Imidazole-thiazole coupled derivatives as novel lanosterol 14-α demethylase inhibitors: ionic liquid mediated synthesis, biological evaluation and molecular docking study
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A novel series of imidazole-thiazole coupled derivatives (7a–7q) were synthesized using Green protocol and identified by different spectroscopic techniques. The synthesized derivatives (7a–7q) 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.
KeywordsImidazole-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.
- 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
- Brown GD, Denning DW, Gow NAR, Levitz SM, Netea MG, White TC (2012) Hidden killers: human fungal infections. SciTransl Med 4:165–13Google Scholar
- 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
- 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 https://doi.org/10.1016/j.jscs.2015.08.001
- Medime E, Capan G (1994) Synthesis and anticonvulsant activity of new 4-thiazolidone and 4-thiazoline derivatives. II Farmaco 49:449–451Google Scholar
- 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
- 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: https://doi.org/10.2174/1570180814666170704101817
- 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
- Zhou CH, Mi JL (2009) Preparation of Fluotrimazole ether derivatives as antimicrobial agents. CN Patent, CN101391986 (A).Google Scholar