eur j life sci

European Journal of Life Sciences

2822-5333

Anadolu University

10.55971/EJLS.1714724

Molecular Docking Pharmaceutical Chemistry

Moleküler Yerleştirme Farmasotik Kimya

Synthesis and antifungal assessment of imidazole-containing compounds: A comprehensive study integrating experimental and computational techniques

https://orcid.org/0000-0002-0635-0664

Halimi Syla

Gresa

ANADOLU ÜNİVERSİTESİ

https://orcid.org/0000-0002-0499-436X

Osmaniye

Derya

ANADOLU UNIVERSITY

https://orcid.org/0000-0002-0151-6266

Sağlık

Begüm Nurpelin

ANADOLU UNIVERSITY

05 01 2026

5 1 15 24 06 04 2025 08 12 2025

2022

European Journal of Life Sciences

The emergence of resistant fungal strains has created an urgent need for novel antifungal agents with improved efficacy and safety profiles. In this study, we report the design, synthesis, and evaluation of a new series of imidazole-containing thiazole derivatives as potential anti-fungal agents. The compounds were synthesized via a two-step process involving thiourea formation, followed by microwave-assisted cyclization with substituted phenacyl bromides. The resulting products, mostly semi-liquid in nature, were characterized by high-resolution mass spectrometry (HRMS) and nuclear magnetic resonance (NMR) spectroscopy. The synthesized derivatives were tested in vitro against clinically relevant fungal pathogens, including Candida albicans, Candida glabrata, Candida parapsilosis, and Candida krusei. Structure-activity relationship (SAR) analysis indicated that the antifungal activity was influenced by the electronic and steric properties of the aromatic substituents. Compound 2b, bearing a para-cyano group, exhibited the highest potency, with MIC50 values of 0.98 µg/mL against C. albicans and C. parapsilosis, comparable to standard antifungal agents. Molecular docking studies supported these findings, revealing favorable interactions with fungal target sites, and ADME predictions suggested drug-like properties. This multidisciplinary approach led to the identification of imidazole-based compounds with potent anti-fungal properties, laying the groundwork for further optimization and preclinical development.

ADME antifungal imidazole molecular docking

Maccallini C, Gallorini M, Sisto F, Akdemir A, Ammazzalorso A, De Filippis B, Fantacuzzi M, Giampietro L, Carradori S, Cataldi A, Amoroso R. New azolyl-derivatives as multitargeting agents against breast cancer and fungal infections: synthesis, biological evaluation and docking study. J Enzyme Inhib Med Chem. (2021);36(1):1631-44. https://doi.org/10.1080/14756366.2021.1954918.

Wang YN, Bheemanaboina RRY, Cai GX, Zhou CH. Novel purine benzimidazoles as antimicrobial agents by regulating ROS generation and targeting clinically resistant Staphylococcus aureus DNA groove. Bioorg Med Chem Lett. (2018);28(9):1621-8. https://doi.org/10.1016/j.bmcl.2018.03.046.

Ansari MA, Fatima Z, Hameed S. Antifungal action of methylene blue involves mitochondrial dysfunction and disruption of redox and membrane homeostasis in C. albicans. Open Microbiol J. (2016);10(1):12-22. https://doi.org/ 10.2174/1874285801610010012.

Gintjee T, Donnelley M, Thompson G. Aspiring antifungals: Review of current antifungal pipeline developments. Journal of Fungi. (2020);6(1):28. https:// doi.org/10.3390/jof6010028.

Xu H, Su X, Guo M bi, An R, Mou Y hua, Hou Z, Guo Ch. Design, synthesis, and biological evaluation of novel miconazole analogues containing selenium as potent antifungal agents. Eur J Med Chem. (2020); 198:112360. https://doi.org/10.1016/j.ejmech.2020.112360.

Negri M, Salci T, Shinobu-Mesquita C, Capoci I, Svidzinski T, Kioshima E. Early state research on antifungal natural products. Molecules. (2014);19(3):2925-56. https://doi.org/10.3390/molecules19032925.

Bondaryk M, Kurzątkowski W, Staniszewska M. Antifungal agents commonly used in the superficial and mucosal candidiasis treatment: mode of action and resistance development. Advances in Dermatology and Allergology. (2013); 5:293-301. https://doi.org/10.5114/pdia.2013.38358.

Srinivasan A, Lopez-Ribot JL, Ramasubramanian AK. Overcoming antifungal resistance. Drug Discov Today Technol. (2014); 11:65-71. https://doi.org/10.1016/j.ddtec.2014.02.005.

Hoenigl M, Arastehfar A, Arendrup MC, Brüggemann R, Carvalho A, Chiller T, Chen Sh, Egger M, Feys S, Gangneux JP, Gold JAW, Groll AH, Heylen J, Jenks JD, Krause R, Lagrou K, Lamoth F, Prattes J, Sedik S, Wauters J, Wiederhold NP, Thompson GR. Novel antifungals and treatment approaches to tackle resistance and improve outcomes of invasive fungal disease. Clin Microbiol Rev. (2024);37(2):e00074-23. https://doi.org/10.1128/cmr.00074-23.

Staniszewska M, Bondaryk M, Wieczorek M, Estrada-Mata E, Mora-Montes HM, Ochal Z. Antifungal effect of novel 2-Bromo-2-chloro-2-(4-chlorophenylsulfonyl)-1-phenylethanone against candida strains. Front Microbiol. (2016);7:1309. https://doi.org/10.3389/fmicb.2016.01309.

Sadeghian S, Bekhradi F, Mansouri F, Razmi R, Mansouri SG, Poustforoosh A, Khabnadideh S, Zomorodian K, Zareshahrabadi Z, Rezaei Z. Imidazole derivatives as novel and potent antifungal agents: Synthesis, biological evaluation, molecular docking study, molecular dynamic simulation and ADME prediction. J Mol Struct. (2024); 1302:137447. https://doi.org/10.1016/j.molstruc.2023.137447.

Biernasiuk A, Berecka-Rycerz A, Gumieniczek A, Malm M, Łączkowski KZ, Szymańska J, Malm A. The newly synthesized thiazole derivatives as potential antifungal compounds against Candida albicans. Appl Microbiol Biotechnol. (2021);105(16):6355-67. https://doi.org/10.1007/s00253-021-11477-7.

Wani MY, Ahmad A, Shiekh RA, Al-Ghamdi KJ, Sobral AJFN. Imidazole clubbed 1,3,4-oxadiazole derivatives as potential antifungal agents. Bioorg Med Chem. (2015);23(15):4172-80. https://doi.org/10.1016/j.bmc.2015.06.053.

Chen L, Zhang L, Xie Y, Wang Y, Tian X, Fang W, Xue X, Wang L. Confronting antifungal resistance, tolerance, and persistence: Advances in drug target discovery and delivery systems. Adv Drug Deliv Rev. (2023); 200:115007. https://doi.org/10.1016/j.addr.2023.115007.

Alghamdi SS, Suliman RS, Almutairi K, Kahtani K, Aljatli D. Imidazole as a promising medicinal scaffold: Current status and future direction. Drug Des Devel Ther. (2021);15:3289-312. https://doi.org/10.2147/DDDT.S307113.

Molina P, Tárraga A, Otón F. Imidazole derivatives: A comprehensive survey of their recognition properties. Org Biomol Chem. (2012);10(9):1711. https://doi.org/10.1039/C2OB06808G.

Rodriguez-Tudela JL, Arendrup MC, Barchiesi F, Bille J, Chryssanthou E, Cuenca-Estrella M, Dannaoui E, Denning DW, Donnelly JP, Dromer F, Fegeler W, Lass-Florl C, Moore C, Richardson M, Sandven P, Velegraki A, Verweij P. EUCAST Definitive Document EDef 7.1: method for the determination of broth dilution MICs of antifungal agents for fermentative yeasts. Clinical Microbiology and Infection. (2008);14(4):398-405. https://doi.org/ 10.1111/j.1469-0691.2007.01935. x.

Palomino JC, Martin A, Camacho M, Guerra H, Swings J, Portaels F. Resazurin microtiter assay plate: simple and inexpensive method for detection of drug resistance in Mycobacterium tuberculosis. Antimicrob Agents Chemother. (2002);46(8):2720-2. https://doi.org/10.1128/aac.46.8.2720-2722.2002.

Kaplancıklı ZA, Levent S, Osmaniye D, Sağlık BN, Çevik UA, Çavuşoğlu BK, Özkay Y, Ilgın S. Synthesis and anticandidal activity evaluation of new benzimidazole-thiazole derivatives. Molecules. (2017) ;22(12):2051. https://doi.org/10.3390/molecules22122051.

Karaburun AÇ, Acar Çevik U, Osmaniye D, Sağlık BN, Kaya Çavuşoğlu B, Levent S, Özkay Y, Koparal AS, Behçet M, Kaplancıklı ZA. Synthesis and evaluation of new 1,3,4-thiadiazole derivatives as potent antifungal agents. Molecules. (2018) ;23(12):3129. https://doi.org/10.3390/molecules23123129.

Osmaniye D, Kaya Cavusoglu B, Saglik BN, Levent S, Acar Cevik U, Atli O, Özkay Y, Kaplancıklı ZA. Synthesis and anticandidal activity of new imidazole-chalcones. Molecules. (2018) ;23(4):831. https://doi.org/10.3390/molecules23040831.

Cytochrome P450 14 alpha-sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with fluconazole. Retrieved October 1, 2024, from https://www.rcsb.org/structure/1EA1.

Schrödinger, LigPrep. New York: Schrödinger; 2020.

Maestro. New York: Schrödinger; 2020.

Schrödinger, Glide. New York: Schrödinger; 2020.

Daina A, Michielin O, Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. (2017); 7:42717. https://doi.org/10.1038/srep42717.