Open for submissionsPeer reviewed, fully open access, and a low article processing charge.Submit manuscript

Research ArticleOpen AccessGoogle Scholar indexed

DFT-Based Chemical Reactivity Descriptors, Pharmacokinetics and Molecular Docking Studies of Thymidine Derivatives

,
,
,
,
,
,
,
,
,
  1. 1 Laboratory of Carbohydrate and Nucleoside Chemistry (LCNC), Department of Chemistry, Faculty of Science, University of Chittagong, Bangladesh
  2. 2 Graduate School of NanoBio Sciences, Yokohama City University, Yokohama, Japan
Computational Chemistry·Volume 11, Issue 4·Pages 81–103·Published 8 December 2023·DOI10.4236/cc.2023.114006
Download PDF

Abstract

Thymidine-containing derivatives are considered to be among the most significant derivatives in medicinal chemistry. In this study, we employed a combined computational approach involving density-functional theory (DFT) calculations, molecular docking simulations, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) property predictions. Prediction of activity spectra for substances (PASS) revealed promising antiviral, antimicrobial and anti-carcinogenic activities of these thymidine derivatives. Using Gaussian 09, we optimized the molecular structures of the thymidine derivatives to obtain their stable conformations and calculate their electronic properties. Subsequently, molecular docking simulations were performed to explore the binding interactions between the thymidine derivatives and the active site of the Candida albicans (PDB: 1IYL and 2Y7L) proteins. The docking results were evaluated based on docking scores, hydrogen bonding, and hydrophobic interactions and revealed favorable binding interactions between the thymidine derivatives and the proteins, suggesting their potential as antifungal agents. The thermodynamic properties, including binding free energy, enthalpy, and entropy changes were determined to assess the stability and strength of the ligands-protein complexes. The calculated pharmacokinetic parameters, such as ADMET properties, provided insights into the drug-likeness and potential bioavailability of the thymidine derivatives. These results offer a foundation for further experimental investigations and the design of novel antifungal agents targeting Candida albicans infections.

KeywordsThymidineDFTMolecular DockingPharmacokineticsCandida albicans
  1. Mahmoud, S., Hasabelnaby, S., Hammad, S.F. and Sakr, T.M. (2018) Antiviral Nucleoside and Nucleotide Analogs: A Review. Journal of Advanced Pharmacy Research, 2, 73-88. https://doi.org/10.21608/aprh.2018.5829
  2. De Clercq, E. and Li, G. (2016) Approved Antiviral Drugs over the Past 50 Years. Clinical Microbiology Reviews, 29, 695-747. https://doi.org/10.1128/CMR.00102-15
  3. Guinan, M., Benckendorff, C., Smith, M. and Miller, G.J. (2020) Recent Advances in the Chemical Synthesis and Evaluation of Anticancer Nucleoside Analogs. Molecules, 25, Article 2050. https://doi.org/10.3390/molecules25092050
  4. Eyer, L., Nencka, R., Huvarová, I., Palus, M., Joao Alves, M., Gould, E.A., De Clercq, E. and Růžek, D. (2016) Nucleoside Inhibitors of Zika Virus. Journal of Infectious Diseases, 214, 707-711. https://doi.org/10.1093/infdis/jiw226
  5. Hamuy, R. and Berman, B. (1998) Topical Antiviral Agents for Herpes Simplex Virus Infections. Drugs Today, 34, 1013-1025. https://doi.org/10.1358/dot.1998.34.12.487486
  6. Kawsar, S.M.A., Islam, M., Jesmin, S., Manchur, M.A., Hasan, I. and Rajia, S. (2018) Evaluation of the Antimicrobial Activity and Cytotoxic Effect of Some Uridine Derivatives. International Journal of Biosciences, 12, 211-219.
  7. Kawsar, S.M.A., Hamida, A.A., Sheikh, A.U., Hossain, M.K., Shagir, A.C., Sanaullah, A.F.M., Manchur, M.A., Imtiaj, H., Ogawa, Y., Fujii, Y., Koide, Y. and Ozeki, Y. (2015) Chemically Modified Uridine Molecules Incorporating Acyl Residues to Enhance Antibacterial and Cytotoxic Activities. International Journal of Organic Chemistry, 5, 232-245. https://doi.org/10.4236/ijoc.2015.54023
  8. Kawsar, S.M.A., Hasan, T., Chowdhury, S.A., Islam, M.M., Hossain, M.K. and Mansur, M.A. (2013) Synthesis, Spectroscopic Characterization, and in vitro Antibacterial Screening of Some D-Glucose Derivatives. International Journal of Pure and Applied Chemistry, 8, 125-135.
  9. Kawsar, S.M.A., Matsumoto, R., Fujii, Y., Matsuoka, H., Masuda, N., Iwahara, C., Yasumitsu, H., Kanaly, R.A., Sugawara, S., Hosono, M., Nitta, K., Ishizaki, N., Dogasaki, C., Hamako, J., Matsui, T. and Ozeki, Y. (2011) Cytotoxicity and Glycan-Binding Profile of α-D-Galactose-Binding Lectin from the Eggs of a Japanese Sea Hare (Aplysia kurodai). The Protein Journal, 30, 509-519. https://doi.org/10.1007/s10930-011-9356-7
  10. Shagir, A.C., Bhuiyan, M.M.R., Ozeki, Y. and Kawsar, S.M.A. (2016) Simple and Rapid Synthesis of Some Nucleoside Derivatives: Structural and spectral Characterization. Current Chemistry Letters, 5, 83-92. https://doi.org/10.5267/j.ccl.2015.12.001
  11. Arifuzzaman, M., Islam, M.M., Rahman, M.M., Mohammad, A.R. and Kawsar, S.M.A. (2018) An Efficient Approach to the Synthesis of Thymidine Derivatives Containing Various Acyl Groups: Characterization and Antibacterial Activities. Acta Pharmaceutica Scientia, 56, 7-22. https://doi.org/10.23893/1307-2080.APS.05622
  12. Maowa, J., Alam, A., Rana, K.M., Hosen, A., Dey, S., Hasan, I., Fujii, Y., Ozeki, Y. and Kawsar, S.M.A. (2021) Synthesis, Characterization, Synergistic Antimicrobial Properties, and Molecular Docking of Sugar-Modified Uridine Derivatives. Ovidius University Annals of Chemistry, 32, 6-21. https://doi.org/10.2478/auoc-2021-0002
  13. Sultana, S., Hossain, A., Islam, M. and Kawsar, S.M.A. (2024) Antifungal Potential of Mannopyranoside Derivatives through Computational and Molecular Docking Studies against Candida albicans 1IYL and 1AI9 Proteins. Current Chemistry Letters, 13, 1-14. https://doi.org/10.5267/j.ccl.2023.9.004
  14. Bulbul, M.Z.H., Chowdhury, T.S., Misbah, M.M.H., Ferdous, J., Dey, S., Hasan, I., Fujii, Y., Ozeki, Y. and Kawsar, S.M.A. (2021) Synthesis of a New Series of Pyrimidine Nucleoside Derivatives Bearing Acyl Moieties as Potential Antimicrobial Agents. Pharmacia, 68, 23-34. https://doi.org/10.3897/pharmacia.68.e56543
  15. Mirajul, M.I., Arifuzzaman, M., Monjur, M.R., Atiar, M.R. and Kawsar, S.M.A. (2019) Novel Methyl 4, 6-O-Benzylidene-α-D-Glucopyranoside Derivatives: Synthesis, Structural Characterization, and Evaluation of Antibacterial Activities. Hacettepe Journal of Biology and Chemistry, 47, 153-164. https://doi.org/10.15671/hjbc.622038
  16. Devi, S.R., Jesmin, S., Rahman, M., Manchur, M.A., Fujii, Y., Kanaly, R.A., Ozeki, Y. and Kawsar, S.M.A. (2019) Microbial Efficacy and Two-Step Synthesis of Uridine Derivatives with Spectral Characterization. Acta Pharmaceutica Sciencia, 57, 47-68. https://doi.org/10.23893/1307-2080.APS.05704
  17. Misbah, M.M.H., Ferdous, J., Bulbul, M.Z.H., Chowdhury, T.S., Dey, S., Hasan, I. and Kawsar, S.M.A. (2020) Evaluation of MIC, MBC, MFC, and Anticancer Activities of Acylated Methyl β-D-Galactopyranoside Esters. International Journal of Biosciences, 16, 299-309.
  18. Alam, A., Hosen, M.A., Islam, M., Ferdous, J., Fujii, Y., Ozeki, Y. and Kawsar, S.M.A. (2021) Synthesis, Antibacterial, and Cytotoxicity Assessment of Modified Uridine Molecules. Current Advances in Chemistry and Biochemistry, 6, 114-129. https://doi.org/10.9734/bpi/cacb/v6/8670D
  19. Farhana, Y., Amin, M.R., Hosen, M.A., Bulbul, M.Z.H., Dey, S. and Kawsar, S.M.A. (2021) Monosaccharide Derivatives: Synthesis, Antimicrobial, PASS, Antiviral, and Molecular Docking Studies against SARS-CoV-2 mpro Inhibitors. Cellulose Chemistry and Technology, 55, 477-499. https://doi.org/10.35812/CelluloseChemTechnol.2021.55.44
  20. Kawsar, S.M.A., Faruk, M.O., Rahman, M.S., Fujii, Y. and Ozeki, Y. (2014) Regioselective Synthesis, Characterization, and Antimicrobial Activities of Some New Monosaccharide Derivatives. Scientia Pharmaceutica, 82, 1-20. https://doi.org/10.3797/scipharm.1308-03
  21. Fujii, Y., Kawsar, S.M.A., Matsumoto, R., Yasumitsu, H., Naoto, I., Dohgasaki, C., Hosono, M., Nitta, K., Hamako, J., Matsui, T. and Ozeki, Y. (2011) A-D-Galactose-Binding Lectin Purified from Coronate Moon Turban, Turbo (Lunella) Coreensis, with a Unique Amino Acid Sequence and the Ability to Recognize Lacto-Series Glycophingolipids. Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology, 158, 30-37. https://doi.org/10.1016/j.cbpb.2010.09.002
  22. Kabir, A.K.M.S., Kawsar, S.M.A., Bhuiyan, M.M.R., Rahman, M.S. and Chowdhury, M.E. (2009) Antimicrobial Screening Studies of Some Derivatives of Methyl α-D-Glucopyranoside. Pakistan Journal of Scientific and Industrial Research, 52, 138-142.
  23. Kabir, A.K.M.S., Kawsar, S.M.A., Bhuiyan, M.M.R., Rahman, M.S. and Banu, B. (2008) Biological Evaluation of Some Octanoyl Derivatives of Methyl 4, 6-O-Cyclohexylidene-α-D-Glucopyranoside. Chittagong University Jour-nal of Biological Sciences, 3, 53-64. https://doi.org/10.3329/cujbs.v3i1.13406
  24. Kabir, A.K.M.S., Kawsar, S.M.A., Bhuiyan, M.M.R., Islam, M.R. and Rahman, M.S. (2004) Biological Evaluation of Some Mannopyranoside Derivatives. Bulletin of Pure & Applied Sciences, 23, 83-91.
  25. Islam, S., Hosen, M.A., Ahmad, S., Qamar, M.T.U., Dey, S., Hasan, I., Fujii, Y., Ozeki, Y. and Kawsar, S.M.A. (2022) Synthesis, Antimicrobial, Anticancer Activities, PASS Prediction, Molecular Docking, Molecular Dynamics, and Pharmacokinetic Studies of Designed Methyl α-D-Glucopyranoside Esters. Journal of Molecular Structure, 1260, Article ID: 132761. https://doi.org/10.1016/j.molstruc.2022.132761
  26. Hosen, M.A., Munia, N.S., Al-Ghorbani, M., Baashen, M., Almalki, F.A., Hadda, T.B., Ali, F., Mahmud, S., Saleh, M.A., Laaroussi, H. and Kawsar, S.M.A. (2022) Synthesis, Antimicrobial, Molecular Docking, and Molecular Dynamics Studies of Lauroyl Thymidine Analogs against SARS-CoV-2: POM Study and Identification of the Pharmacophore Sites. Bioorganic Chemistry, 125, Article ID: 105850. https://doi.org/10.1016/j.bioorg.2022.105850
  27. Farhana, Y., Amin, M.R., Hosen, A. and Kawsar, S.M.A. (2021) Bromobenzoylation of Methyl α-D-Mannopyranoside: Synthesis and Spectral Characterization. Journal of Siberian Federal University, Chemistry, 14, 171-183. https://doi.org/10.17516/1998-2836-0226
  28. Rana, K.M., Ferdous, J., Hosen, A. and Kawsar, S.M.A. (2020) Ribose Moieties Acylation and Characterization of Some Cytidine Analogs. Journal of Siberian Federal University, Chemistry, 13, 465-478. https://doi.org/10.17516/1998-2836-0199
  29. Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, A., Cheeseman, J.R., Scalmani, G., Barone, V., Mennucci, B., Petersson, G.A., et al. (2009) Gaussian 09. Gaussian Inc, Wallingford.
  30. Tirado-Rives, J. and Jorgensen, W.L. (2008) Performance of B3LYP Density Functional Methods for a Large Set of Organic Molecules. Journal of Chemical Theory and Computation, 4, 297-306. https://doi.org/10.1021/ct700248k
  31. Becke, A.D. (1988) Density-Functional Exchange-Energy Approximation with Correct Asymptotic Behavior. Physical Review A, 38, 3098-3100. https://doi.org/10.1103/PhysRevA.38.3098
  32. Lee, C., Yang, W. and Parr, R.G. (1988) Development of the Colle-Salvetti Correlation-Energy Formula into a Functional of the Electron Density. Physical Review B, 37, 785-789. https://doi.org/10.1103/PhysRevB.37.785
  33. Parr, R.G. (1980) Density Functional Theory of Atoms and Molecules. In: Fukui, K. and Pullman, B., Eds., Horizons of Quantum Chemistry, Springer, Dordrecht, 5-15. https://doi.org/10.1007/978-94-009-9027-2_2
  34. Kumaresan, S., Senthilkumar, V., Stephen, A. and Balakumar, B. (2015) GC-MS Analysis and PASS-Assisted Prediction of Biological Activity Spectra of Extract of Phomopsis sp. Isolated from Andrographis paniculata. World Journal of Pharmaceutical Research, 4, 1035-1053.
  35. Kawsar, S.M.A., Kumer, A., Munia, N.S., Hosen, M.A., Chakma, U. and Akash, S. (2022) Chemical Descriptors, PASS, Molecular Docking, Molecular Dynamics and ADMET Predictions of Glucopyranoside Derivatives as Inhibitors to Bacteria and Fungi Growth. Organic Communications, 15, 184-203. https://doi.org/10.25135/acg.oc.122.2203.2397
  36. Kawsar, S.M.A., Hosen, M.A., Chowdhury, T.S., Rana, K.M., Fujii, Y. and Ozeki, Y. (2021) Thermochemical, PASS, Molecular Docking, Drug-Likeness and in Silico ADMET Prediction of Cytidine Derivatives against HIV-1 Reverse Transcriptase. Revista de Chimie, 72, 159-178. https://doi.org/10.37358/RC.21.3.8446
  37. Hosen, M.A., Alam, A., Islam, M., Fujii, Y., Ozeki, Y. and Kawsar, S.M.A. (2021) Geometrical Optimization, PASS Prediction, Molecular Docking, and in Silico ADMET Studies of Thymidine Derivatives against FimH Adhesin of Escherichia coli. Bulgarian Chemical Communications, 53, 327-342.
  38. Alam, A., Hosen, M.A., Hosen, A., Fujii, Y., Ozeki, Y. and Kawsar, S.M.A. (2021) Synthesis, Characterization, and Molecular Docking against a Receptor Protein FimH of Escherichia coli (4XO8) of Thymidine Derivatives. Journal of the Mexican Chemical Society, 65, 256-276. https://doi.org/10.29356/jmcs.v65i2.1464
  39. Maowa, J., Hosen, M.A., Alam, A., Rana, K.M., Fujii, Y., Ozeki, Y. and Kawsar, S.M.A. (2021) Pharmacokinetics and Molecular Docking Studies of Uridine Derivatives as SARS-CoV-2 Mpro Inhibitors. Physical Chemistry Research, 9, 385-412.
  40. Sim, F., St-Amant, A., Papai, I. and Salahub, D.R. (1992) Gaussian Density Functional Calculations on Hydrogen-Bonded Systems. Journal of the American Chemical Society, 114, 4391-4400. https://doi.org/10.1021/ja00037a055
  41. Shamsuddin, T., Hosen, M.A., Alam, M.S., Emran, T.B. and Kawsar, S.M.A. (2021) Uridine Derivatives: Antifungal, PASS Outcomes, ADME/T, Drug-Likeliness, Molecular Docking and Binding Energy Calculations. Medicine Science-International Medical Journal, 10, 1373-1386. https://doi.org/10.5455/medscience.2021.05.175
  42. Amin, M.R., Yasmin, F., Dey, S., Mahmud, S., Saleh, M.A., Emran, T.B., Hasan, I., Rajia, S., Ogawa, Y., Fujii, Y., Yamada, M., Ozeki, Y. and Kawsar, S.M.A. (2021) Synthesis, Antimicrobial, Anticancer, PASS, Molecular Docking, Molecular Dynamic Simulations and Pharmacokinetic Predictions of Some Methyl β-D-Galactopyranoside Analogs. Molecules, 26, Article 7016. https://doi.org/10.3390/molecules26227016
  43. Amin, M.R., Yasmin, F., Hosen, M.A., Dey, S., Mahmud, S., Saleh, M.A., Emran, T.B., Hasan, I., Fujii, Y., Yamada, M., Ozeki, Y. and Kawsar, S.M.A. (2021) Methyl β-D-Galactopyranoside Esters as Potential Inhibitors for SARS-CoV-2 Protease Enzyme: Synthesis, Antimicrobial, PASS, Molecular Docking, Molecular Dynamics Simulations and Quantum Computations. Glycoconjugate Journal, 39, 261-290. https://doi.org/10.1007/s10719-021-10039-3
  44. Kawsar, S.M.A., Hosen, M.A., Fujii, Y. and Ozeki, Y. (2020) Thermochemical, DFT, Molecular Docking and Pharmacokinetic Studies of Methyl β-D-Galactopyranoside Esters. Journal of Computational Chemistry and Molecular Modeling, 4, 452-462. https://doi.org/10.25177/JCCMM.4.4.RA.10663
  45. Kawsar, S.M.A. and Hosen, M.A. (2020) An Optimization and Pharmacokinetic Studies of Some Thymidine Derivatives. Turkish Computational and Theoretical Chemistry, 4, 59-66. https://doi.org/10.33435/tcandtc.718807
  46. Kawsar, S.M.A. and Kumar, A. (2021) Computational Investigation of Methyl α-D-Glucopyranoside Derivatives as Inhibitors against Bacteria, Fungi, and COVID-19 (SARS-2). Journal of the Chilean Chemical Society, 66, 5206-5214. https://doi.org/10.4067/S0717-97072021000205206
  47. Politzer, P. and Murray, J.S. (1991) Molecular Electrostatic Potentials and Chemical Reactivity. Reviews in Computational Chemistry, 2, 273-312. https://doi.org/10.1002/9780470125793.ch7
  48. Alam, A., Rana, K.M., Hosen, M.A., Dey, S., Bezbaruah, B. and Kawsar, S.M.A. (2022) Modified Thymidine Derivatives as Potential SARS-CoV Inhibitors: An Approach of PASS Prediction, in vitro Antimicrobial, Physicochemical, and Molecular Docking Studies. Physical Chemistry Research, 10, 391-409.
  49. Pearson, R.G. (1988) Absolute Electronegativity and Hardness: Application to Organic Chemistry. Journal of Organic Chemistry, 27, 734-740. https://doi.org/10.1021/ic00277a030
  50. Islam, A.U., Serseg, T., Benarous, K., Ahmmed, F. and Kawsar, S.M.A. (2023) Synthesis, Antimicrobial Activity, Molecular Docking and Pharmacophore Analysis of New Propionyl Mannopyranosides. Journal of Molecular Structure, 1292, Article ID: 135999. https://doi.org/10.1016/j.molstruc.2023.135999
  51. Murray, J.S. and Politzer, P. (2017) Molecular Electrostatic Potentials and Noncovalent Interactions. WIREs Computational Molecular Science, 7, e1326. https://doi.org/10.1002/wcms.1326
  52. Daina, A., Michielin, O. and Zoete, V. (2017) SwissADME: A Free Web Tool to Evaluate Pharmacokinetics, Drug-Likeness and Medicinal Chemistry Friendliness of Small Molecules. Scientific Reports, 7, Article No. 42717. https://doi.org/10.1038/srep42717
  53. Pires, D.E.V., Blundell, T.L. and Ascher, D.B. (2015) pkCSM: Predicting Small-Molecule Pharmacokinetic and Toxicity Properties Using Graph-Based Signatures. Journal of Medicinal Chemistry, 58, 4066-4072. https://doi.org/10.1021/acs.jmedchem.5b00104
  54. Kawsar, S.M.A., Hosen, M.A., El Bakri, Y., Ahmad, S., Affi, S.T. and Goumri-Said, S. (2022) In Silico Approach for Potential Antimicrobial Agents through Antiviral, Molecular Docking, Molecular Dynamics, Pharmacokinetic and Bioactivity Predictions of Galactopyranoside Derivatives. Arabian Journal of Basic and Applied Sciences, 29, 99-112. https://doi.org/10.1080/25765299.2022.2068275
  55. Yang, H., et al. (2019) admetSAR 2.0: Web-Service for Prediction and Optimization of Chemical ADMET Properties. Bioinformatics, 35, 1067-1069. https://doi.org/10.1093/bioinformatics/bty707
  56. Shen, J., Cheng, F., Xu, Y., Li, W. and Tang, Y. (2010) Estimation of ADME Properties with Substructure Pattern Recognition. Journal of Chemical Information and Modeling, 50, 1034-1041. https://doi.org/10.1021/ci100104j
  57. Wang, Z., et al. (2018) In Silico Prediction of Blood-Brain Barrier Permeability of Compounds by Machine Learning and Resampling Methods. ChemMedChem, 13, 2189-2201. https://doi.org/10.1002/cmdc.201800533
  58. Cheng, F., et al. (2011) Classification of Cytochrome P450 Inhibitors and Noninhibitors Using Combined Classifiers. Journal of Chemical Information and Modeling, 51, 996-1011. https://doi.org/10.1021/ci200028n
  59. Sun, L., et al. (2015) In Silico Prediction of Chemical Aquatic Toxicity with Chemical Category Approaches and Substructural Alerts. Toxicology Research, 4, 452-463. https://doi.org/10.1039/C4TX00174E
  60. Zhu, H., Martin, T.M., Ye, L., Sedykh, A., Young, D.M. and Tropsha, A. (2009) Quantitative Structure-Activity Relationship Modeling of Rat Acute Toxicity by Oral Exposure. Chemical Research in Toxicology, 22, 1913-1921. https://doi.org/10.1021/tx900189p
  61. Wang, J., Krudy, G., Hou, T., Zhang, W., Holland, G. and Xu, X. (2007) Development of Reliable Aqueous Solubility Models and Their Application in Druglike Analysis. Journal of Chemical Information and Modeling, 47, 1395-1404. https://doi.org/10.1021/ci700096r
  62. Huang, F.D., Chen, J., Lin, M., Keating, M.T. and Sanguinetti, M.C. (2001) Long-QT Syndrome-Associated Missense Mutations in the Pore Helix of the HERG Potassium Channel. Circulation, 104, 1071-1075. https://doi.org/10.1161/hc3501.093815
  63. Lipinski, C.A., Lombardo, F., Dominy, B.W. and Feeney, P.J. (2001) Experimental and Computational Approaches to Estimate Solubility and Permeability in Drug Discovery and Development Settings. Advanced Drug Delivery Reviews, 46, 3-26. https://doi.org/10.1016/S0169-409X(00)00129-0
  64. Mandloi, D., Dabade, S.J., Bajaj, A.V. and Atre, H. (2020) Molecular Docking and QSAR Studies for Modeling Antifungal Activity of Triazine Analogs against Therapeutic Target NMT of Candida albicans. International Journal of Pharmaceutical Sciences and Drug Research, 13, 140-146. https://doi.org/10.25004/IJPSDR.2021.130204
  65. Bouamrane, S., Khaldan, A., Hajji, H., El-Mernissi, R., Maghat, H., Ajana, M.A., Sbai, A., Bouachrine, M. and Bouachrine, M. (2022) 3D-QSAR, Molecular Docking, Molecular Dynamic Simulation, and ADMET Study of Bioactive Compounds against Candida albicans. Moroccan Journal of Chemistry, 10, 523-541.