Synthesis, Antibacterial Activity and Molecular Modelling of Benzyl Acetate Derivatives

Öz

Benzyl alcohol derivatives are known for their antibacterial efficacy. In this work five known benzyl acetate derivatives were synthesized by the acetylation of their corresponding benzyl alcohol derivatives and their structures confirmed using 1H, 13C NMR and FTIR spectroscopic techniques. The synthesized compounds were tested for antibacterial activity against Staphylococcus aureus and Shigella spp using disc diffusion method. Also the activity of amoxicillin disc (0.5 g/L ) was measured as a positive control. Furthermore, the drug-likeness as well as the interactions of the compounds against the active site of E. coli carbonic anhydrase which share >98% similarity to that of S. spp were studied using molecular modelling method. The antibacterial activity showed that all the five compounds 3a-e inhibited the two organisms at 100 µg/ml compared to the positive control. The largest inhibition zones of Staphylococcus aureus and Shigella spp were found to be 16.5 mm and 17.5 mm for compound 3d and 3e, respectively. Molecular modelling predicted the compounds to be water soluble, highly absorbed through GI tract, not Pgp substrates and not CYP3A4 inhibitors. Molecular docking studies showed that the compounds showed affinity to E. coli carbonic anhydrase active site, blocking access to the Zn2+ cofactor.

Anahtar Kelimeler

• Antibacterial activity
• benzyl acetate derivatives
• molecular modeling
• Staphylococcus aureus
• Shigella spp.

Kaynakça

1. [1] MacGowan, A., Macnaughton, E. (2017). Antibiotic resistance. Medicine, 45(10), 622-628.
2. [2] Tackling Drug-Resistant Infections Globally: Final Report and Recommendations, Review on Antimicrobial Resistance.https://amrreview.org (accessed on April 2017).
3. [3] El Faydy, M., Dahaieh, N., Ounine, K., Lakhrissi, B., Warad, I., Tüzün, B., Zarrouk, A. (2021). Synthesis, Identification, Antibacterial Activity, ADME/T and 1BNA Docking Investigations of 8 Quinolinol Analogs Bearing a Benzimidazole Moiety. Arab. J. Sci. Eng. 47(1), 497-510.
4. [4] Nehra, N., Tittal, R., K., Ghule, V. D. (2021). 1,2,3-Triazoles of 8 Hydroxyquinoline and HBT: Synthesis and Studies (DNA Binding, Antimicrobial, Molecular Docking, ADME, and DFT). ACS Omega, 6, 27089−27100.
5. [5] Salihovic, M., Pazaljaa, M., Halilovic, S. S., Veljovic, E., Mahmutovic-Dizdarevi, I., Roca, S., Novakovic, I., Trifunovic, S. (2021). Synthesis, characterization, antimicrobial activity and DFT study of some novel Schiff bases. J. Mol. Struct., 1241, 130670.
6. [6] Cetin, A., Bildirici, I. (2018). A study on synthesis and antimicrobial activity of 4-acyl-pyrazoles. J. Saudi Chem. Soc., 22, 279–296.
7. [7] Sulaiman, M., Hassan, Y., Taskin-Tok, T., Siwe-Noundou, X. (2020). Synthesis, Antibacterial Activity And Docking Studies Of Benzyl Alcohol Derivatives. JOTCSA, 7(2), 481–8.
8. [8] Ogala, J. B., Hassan, Y., Samaila, A., Bindawa, M. I., Taskin-Tok, T. (2022). Synthesis, Antifungal Activity, and In Silico ADMET Studies of Benzyl alcohol Derivatives. Istanbul J. Pharm., 52(1), 47-53.

9. [9] Romano, M., Cianci, E., Simiele, F., Recchiuti, A. (2015). Lipoxins and aspirin-triggered lipoxins in resolution of inflammation. Eur. J. Pharmacol., 760, 49-63.
10. [10] Farid, N. A., Kurihara, A., Wrighton, S. A. (2010). Metabolism and disposition of the thienopyridine antiplatelet drugs ticlopidine, clopidogrel, and prasugrel in humans. J. Clin. Pharmacol., 50, 126-142.
11. [11] Endo, A. A. (2010). Historical perspective on the discovery of statins. Proc. Jpn. Acad. B: Phys. Biol. Sci., 86(5), 484-493.
12. [12] Carta, F., Innocenti, A., Hall, R. A., Muhlschlegel, F. A., Scozzafava, A., Supuran, C. T. (2011). Carbonic anhydrase inhibitors. Inhibition of the beta-class enzymes from the fungal pathogens Candida albicans and Cryptococcus neoformans with branched aliphatic/aromatic carboxylates and their derivatives. Bioorg. Med. Chem. Lett., 21(8), 2521-2526.
13. [13] Carta, F., Vullo, D., Maresca, A., Scozzafava, A., Supuran, C. T. (2013). Mono-/dihydroxybenzoic acid esters and phenol pyridinium derivatives as inhibitors of the mammalian carbonic anhydrase isoforms I, II, VII, IX, XII and XIV. Bioorg. Med. Chem., 21(6), 1564-1569.
14. [14] Supuran, C. T, Capasso, C. (2017). An Overview of the Bacterial Carbonic Anhydrases. Metabolites, 7(4), 56.
15. [15] Tamang, S. R., Cozzolino, A. F., Findlater, M. (2019). Iron catalysed selective reduction of esters to alcohols. Org. Biomol. Chem., 17(7), 1834-8.
16. [16] Yoshida, M., Hirahata, R., Inoue, T., Shimbayashi, T., Fujita, K. I. (2019). Iridium-catalyzed transfer hydrogenation of ketones and aldehydes using glucose as a sustainable hydrogen donor. Catalysts., 9(6), 503.
17. [17] Mojtahedi, M. M., Samadian, S. (2013). Efficient and rapid solvent-free acetylation of alcohols, phenols, and thiols using catalytic amounts of sodium acetate trihydrate. J. Chem., 2013.
18. [18] Cronk, J. D., Endrizzi, J. A., Cronk, M. R., O'Neill, J. W., Zhang, K. Y. (2001). Crystal structure of E. coli beta-carbonic anhydrase, an enzyme with an unusual pH-dependent activity. Protein Sci., 10(5), 911-922.
19. [19] Lu, C., Wu, C., Ghoreishi, D., Chen, W., Wang, L., Damm, W., Dahlgren, M. K., Russell, E., Von Bargen, C. D., Abel, R. (2021). OPLS4: Improving Force Field Accuracy on Challenging Regimes of Chemical Space. J. Chem. Theory Comput., 17(7), 4291–300.
20. [20] Daina, A., Michielin, O., Zoete, V. (2017). SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 7, 42717.
21. [21] Daina, A., Michielin, O., Zoete, V. SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res. 2019; 47: W1, W357-W64.
22. [22] Johnson, M., Zaretskaya, I., Raytselis, Y., Merezhuk, Y., McGinnis, S., Madden, T. L. (2008). NCBI BLAST: a better web interface. Nucleic Acids Res., 36: (Web Server issue):W5-9.
23. [23] Sastry, G. M., Adzhigirey, M., Day, T., Annabhimoju, R., Sherman, W. (2013). Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J. Comput. Aided Mol. Des., 27(3), 221-234.
24. [24] Friesner, R. A., Murphy, R. B., Repasky, M. P., Frye, L. L., Greenwood, J. R., Halgren, T. A., Sanschagrin, P. C., Mainz, D. T. (2006). Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes. J. Med. Chem., 49(21), 6177-6196.
25. [25] Jacobson, M. P., Friesner, R. A., Xiang, Z., Honig, B. (2002). On the role of the crystal environment in determining protein side-chain conformations. J. Mol. Biol., 320(3), 597-608.
26. [26] Lipinski, C. A., Lombardo, F., Dominy, B. W., Feeney, P. J. (2012). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev., 64, 4-17.
27. [27] Veber, D. F., Johnson, S. R., Cheng, H. Y., Smith, B. R., Ward, K. W., Kopple, K. D. (2002). Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem., 45(12), 2615-2623.
28. [28] Ghose, A. K., Viswanadhan, V. N., Wendoloski, J. J. (1999). A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. J. Comb. Chem., 1(1), 55-68.
29. [29] Dvorak, Z. (2011). Drug-drug interactions by azole antifungals: Beyond a dogma of CYP3A4 enzyme activity inhibition. Toxicol. Lett., 202( 2), 129-132.
30. [30] Glaeser, H. Importance of P-glycoprotein for Drug–Drug Interactions. In: Fromm, M., Kim, R. (eds) Drug Transporters. Handbook of Experimental Pharmacology, vol 201. Springer, Berlin, Heidelberg, 2011.
31. [31] Baell, J., Walters, M. A. (2014). Chemistry: Chemical con artists foil drug discovery. Nature, 513(7519), 481-483.
32. [32] Kimber, M. S., Pai, E. F. (2000). The active site architecture of Pisum sativum beta-carbonic anhydrase is a mirror image of that of alpha-carbonic anhydrases. EMBO J., 19(7), 1407-1418.
33. [33] Mitsuhashi, S., Mizushima, T., Yamashita, E., Yamamoto, M., Kumasaka, T., Moriyama, H., Ueki, T., Miyachi, S., Tsukihara, T. (2000). X-ray structure of beta-carbonic anhydrase from the red alga, Porphyridium purpureum, reveals a novel catalytic site for CO(2) hydration. J. Biol. Chem., 275(8), 5521-5526.