QSAR Study of Some 1,3-Oxazolylphosphonium Derivatives as New Potent Anti-Candida Agents and Their Toxicity Evaluation

Author(s): Maria M. Trush*, Vasyl Kovalishyn, Alla D. Ocheretniuk, Oleksandr L. Kobzar, Maryna V. Kachaeva, Volodymyr S. Brovarets, Larisa O. Metelytsia.

Journal Name: Current Drug Discovery Technologies

Volume 16 , Issue 2 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Background: The incidence of invasive fungal infections caused by Candida spp. has increased continuously in recent decades, especially in populations of immunocompromised patients or individuals hospitalized with serious underlying diseases. Therefore, the goal of our study was the search for new potent Candida albicans inhibitors via the development of QSAR models that could speed up this search process. A number of the most promising 1,3-oxazol-4-yltriphenylphosphonium derivatives with predicted activities were synthesized and experimentally tested. Furthermore, the toxicity of the studied compounds was determined in vitro using acetylcholinesterase enzyme as a biological marker.

Methods: The classification QSAR models were created using Random Forests (WEKA-RF), k-Nearest Neighbors and Associative Neural Networks methods and different combinations of descriptors on the Online Chemical Modeling Environment (OCHEM) platform. Аntifungal properties of the investigated compounds were performed using standard disk diffusion method. The enzyme inhibitory action of the compounds was determined by modified Ellman's method using acetylcholinesterase from the electric organ of Electrophorus electricus.

Results: Three classification QSAR models were developed by the WEKA-RF, k-NN and ASNN methods using the ALogPS, E-State indices and Dragon v.7 descriptors. The predictive ability of the models was tested through cross-validation, giving a balanced accuracy BA = 80-91%. All compounds demonstrated good antifungal properties against Candida spp. and slight inhibition of the acetylcholinesterase activity.

Conclusion: The high percentage of coincidence between the QSAR predictions and the experimental results confirmed the high predictive power of the developed QSAR models that can be applied as tools for finding new potential inhibitors against Candida spp. Furthermore, 1,3-oxazol-4- yl(triphenyl)phosphonium salts could be considered as promising candidates for the treatment of candidiasis and the disinfection of medical equipment.

Keywords: Antifungal activity, QSAR, oxazolylphosphonium salts, Candida albicans, acetylcholinesterase inhibition assay, fungal infections.

Hani U, Shivakumar HG, Vaghela R, Osmani RA, Shrivastava A. Candidiasis: a fungal infection—current challenges and progress in prevention and treatment. Infect Disord Drug Targets 2015; 15: 42-52.
Brown GD, Denning DW, Levitz SM. Tackling human fungal infections. Science 2012; 336: 647.
Mayer FL, Wilson D, Hube B. Candida albicans pathogenicity mechanisms. Virulence 2013; 4: 119-28.
Fanning S, Mitchell AP. Fungal Biofilms. PLoS Pathog 2012; 8(4): e1002585.
Pfaller MA, Messer SA, Boyken L, et al. Geographic variation in the susceptibilities of invasive isolates of Candida glabrata to seven systemically active antifungal agents: A global assessment from the ARTEMIS Antifungal Surveillance Program conducted in 2001 and 2002. J Clin Microbiol 2004; 42(7): 3142-6.
Kale P, Johnson LB. Second-generation azole antifungal agents. Drugs Today 2005; 41: 91-105.
Trnka J, Elkalaf M, Andel M. Lipophilic triphenylphosphonium cations inhibit mitochondrial electron transport chain and induce mitochondrial proton leak. PLoS One 2015; 10(4): e0121837.
Cieniecka-Rosłonkiewicz A, Pernak J, Kubis-Feder J, et al. Synthesis, anti-microbial activities and anti-electrostatic properties of phosphonium-based ionic liquids. Green Chem 2005; 7(12): 855-62.
Trush MM, Kovalishyn VV, Blagodatnyi VM, et al. QSAR studies and antimicrobial potential of 1,3-thiazolylphosphonium salts. Ukr Biochem J 2016; 88(4): 57-65.
Stock F, Hoffmann J, Ranke J, et al. Effects of ionic liquids on the acetylcholinesterase - a structure–activity relationship considera-tion. Green Chem 2004; 6(6): 286-90.
Sosnowska A, Barycki M, Zaborowska M, et al. Towards designing environmentally safe ionic liquids: the influence of the cation structure. Green Chem 2014; 16(11): 4749-57.
OCHEM. Available from: https://ochem.eu (Accessed in January, 2014).
Tetko IV. Neural network studies. 4. Introduction to associative neural network. J Chem Inf Comput Sci 2002; 42: 717-28.
Vorberg S, Tetko IV. Modeling the biodegradability of chemical compounds using the Online Chemical Modeling Environment (OCHEM). Molecular Informat 2014; 33: 73-85.
Livingston F. Implementation of Breiman’s random forest machine learning algorithm ECE591Q Mach Learn J Pap 2005.
Kier LB, Hall LH. An electrotopological-state index for atoms in molecules. Pharm Res 1990; 7(8): 801-7.
Tetko IV, Tanchuk VY. Application of associative neural networks for prediction of lipophilicity in ALOGPS 2.1 program. J Chem Inf Comput Sci 2002; 42(5): 1136-45.
Dragon v.7 descriptors. Available from: http://www.talete.mi.it/ products/dragon_description.htm (Accessed in June, 2015).
Martynyuk AP, Brovarets VS, Lobanov OP, Drach BS. Phosporus-containing derivatives of N-2,2-dichlorovinylcarbamide. Zhurn Obsh Khim 1984; 54(10): 2186-200.
Lobanov OP, Martynyuk P, Drach BS. Reactions of (2,2‐dichloro‐1‐acylaminovinyl) triphenylphosphonium chlorides with nucleophiles. Zhurn Obsh Khim 1980; 50(10): 2248-57.
Brovarets VS, Lobanov OP, Drach BS. New synthesis of phosphorylated azoles. J Gen Chem USSR (Engl. Transl.) 1982; 52 (6): 1438-39.
Bauer AW, Kirby WM, Sherris JC, Turck M. Antibiotic susceptibility testing by a standardized single disk method. Am J Clin Pathol 1966; 45(4): 493-6.
Ellman GL, Courtney KD. Andres VJr Featherstone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 1961; 7: 88-95.
Queiroz MMF, Queiroz EF, Zeraik ML, et al. Antifungals and acetylcholinesterase inhibitors from the stem bark of Croton heliotropiifolius. Phytochem Lett 2014; 10: 88-93.
Elumalai K, Ali MA, Elumalai M, et al. Acetylcholinesterase inhibitor and cytotoxic activity of some novel acetazolamide cyclocondensed azetidinones. J Acute Med 2014; 4(1): 20-5.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [204 - 209]
Pages: 6
DOI: 10.2174/1570163815666180418145422
Price: $65

Article Metrics

PDF: 38