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Design, synthesis, molecular docking and in silico ADMET investigations of novel piperidine-bearing cinnamic acid hybrids as potent antimicrobial agents

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Abstract

In order to combat microbial infections and to address the issue of multi-drug resistance, a class of novel piperidine-bearing cinnamic acid hybrids 4a–4l were synthesized and validated using various spectroscopic techniques like IR, NMR, and mass spectrometry. In addition, the compounds were assessed for antimicrobial activity. Compound 4l demonstrated significant activity against Pseudomonas aeruginosa and Escherichia coli strains with MIC = 50 and 12.5 µg/mL, and compounds 4a, 4d, 4e, and 4l exhibited considerable activity against all fungal strains ranging from MFC = 125–250 µg/mL. An in silico ADMET study indicated that most compounds show favorable drug-like and toxicological properties. Furthermore, a molecular docking study revealed that compounds 4d, 4e, 4h, and 4j could be lodged in the active pocket and inhibit human fungal Candida albicans Hsp90 NBD protein via various interactions, and results indicated the synthesized analogs to be promising lead compounds in the search for novel antifungal drug-like molecules to be orally bioavailable.

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References

  1. E.G. Brown, Ring nitrogen and key biomolecules. Ring Nitrogen Key Biomol. (1998). https://doi.org/10.1007/978-94-011-4906-8

    Article  Google Scholar 

  2. G. Facchetti, I. Rimoldi, Anticancer platinum(II) complexes bearing N-heterocyclerings. Bioorg. Med. Chem. Lett. 29, 1257–1263 (2019). https://doi.org/10.1016/J.BMCL.2019.03.045

    Article  CAS  PubMed  Google Scholar 

  3. X. Liang, L. Zhang, F. Li, S. Luan, C. He, L. Yin, Z. Yin, Y. Zou, G. Yue, L. Li, X. Song, C. Lv, W. Zhang, B. Jing, Autophagy-regulating N-heterocycles derivatives as potential anticancer agents. Future Med. Chem. 12, 223–242 (2019). https://doi.org/10.4155/FMC-2019-0294

    Article  PubMed  Google Scholar 

  4. K.B. Patel, P. Kumari, Anticancer activity and docking study of flavone derivatives as peroxisome proliferator-activated receptorγ inhibitors. Struct. Chem. (2022). https://doi.org/10.1007/S11224-022-01926-Y

    Article  PubMed  PubMed Central  Google Scholar 

  5. A.A. Shaddy, A.A. Kamel, W.M. Abdou, Synthesis, quantitative structure-activity relationship, and anti-inflammatory profiles of substituted 5- and 6-N-heterocycle bisphosphonate esters. Synth. Commun. 43, 236–252 (2012). https://doi.org/10.1080/00397911.2011.595603

    Article  CAS  Google Scholar 

  6. N. Desideri, R. Fioravanti, L.P. Monaco, E.M. Atzori, A. Carta, I. Delogu, G. Collu, R. Loddo, Design, synthesis, antiviral evaluation, and sar studies of new 1-(phenylsulfonyl)-1H-pyrazol-4-yl-methylaniline derivatives. Front. Chem. 7, 214 (2019). https://doi.org/10.3389/FCHEM.2019.00214

    Article  PubMed  PubMed Central  Google Scholar 

  7. R. Ardeleanu, A. Dascălu, S. Shova, A. Nicolescu, I. Roşca, B.I. Bratanovici, V. Lozan, G. Roman, 4′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-carboxylic acid: Synthetic approaches, single crystal X-ray structures and antimicrobial activity of intermediates. J. Mol. Struct. 1173, 63–71 (2018). https://doi.org/10.1016/J.MOLSTRUC.2018.06.086

    Article  CAS  Google Scholar 

  8. Prachayasittikul, S., Worachartcheewan, A., & Lawung, R. Activities ofthiotetrahydropyridines asantioxidantandantimicrobialagents. (2009). https://doi.org/10.17877/DE290R-14217

  9. Y. Zhou, V.E. Gregor, B.K. Ayida, G.C. Winters, Z. Sun, D. Murphy, G. Haley, D. Bailey, J.M. Froelich, S. Fish, S.E. Webber, T. Hermann, D. Wall, Synthesis and SAR of 3,5-diamino-piperidine derivatives: novel antibacterial translation inhibitors as aminoglycoside mimetics. Bioorg. Med. Chem. Lett. 17, 1206–1210 (2007). https://doi.org/10.1016/J.BMCL.2006.12.024

    Article  CAS  PubMed  Google Scholar 

  10. R. Aeluri, M. Alla, V.R. Bommena, R. Murthy, N. Jain, Synthesis and antiproliferative activity of polysubstituted tetrahydropyridine and piperidin-4-one-3-carboxylate derivatives. Asian J. Org. Chem. 1, 71–79 (2012). https://doi.org/10.1002/AJOC.201200010

    Article  CAS  Google Scholar 

  11. A. Ravindernath, M.S. Reddy, Synthesis and evaluation of anti-inflammatory, antioxidant and antimicrobial activities of densely functionalized novel benzo [d] imidazolyl tetrahydropyridine carboxylates. Arab. J. Chem. 10, S1172–S1179 (2017). https://doi.org/10.1016/J.ARABJC.2013.02.011

    Article  CAS  Google Scholar 

  12. A. Mochizuki, Y. Nakamoto, H. Naito, K. Uoto, T. Ohta, Design, synthesis, and biological activity of piperidine diamine derivatives as factor Xa inhibitor. Bioorg. Med. Chem. Lett. 18(2), 782–787 (2008). https://doi.org/10.1016/J.BMCL.2007.11.037

    Article  CAS  PubMed  Google Scholar 

  13. R.S. Dawood, S.A. Dayl, Synthesis, identification and molecular docking studies of N-functionalized piperidine derivatives linked to 1,2,3-triazole ring. Synth. Commun. 50, 2422–2431 (2020). https://doi.org/10.1080/00397911.2020.1776876

    Article  CAS  Google Scholar 

  14. A.B. Patel, K.H. Chikhalia, P. Kumari, Access to antimycobacterial and anticancer potential of some fused quinazolines. Res. Chem. Intermed. 41, 4439–4455 (2015). https://doi.org/10.1007/S11164-014-1542-8

    Article  CAS  Google Scholar 

  15. A.B. Patel, K.H. Chikhalia, P. Kumari, Study of new β-lactams-substituted s-triazine derivatives as potential bioactive agents. Med. Chem. Res. 24, 468–481 (2019). https://doi.org/10.1007/S00044-014-1151-5

    Article  Google Scholar 

  16. D. Patel, P. Kumari, N.B. Patel, Synthesis and biological evaluation of coumarin based isoxazoles, pyrimidinthiones and pyrimidin-2-ones. Arab. J. Chem. 10, S3990–S4001 (2017). https://doi.org/10.1016/J.ARABJC.2014.06.010

    Article  CAS  Google Scholar 

  17. R.V. Patel, P. Kumari, D.P. Rajani, K.H. Chikhalia, Synthesis, characterization and pharmacological activities of 2-[4-cyano-(3-trifluoromethyl)phenyl amino)]-4-(4-quinoline/coumarin-4-yloxy)-6-(fluoropiperazinyl)-s-triazines. J. Fluor. Chem. 132, 617–627 (2011). https://doi.org/10.1016/J.JFLUCHEM.2011.06.021

    Article  CAS  Google Scholar 

  18. G.D. Brown, D.W. Denning, N.A.R. Gow, S.M. Levitz, M.G. Netea, T.C. White, Hidden killers: human fungal infections. Sci. Transl. Med. (2012). https://doi.org/10.1126/SCITRANSLMED.3004404

    Article  PubMed  PubMed Central  Google Scholar 

  19. M.A. Pfaller, D.J. Diekema, Epidemiology of invasive candidiasis: a persistent public health problem. Clin. Microbiol. Rev. 20, 133–163 (2007). https://doi.org/10.1128/CMR.00029-06

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. N. Robbins, G.D. Wright, L.E. Cowen, Antifungal drugs: the current armamentarium and development of new agents. Microbiol. Spectr. (2016). https://doi.org/10.1128/MICROBIOLSPEC.FUNK-0002-2016

    Article  PubMed  Google Scholar 

  21. M.C. Fisher, N.J. Hawkins, D. Sanglard, S.J. Gurr, Worldwide emergence of resistance to antifungal drugs challenges human health and food security. Science 360, 739–742 (2018). https://doi.org/10.1126/SCIENCE.AAP7999

    Article  CAS  PubMed  Google Scholar 

  22. A. Makowska, F. Saczewski, P.J. Bednarski, J. Saczewski, Ł Balewski, Hybrid molecules composed of 2,4-diamino-1,3,5-triazines and 2-imino-coumarins and coumarins. Synthesis and cytotoxic properties. Molecules 23, 1616 (2018). https://doi.org/10.3390/MOLECULES23071616

    Article  PubMed  PubMed Central  Google Scholar 

  23. H. Seyrani, S. Ramezanpour, A. Vaezghaemi, F. Kobarfard, A sequential Ugi–smiles/transition-metal-free endo-dig Conia–ene cyclization: the selective synthesis of saccharin substituted 2,5-dihydropyrroles. New J. Chem. 45, 15647–15654 (2021). https://doi.org/10.1039/D1NJ01159F

    Article  CAS  Google Scholar 

  24. J.S. Lan, J.W. Hou, Y. Liu, Y. Ding, Y. Zhang, L. Li, T. Zhang, Design, synthesis and evaluation of novel cinnamic acid derivatives bearing N-benzyl pyridinium moiety as multifunctional cholinesterase inhibitors for Alzheimer’s disease. J. Enzym. Inhib. Med. Chem. 32, 776–788 (2018). https://doi.org/10.1080/14756366.2016.1256883

    Article  CAS  Google Scholar 

  25. X.T. Xu, X.Y. Deng, J. Chen, Q.M. Liang, K. Zhang, D.L. Li, P.P. Wu, X. Zheng, R.P. Zhou, Z.Y. Jiang, A.J. Ma, W.H. Chen, S.H. Wang, Synthesis and biological evaluation of coumarin derivatives as α-glucosidase inhibitors. Eur. J. Med. Chem. 189, 112013 (2020). https://doi.org/10.1016/J.EJMECH.2019.112013

    Article  PubMed  Google Scholar 

  26. G.D.A. de Lima, M.P. Rodrigues, T.A.O. de Mendes, G.A. Moreira, R.P. Siqueira, A.M. da Silva, B.G. Vaz, J.L.R. Fietto, G.C. Bressan, M. Machado-Neves, R.R. Teixeira, Synthesis and antimetastatic activity evaluation of cinnamic acid derivatives containing 1,2,3-triazolic portions. Toxicol. Vitro Int. J. Publ. Assoc. BIBRA 53, 1–9 (2018). https://doi.org/10.1016/J.TIV.2018.07.015

    Article  CAS  Google Scholar 

  27. I. Perković, S. Raić-Malić, D. Fontinha, M. Prudêncio, L. Pessanha de Carvalho, J. Held, T. Tandarić, R. Vianello, B. Zorc, Z. Rajić, Harmicines−harmine and cinnamic acid hybrids as novel antiplasmodial hits. Eur. J. Med. Chem. 187, 111927 (2020). https://doi.org/10.1016/J.EJMECH.2019.111927

    Article  PubMed  Google Scholar 

  28. J.D. Guzman, Natural cinnamic acids, synthetic derivatives and hybrids with antimicrobial activity. Molecules 19, 19292–19349 (2014). https://doi.org/10.3390/MOLECULES191219292

    Article  PubMed  PubMed Central  Google Scholar 

  29. A.R. Zala, D.P. Rajani, I. Ahmad, H. Patel, P. Kumari, Synthesis, characterization, molecular dynamic simulation, and biological assessment of cinnamates linked to imidazole/benzimidazole as a CYP51 inhibitor. J. Biomol. Struct. Dyn. (2023). https://doi.org/10.1080/07391102.2023.2170918

    Article  PubMed  Google Scholar 

  30. B.F. Ruan, W.W. Ge, H.J. Cheng, H.J. Xu, Q.S. Li, X.H. Liu, Resveratrol-based cinnamic ester hybrids: synthesis, characterization, and anti-inflammatory activity. J. Enzym. Inhib. Med. Chem. 32, 1282–1290 (2017). https://doi.org/10.1080/14756366.2017.1381090

    Article  CAS  Google Scholar 

  31. B. Korošec, M. Sova, S. Turk, N. Kraševec, M. Novak, L. Lah, J. Stojan, B. Podobnik, S. Berne, N. Zupanec, M. Bunc, S. Gobec, R. Komel, Antifungal activity of cinnamic acid derivatives involves inhibition of benzoate 4-hydroxylase (CYP53). J. Appl. Microbiol. 116, 955–966 (2014). https://doi.org/10.1111/JAM.12417

    Article  PubMed  Google Scholar 

  32. B. Podobnik, J. Stojan, L. Lah, N. Kraševec, M. Seliškar, T.L. Rižner, D. Rozman, R. Komel, CYP53A15 of Cochliobolus lunatus, a target for natural antifungal compounds. J. Med. Chem. 51, 3480–3486 (2008). https://doi.org/10.1021/JM800030E

    Article  CAS  PubMed  Google Scholar 

  33. A.R. Zala, D.P. Rajani, P. Kumari, Design, synthesis, molecular docking and antimicrobial and antimycobacterial activities of novel hybrid of coumarin-cinnamic acids. Chem. Data Collect. 39, 100862 (2022). https://doi.org/10.1016/J.CDC.2022.100862

    Article  CAS  Google Scholar 

  34. A.R. Zala, D.P. Rajani, P. Kumari, Synthesis, molecular docking, ADME study, and antimicrobial potency of piperazine based cinnamic acid bearing coumarin moieties as a DNA gyrase inhibitor. J. Biochem. Mol. Toxicol. (2022). https://doi.org/10.1002/jbt.23231

    Article  PubMed  Google Scholar 

  35. K. Drlica, X. Zhao, DNA gyrase, topoisomerase IV, and the 4-quinolones. Microbiol. Mol. Biol. Rev. 61(3), 377–392 (1997). https://doi.org/10.1128/MMBR.61.3.377-392.1997

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. S.M. Hammond, 3 biological activity of polyene antibiotics. Prog. Med. Chem. 14(1), 105–179 (1977). https://doi.org/10.1016/S0079-6468(08)70148-6

    Article  CAS  PubMed  Google Scholar 

  37. Y. Kiat, Y. Vortman, N. Sapir, Feather moult and bird appearance are correlated with global warming over the last 200 years. Nat. Commun. 10, 1–7 (2019). https://doi.org/10.1038/s41467-019-10452-1

    Article  CAS  Google Scholar 

  38. R.A. Friesner, J.L. Banks, R.B. Murphy, T.A. Halgren, J.J. Klicic, D.T. Mainz, M.P. Repasky, E.H. Knoll, M. Shelley, J.K. Perry, D.E. Shaw, P. Francis, P.S. Shenkin, Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J. Med. Chem. 47, 1739–1749 (2004). https://doi.org/10.1021/JM0306430

    Article  CAS  PubMed  Google Scholar 

  39. T.A. Halgren, R.B. Murphy, R.A. Friesner, H.S. Beard, L.L. Frye, W.T. Pollard, J.L. Banks, Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J. Med. Chem. 47, 1750–1759 (2004). https://doi.org/10.1021/JM030644S

    Article  CAS  PubMed  Google Scholar 

  40. H.M. Berman, J. Westbrook, Z. Feng, G. Gilliland, T.N. Bhat, H. Weissig, I.N. Shindyalov, P.E. Bourne, The protein data bank. Nucleic Acids Res. 28, 235–242 (2000). https://doi.org/10.1093/NAR/28.1.235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. C. Tang, Y. Ye, Y. Feng, R.J. Quinn, TCM, brain function and drug space. Nat. Prod. Rep. 33, 6–25 (2015). https://doi.org/10.1039/C5NP00049A

    Article  Google Scholar 

  42. D.G. Levitt, M.D. Levitt, Human serum albumin homeostasis: a new look at the roles of synthesis, catabolism, renal and gastrointestinal excretion, and the clinical value of serum albumin measurements. Int. J. Gen. Med. 9, 229–255 (2016). https://doi.org/10.2147/IJGM.S102819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank Microcare Laboratory-Surat, Gujarat, India, for performing in vitro antimicrobial activity and IISc, Bangalore, India for providing spectral data of synthesized compounds. The authors are also thankful to Schrödinger Inc. for providing the demo license of Schrödinger Suite that has tremendously helped in the computational study. The authors are thankful to the Department of Chemistry of S.V. National Institute Technology, Surat, Gujarat, India, for providing all the facilities for the research work.

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  1. Department of Chemistry, Sardar Vallabhbhai National Institute of Technology, Surat, Gujarat, 395007, India

    Ajayrajsinh R. Zala & Premlata Kumari

  2. Microcare Laboratory, Surat, Gujarat, 395001, India

    Dhanji P. Rajani

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Zala, A.R., Rajani, D.P. & Kumari, P. Design, synthesis, molecular docking and in silico ADMET investigations of novel piperidine-bearing cinnamic acid hybrids as potent antimicrobial agents. J IRAN CHEM SOC 20, 1843–1856 (2023). https://doi.org/10.1007/s13738-023-02801-1

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