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Ukr. Bioorg. Acta 2021, Vol. 16, N2, 29-37.

DOI: https://doi.org/10.15407/bioorganica2021.02.023

Cytisine derivatives as new anti-Escherichia coli agents: in silico and in vitro studies

Diana M. Hodyna1, Vasyl V. Kovalishyn1, Volodymyr M. Blagodatnyi1,
Svitlana P. Bondarenko
2, Galyna P. Mrug1, Mykhaylo S. Frasinyuk1, Larysa O. Metelytsia1*

1 V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine
e-mail: larisametelitsa@gmail.com
2 National University of Food Technologies, 68 Volodymyrska St., Kyiv, 01601, Ukraine

ABSTRACT
QSAR analysis of a 5143 compounds set of previously synthesized compounds tested against multi-drug resistant (MDR) clinical isolate Escherichia coli strains was done by using Online Chemical Modeling Environment (OCHEM).The predictive ability of the regression models was tested through cross-validation, giving coefficient of determination q
2=0.72-0.8. The validation of the models using an external test set proved that the models can be used to predict the activity of newly designed compounds with reasonable accuracy within the applicability domain (q2=0.74-0.8). The models were applied to screen a virtual chemical library of cytisine derivatives, which was designed to have antibacterial activity. The QSAR modeling results allowed to identify a number of cytisine derivatives as effective antibacterial agents against antibiotic-resistant E. coli strains. Seven compounds were selected for synthesis and biological testing. In vitro investigation of the selected cytisine derivatives have shown that all studied compounds are potential antibacterial agents against MDR E. coli strains.

KEYWORDS
cytisine derivatives, QSAR, Escherichia coli, antibacterial activity

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REFERENCES

    1. Laws, M.; Shaaban, A.; Rahman, K.M. Antibiotic resistance breakers: current approaches and future directions. FEMS Microbiology Reviews. 2019, 43, 490-516.
    2. Pietsch, F.; O'Neill, A.J.; Ivask, A.; Jenssen, H.; Inkinen, J.; Kahru, A.; Ahonen, M.; Schreiber, F. Selection of resistance by antimicrobial coatings in the healthcare setting. J Hosp Infect. 2020, 106, 115-125.
    3. Ahmad, S.; Sahar, Q.; Raza, K. Translational bioinformatics methods for drug discovery and drug repurposing. Translational Bioinformatics in Healthcare and Medicine. 2021, 13, 127-139.
    4. Doan, T.L.; Pollastri, M.; Walters, M. A.; Georg, G. I.The Future of Drug Repositioning: Old Drugs, New Opportunities. Annual Reports in Medicinal Chemistry. 2011, 46, 385-401.
    5. Cahlikova, L.; Breiterova, K.; Opletal, L. Chemistry and Biological Activity of Alkaloids from the Genus Lycoris (Amaryllidaceae). Molecules. 2020, 25, 4797-4817.
    6. Thawabteh, A.; Juma, S.; Bader, M.; Karaman, D.; Scrano, L.; Bufo, S. A.; Karaman, Rafik. The Biological Activity of Natural Alkaloids against Herbivores, Cancerous Cells and Pathogens. Toxins (Basel). 2019, 11, 656-679.
    7. Mineur, Y.S.; Einstein, E.B.; Bentham, M.P.; Wigestrand, M.B.; Blakeman, S.; Newbold, S.A.; Picciotto, M.R. Expression of the 5-HT1A serotonin receptor in the hippocampus is required for social stress resilience and the antidepressant-like effects induced by the nicotinic partial agonist cytisine. Neuropsychopharmacology. 2015, 40, 938-946.
    8. Gotti, C.; Clementi, F. Cytisine and cytisine derivatives. More than smoking cessation aids. Pharmacological Research. 2021, 170, 105700.
    9. Kulakov, I.V.; Nurkenov, O.A. Synthesis and Biological Activityof the Derivatives of Alkaloid Cytisine. Chemistry for Sustainable Development. 2012, 20, 237-250.
    10. Metelytsia, L.O.; Trush, M.M.; Kovalishyn V.V., Hodyna, D.M.; Kachaeva, M.V.; Brovarets, V.S.; Pilyo, S.G.; Sukhoveev, V.V.; Tsyhankov, S.A.; Blagodatnyi, V.M.; Semenyuta, I.V. 1,3-Oxazole derivatives of cytisine as potential inhibitors of glutathione reductase of Candida spp.: QSAR modeling, docking analysis and experimental study of new anti-Candida agents. Computational Biology and Chemistry. 2021, 90, 107407.
    11. Karpov, P.; Godin, G.; Tetko, I.V. Transformer-CNN: Swiss knife for QSAR modeling and interpretation. J. Cheminform. 2020, 12, 17.
    12. Tetko, I. V. Associative neural network. Methods Mol. Biol. 2008, 458, 185-202.
    13. Breiman, L. Random Forests. Mach. Learn. 2001, 45, 5-32.
    14. Hall, L. H.; Kier, L. B. Electrotopological State Indexes for Atom Types - a Novel Combination of Electronic, Topological, and Valence State Information, J. Chem. Inf. Comput. Sci. 1995, 35, 1039-1045.
    15. Tetko, I. V.; Tanchuk, V. Y.; Kasheva, T. N.; Villa, A. E. P. Estimation of Aqueous Solubility of Chemical Compounds Using E-State Indices. J. Chem. Inf. Comput. Sci. 2001, 41, 1488-1493.
    16. Chemistry Development Kit. Available online: https://cdk.github.io/ (accessed on September 2021).
    17. Sushko, Y.; Novotarskyi, S.; Korner, R.; Pandey, A. K.; Kovalishyn, V. V.; Prokopenko, V. V.; Tetko I. V. Applicability domain for in silico models to achieve accuracy of experimental measurements. J. Chemom. 2010, 24, 202-208.
    18. DataWarrior. Available from: https://openmolecules.org/datawarrior (accessed on September 10, 2021).
    19. Sushko, I.; Novotarskyi, S.; Korner, R.; Pandey, A. K.; Rupp, M.; Teetz, W.; Brandmaier, S.; Abdelaziz, A.; Prokopenko, V. V.; Tanchuk, V. Y.; Todeschini, R.; Varnek, A.; Marcou, G.; Ertl, P.; Potemkin, V.;  Grishina, M.; Gasteiger, J.; Schwab, C.; Baskin, I. I.; Palyulin, V. A.; Radchenko, E. V., Welsh, W. J.;  Kholodovych, V.; Chekmarev, D.; Cherkasov, A.; Aires-de-Sousa, J.; Zhang, Q. Y.; Bender, A.; Nigsch, F.; Patiny, L.; Williams, A.; Tkachenko, V.; Tetko, I.V. Online chemical modeling environment (OCHEM): web platform for data storage, model development and publishing of chemical information. J. Comput. Aided Mol. Des. 2011, 25, 533-554.
    20. Tollenaere, T. SuperSAB: Fast Adaptive Back Propagation with Good Scaling Properties. Neural Networks. 1990, 3, 561-573.
    21. Whitley, D. C.; Ford, M.G.; Livingstone D. J. Unsupervised forward selection: a method for eliminating redundant variables. J. Chem. Inf. Comput. Sci. 2000, 40, 1160-8116.
    22. Tetko, I. V.; Sushko, I.; Pandey, A. K.; Zhu, H.; Tropsha, A.; Papa, E.; Oberg, T.; Todeschini, R.; Fourches, D.; Varnek, A. Critical assessment of QSAR models of environmental toxicity against Tetrahymena pyriformis: focusing on applicability domain and overfitting by variable selection. J. Chem. Inf. Model. 2008, 48, 1733-1746.
    23. OCHEM docs. Available from: http://docs.ochem.eu/display/MAN (accessed on December 20, 2021).
    24. Bondarenko, S. P.; Makarenko, O. G.; Vinogradova, V. I.; Frasinyuk, M. S. Synthesis of 7-(N-12-cytisinylpropoxy)isoflavones. Chem. Nat. Compd. 2020, 56, 1040-1043.
    25. Bondarenko, S. P.; Frasinyuk, M. S.; Vinogradova, V. I.; Khilya, V. P. Synthesis of 4-aryl-5-[2-hydroxy-4-(2-cytisin-12-ylethoxy)phenyl]isoxazoles. Chem. Nat. Compd. 2016, 52, 463-465.
    26. Bondarenko, S. P.; Frasinyuk, M. S.; Vinogradova, V. I.; Khilya, V. P. Synthesis of 4-aryl-3-[2-hydroxy-4-(2-cytisin-12-ylethoxy)phenyl]-pyrazoles. Chem. Nat. Compd. 2014, 50, 889-891.
    27. Mrug, G. P.; Biletska, I. M.; Bondarenko, S. P.; Sviripa, V. M.; Frasinyuk, M. S. Trifluoroacetylation of 2-methyl- and 2-ethylchromones: a convenient access to 2-trifluoroacetonyl chromones. ChemistrySelect 2019, 4, 11506-11510.
    28. Popova, A. V.; Frasinyuk, M. S.; Bondarenko, S. P.; Zhang, W.; Xie, Y.; Martin, Z. M.; Cai, X.; Fiandalo, M. V.; Mohler, J. L.; Liu, C.; Watt, D. S.; Sviripa, V. M. Efficient synthesis of aurone Mannich bases and evaluation of their antineoplastic activity in PC-3 prostate cancer cells. Chem. Pap. 2018, 72, 2443-2456.
    29. Blackburn, J. S.; Frasinyuk, M.; Liu, C.; Xie, Y.; Watt, D. S.;  Patent WO 2019144009.
    30. Mrug, G. P.; Bondarenko, S. P.; Khilya, V. P.; Frasinyuk, M. S. Synthesis and aminomethylation of 7-hydroxy-5-methoxyisoflavones. Chem. Nat. Compd. 2013, 49, 235-241.
    31. Bondarenko, S. P.; Frasinyuk, M. S.; Khilya, V. P. New Aloperine–Isoflavone Conjugates. Chem. Nat. Compd. 2016, 52, 615-619.
    32. Bondarenko, S. P.; Frasinyuk, M. S.; Vinogradova, V. I.; Khilya, V. P. Synthesis of cytisine derivatives of flavonoids. 2. Aminomethylation of 7-hydroxyisoflavones. Chem. Nat. Compd. 2011, 47, 604-607.
    33. Bauer, A. W.; Kirby, W. M.; Sherris, J. C.; Turck, M. Antibiotic susceptibility testing by a standardized single disk method. Am. J. Clin. Pathol., 1966, 45, 493-496.
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