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Ukr. Bioorg. Acta 2021, Vol. 16, N1, 25-33.

In vitro and in silico study of 1,3-oxazol-4-yltriphenylphosphonium salts as potential inhibitors of Candida albicans transglycosylase

Ivan V. Semenyuta*, Maria M. Trush, Diana M. Hodyna, Maryna V. Kachaeva,
Larysa O. Metelytsia, Volodymyr S. Brovarets

V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine
tel.: +380-44-573-2595; e-mail: ivan@bpci.kiev.ua

ABSTRACT
The previously established in vitro high antimicrobial potential of triphenylphosphonium salts (TPPs) against bacterial (Staphylococcus aureus ATCC 25923 and multi-drug resistant (MDR)) and fungal (Candida albicans ATCC 10231 and MDR) strains made it possible to propose a molecular mechanism of action of these compounds associated with transglycosylase (TG) activity. The hypothesis was based on the well-known literature data on TPPs as inhibitors of S. aureus TG. The created homology model of TG C. albicans is optimal in terms of such quality indicators as GMQE (0.61), ERRAT (overall quality factor 95.904) and Ramachandran plot analysis (90% amino acid residues in the favored regions). Molecular docking of the most active ligands 1a-d, 3c into the active center of the created homology C. albicans TG model demonstrated the formation of stable ligand-protein complexes with binding energies in the range from -8.9 to -9.7 kcal/mol due to the various types of interactions. An important role in complex formation belongs to amino acid residues TYR307, TYR107, GLU275, ALA108 and PRO136. The presented qualitative homologous model of C. albicans TG can be used to search and create new agents with a dual mechanism of antimicrobial action. 1,3-oxazol-4-yltriphenylphosphonium salts 1a-d, 3c perform the perspective objects for further study as antimicrobials against infectious MDR pathogens.

KEYWORDS
transglycosylase; triphenylphosphonium salts; 1,3-oxazole; Candida albicans; Staphylococcus aureus.

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REFERENCES
1. Boev, C.; Kiss, E. Hospital-Acquired Infections: Current Trends and Prevention. Crit. Care Nurs. Clin. 2017, 1, 51-65.
2. Jacopin, E.; Lehtinen, S.; Debarre, F.; Blanquart, F. Factors favouring the evolution of multidrug resistance in bacteria. J. R. Soc. Interface. 2020, 1720200105.
3. Xiaorui, C.; Chi-Huey, W.; Che, M. Targeting the Bacterial Transglycosylase: Antibiotic Development from a Structural Perspective. ACS Infect. Dis. 2019, 9, 1493-1504.
4. Raghavan, R.; Mandal, J. Use of Bacterial Cell Wall Recycle Inhibitors to Combat Antimicrobial Resistance. In: Thomas S. (eds) Antimicrobial Resistance. Springer: Singapore, 2020.
5. Liu, J.; Balasubramanian, MK. 1,3-beta-Glucan synthase: a useful target for antifungal drugs. Curr. Drug. Targets Infect. Disord. 2001, 2, 159-169.
6. Handbook of Pharmacogenomics and Stratified Medicine, Padmanabhan, S., Academic Press / Elsevier: London, 2014.
7. Goude, R.; Amin, AG.; Chatterjee, D.; Parish, T. The arabinosyltransferase EmbC is inhibited by ethambutol in Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 2009, 10, 4138-4146.
8. Ostash, B.; Doud, E.; Fedorenko, V. The molecular biology of moenomycins: towards novel antibiotics based on inhibition of bacterial peptidoglycan glycosyltransferases. Biol. Chem. 2010, 5, 499-504.
9. Gaughran, J.P.; Lai, M.H.; Kirsch, D.R.; Silverman, S.J. Nikkomycin Z is a specific inhibitor of Saccharomyces cerevisiae chitin synthase isozyme Chs3 in vitro and in vivo. J. Bacteriol. 1994, 18, 5857-5860.
10. Cheng, T.J.; Wu, Y.T.; Yang, S.T.; Lo, K.H.; Chen, S.K.; Chen, Y.H.; Huang, W.I.; Yuan, C.H.; Guo, C.W.; Huang, L.Y.; Chen, K.T.; Shih, H.W.; Cheng, Y.S.; Cheng, W.C.; Wong, C.H. High-throughput identification of antibacterials against methicillin-resistant Staphylococcus aureus (MRSA) and the transglycosylase. Bioorg. Med. Chem. 2010, 24, 8512-8529.
11. Bioassay ID=CHEMBL1640432. In ChEMBL Database. European Molecular Biology Laboratory [Internet]. Available from: https://www.ebi.ac.uk/chembl/assay_report_card/CHEMBL1640432/ (accessed on April 16, 2021).
12. Manzano, J.I.; Cueto-Diaz, E.J.; Olias-Molero, A.I.; Perea, A.; Herraiz, T.; Torrado, J.J.; Alunda, J.M.;, Gamarro, F.; Dardonville, C. Discovery and Pharmacological Studies of 4-Hydroxyphenyl-Derived Phosphonium Salts Active in a Mouse Model of Visceral Leishmaniasis. J. Med. Chem. 2019, 23, 10664-10675.
13. Taladriz, A.; Healy, A.; Flores Perez, E.J.; Herrero Garcia, V.; Rios Martinez, C.; Alkhaldi, A.A.; Eze, A.A.; Kaiser, M.; de Koning, H.P.; Chana, A.; Dardonville, C. Synthesis and structure-activity analysis of new phosphonium salts with potent activity against African trypanosomes. J. Med. Chem. 2012, 6, 2606-2622.
14. Long, T.E.; Lu, X.; Galizzi, M.; Docampo, R.; Gut, J.; Rosenthal, P.J. Phosphonium lipocations as antiparasitic agents. Bioorg. Med. Chem. Lett. 2012, 8, 2976-2979.
15. McAllister, P.R.; Dotson, M.J.; Grim, S.O.; Hillman, G.R. Effects of phosphonium compounds on Schistosoma mansoni. J. Med. Chem. 1980, 8, 862-865.
16. Korshunova, G.A.; Shishkina, A.V.; Skulachev, M.V. Design, synthesis, and some aspects of the biological activity of mitochondria-targeted antioxidants. Biochemistry (Moscow). 2017, 82, 760-777.
17. Levi-Schaffer, F.; Tarrab-Hazdai, R.; Meshulam, H.; Arnon, R.; Effect of phosphonium salts and phosphoranes on the acetylcholinesterase activity and on the viability of Schistosoma mansoni parasites. Int. Immunopharmacol. 1984, 6, 619-627.
18. Bergeron, K.L.; Murphy, E.L.; Majofodun, O.; Munoz, L.D.; Williams, J.C.; Almeida, K.H. Arylphosphonium salts interact with DNA to modulate cytotoxicity. Mutat. Res. 2009, 2, 141-148.
19. Blank, B.; DiTullio, N.W.; Deviney, L.; Roberts, J.T.; Saunders, H.L. Synthesis and hypoglycemic activity of phenacyl-triphenylphosphoranes and phosphonium salts. J. Med. Chem. 1975, 9, 952-954.
20. Rideout, D.C.; Calogeropoulou, T.; Jaworski, J.S.; Dagnino, R.;  McCarthy, M.R. Phosphonium salts exhibiting selective anti-carcinoma activity in vitro. Anticancer Drug Des. 1989, 4, 265-280.
21. Lobanov, O. P.; Martyn'yuk, A. P.; Drach, B. S. Reactions of (2,2-dichloro-1-acylaminovinyl)triphenylphosphonium chlorides with nucleophiles. Zh. Obshch. Khim. 1980, 50, 2248-2257.
22. Golovchenko, A. V.; Brovarets, V. S.; Drach, B. S. A Convenient Procedure for Introducing Arylsulfanyl and Heterylsulfanyl Groups into the 5 Position of the Oxazole Ring. Rus. J. Gen. Chem. 2004, 74, 1414-1417.
23. Martynyuk, A. P.; Brovarets, V. S.; Lobanov, O. P.; Drach, B. S. Phosphorus-containing derivatives of N-2,2-dichlorovinylurea. Zh. Obshch. Khim. 1984, 54, 2186-2200.
24. Abdurakhmanova, E. R.; Pil’o, S. G.; Kondratyuk, K. M.; Golovchenko, A. V.; Brovarets, V. S. 1,3-Oxazole derived cytisines. Russ. J. Gen. Chem. 2017, 87, 244-251.
25. Trush, M.M.; Kovalishyn, V.; Ocheretniuk, A.D.; Kovalishyn, V.; Ocheretniuk, A.D.;Kachaeva, M.V.; Brovarets, V.S.; Metelytsia, L.O. QSAR Study of Some 1,3-Oxazolylphosphonium Derivatives as New Potent Anti-Candida Agents and Their Toxicity Evaluation. Curr. Drug Discov. Technol. 2019, 16, 204-209.
26. Trush, M.M.; Kovalishyn, V.; Ocheretniuk, A.D.; Kalashnikova, L.E.; Prokopenko, V.M.; Holovchenko, O.V.; Kobzar, O.L.; Brovarets V.S.; Metelytsia, L.O. New 1,3-oxazolylphosphonium Salts as Potential Biocides: QSAR Study, Synthesis, Antibacterial Activity and Toxicity Evaluation. Lett Drug Des Discov. 2018, 15, 1259.
27. Trush, M. M.; Kovalishyn, V.; Hodyna, D.; Golovchenko, O. V.; Chumachenko, S.; Tetko, I. V.; Brovarets, V. S.; Metelytsia, L. In silico and in vitro studies of a number PILs as new antibacterials against MDR clinical isolate Acinetobacter baumannii. Chem. Biol.DrugDes. 2020, 95, 624-630.
28. WO Patent No 2006105669 A1. Antimicrobial solution comprising a metallic salt and a surfactant / Tessier, D.; Filteau, M.; Radu I. Patent appl. No PCT/CA2006/000543 07.04.2006. Publ. 12.10.2006.
29. Brovarets, V. S.; Lobanov, O. P.; Drach, B. S. Syntheses of 2,5-substituted azoles from (2,2-dichloro-1-acylaminovinyl) triphenylphosphonium chlorides. Zh. Obshch. Khim. 1983, 53, 2015-2020.
30. Drach, B. S.; Sviridov, E. P.; Kirsanov, A. V. Reaction of 1,2,2,2-tetrachloroethylamides of acids with the ethyl ester of diphenylphosphinous acid and with triphenylphosphene. Zh. Obshch. Khim. 1975, 45, 12-16.
31. A. W. Bauer, W. M. Kirby, J. C. Sherris, M. Turck. Am. J. Clin. Pathol. 1966, 45, 493-496.
32. The UniProt Consortium, UniProt: the universal protein knowledgebase in 2021. Nucleic Acids Res. 2021, 49, 480-489, Available from: https://www.uniprot.org/uniprot/C4YFM5 (accessed on April 16, 2021).
33. Waterhouse, A.; Bertoni, M.; Bienert, S.; Studer, G.; Tauriello, G.; Gumienny, R.; Heer, F.T.; de Beer, T.A.P.; Rempfer, C.; Bordoli, L.; Lepore, R.; Schwede, T. SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res. 2018, 46, 296-303.
34. Camacho, C.; Coulouris, G.; Avagyan, V.; Ma, N.; Papadopoulos, J.; Bealer, K.; Madden, T.L. BLAST+: architecture and applications. BMC Bioinformatics 2009, 10, 421-430.
35. Steinegger, M.; Meier, M.; Mirdita, M.; Vohringer, H.; Haunsberger, S. J.; Soding, J. HH-suite3 for fast remote homology detection and deep protein annotation. BMC Bioinformatics 2019, 20, 473.
36. Benkert, P.; Biasini, M.; Schwede, T. Toward the estimation of the absolute quality of individual protein structure models. Bioinformatic 2011, 27, 343-350.
37. C. Colovos, T.O. Yeates, Verification of protein structures: patterns of nonbonded atomic interactions. Protein Sci. 1993, 2, 1511-1519.
38. R.A. Laskowski, M.W. MacArthur, D.S. Moss, J.M. Thornton, PROCHECK - a program to check the stereochemical quality of protein structures. J. App. Cryst. 1993, 26, 283-291.
39. Sanner, M.F.; Python: A programming language for software integration and development. J. Mol. Graph. Model. 1999, 17, 57-61.
40. Marvin Sketch was used for drawing, displaying and optimization chemical structures; MarvinSketch 5.3.735, 2017, ChemAxon website [Internet]. Available from: http://www.chemaxon.com (accessed on April 16, 2021).
41. Hanwell, M.D.; Curtis, D.E.; Lonie, D.C.; Vandermeersch, T.;  Zurek, T.; Hutchison, G.R. Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. J. Cheminform. 2012, 4, 17.
42. Trott, O.; Olson, A.J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 2010, 31, 455-461.
43. Dassault Systemes BIOVIA, Discovery Studio Visualizer, v4.0.100.13345, San Diego: Dassault Systemes, 2020.

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