Chem 15:3997–4008CrossRefPubMedGoogle Scholar
  20. Tiwari SV, Seijas JA, Vazquez-Tato MP, Sarkate AP, Karnik KS, Nikalje AP (2017a) Facile synthesis of novel coumarin derivatives, antimicrobial analysis, enzyme assay, docking study, ADMET prediction and toxicity study. Molecules 22:1172–1180CrossRefGoogle Scholar
  21. Tiwari SV, Nikalje APG, Lokwani DK, Sarkate AP, Jamir K (2017b) Synthesis, biological evaluation, molecular docking study and acute oral toxicity study of coupled Imidazolyl-Pyrimidine derivatives. Lett Drug Des Discov 14:
  22. Turan-Zitouni G, Kaplancikli ZA, Yildiz MT, Chevallet P, Kaya D (2005) Synthesis and antimicrobial activity of 4-phenyl/cyclohexyl-5-(1-phenoxyethyl)-3-[N-(2-thiazolyl)acetamido]thio-4H-1,2,4-triazole derivatives. Eur J Med Chem 40:607–613CrossRefPubMedGoogle Scholar
  23. Tsuruoka A, Kaku Y, Kakinuma H, Tsukada I, Yanagisawa M, Nara K, Naito T (1998) Synthesis and antifungal activity of novel thiazole-containing triazole antifungals. II. optically active ER-30346 and its derivatives. Chem Pharm Bull 46:623–630CrossRefPubMedGoogle Scholar
  24. Tsuruoka A, Kaku Y, Kakinuma H, Tsukada I, Yanagisawa M, Naito T (1997) Synthesis and antifungal activity of novel thiazole-containing triazole antifungals. Chem Pharm Bull 45:1169–1176CrossRefPubMedGoogle Scholar
  25. Nimbalkar UD, Tupe SG, Seijas Vazquez JA, Khan FAK, Sangshetti JN, Nikalje APG (2016) Ultrasound and molecular sieves-assisted synthesis, molecular docking and antifungal evaluation of 5-(4-(benzyloxy)-substituted phenyl)-3-((phenylamino)methyl)-1,3,4-oxadiazole-2(3H)-thiones. Molecules 21:484–497CrossRefGoogle Scholar
  26. Vichai V, Kirtikara K (2006) Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Prot 1:1112–1116CrossRefGoogle Scholar
  27. Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD (2002) Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 45:2615–2623CrossRefPubMedGoogle Scholar
  28. Vandenberg JI, Walker BD, Campbell TJ (2001) HERG K+ channels: friend and foe. Trends PharmacolSci 22:240–246CrossRefGoogle Scholar
  29. Yasnitskii BG, Dolberg EB (1971) Mechanism of the formation of 2-aminothiazole in the reaction of chloroacetaldehyde with thiourea. Chem Heterocycl Comp 7:866–868CrossRefGoogle Scholar
  30. Zhai B, Lin XR (2011) Recent progress on antifungal drug development. Curr Pharm Biotechnol 12:1255–1262CrossRefPubMedGoogle Scholar
  31. Zhou CH, Mi JL (2009) Preparation of Fluotrimazole ether derivatives as antimicrobial agents. CN Patent, CN101391986 (A).Google Scholar
  32. Zhao B, Zhou YC, Fan MJ, Li ZY, Wang LY, Deng QG (2013) Synthesis, fluorescence properties and selective Cr(III) recognition of tetraaryl imidazole derivatives bearing thiazole group. Chinese Chem Lett 24:257–259CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Anna Pratima G. Nikalje
    • 1
  • Shailee V. Tiwari
    • 1
  • Aniket P. Sarkate
    • 2
  • Kshipra S. Karnik
    • 2
  1. 1.Y. B. Chavan College of PharmacyDr. Rafiq Zakaria CampusAurangabadIndia
  2. 2.Department of Chemical TechnologyDr. Babasaheb Ambedkar Marathwada UniversityAurangabadIndia

Personalised recommendations