Ukr.Biochem.J. 2022; Volume 94, Issue 3, May-Jun, pp. 68-80

doi: https://doi.org/10.15407/ubj94.03.068

Synthesis of the novel cage amides and imides and evaluation of their antibacterial and antifungal activity

V. Palchykov1*, A. Gaponov1, N. Manko2,3, N. Finiuk2,
О. Novikevych4, O. Gromyko3, R. Stoika2, N. Pokhodylo3,4*

1Research Institute of Chemistry and Geology, Oles Honchar Dnipro National University, Ukraine;
2Institute of Cell Biology of National Academy of Sciences of Ukraine, Lviv;
3Ivan Franko National University of Lviv, Ukraine;
4Stepan Gzhytskyi National University of Veterinary Medicine and Biotechnologies Lviv, Ukraine;
*e-mail: pokhodylo@gmail.com; palchikoff82@gmail.com

Received: 28 December 2021; Revised: 29 June 2022;
Accepted: 29 September 2022; Available on-line: 06 October 2022

Cage amides and imides bearing bicyclo[2.2.1]- and bicyclo[2.2.2]-subunits were synthesized and evaluated both for antimicrobial activity toward five key ESKAPE pathogenic bacteria: one Gram‐positive bacteria methicillin‐resistant Staphylococcus aureus (ATCC 43300), four Gram‐negative bacteria Escherichia coli (ATCC 25922), Klebsiella pneumoniae (ATCC 700603), Acinetobacter baumannii (ATCC 19606) and Pseudomonas aeruginosa (ATCC 27853) and for antifungal activity towards pathogenic fungal strains Candida albicans (ATCC 90028) and Cryptococcus neoformans var. Grubii (H99; ATCC 208821). Compound VP-4539 with bicyclo[2.2.2]octene motif demonstrated the highest cytotoxic activity towards C. neoformans, while human keratinocytes of HaCaT line, murine fibroblasts of Balb/c 3T3 line and mitogen-activated lymphocytes of peripheral human blood were found to be tolerant to its action. VP-4539 compound did not intercalate into salmon sperm DNA indicating that its cytotoxicity is not related to intercalation into nucleic acid.

Keywords: , , , , , , , ,


References:

  1. Yuan K, Gong YM, Liu L, Sun YK, Tian SS, Wang YJ, Zhong Y, Zhang AY, Su SZ, Liu XX, Zhang YX, Lin X, Shi L, Yan W, Fazel S, Vitiello MV, Bryant RA, Zhou XY, Ran MS, Bao YP, Shi J, Lu L. Prevalence of posttraumatic stress disorder after infectious disease pandemics in the twenty-first century, including COVID-19: a meta-analysis and systematic review. Mol Psychiatry. 2021;26(9):4982-4998. PubMed, PubMedCentral, CrossRef
  2. Houšť J, Spížek J, Havlíček V. Antifungal Drugs. Metabolites. 2020;10(3):106. PubMed, PubMedCentral, CrossRef
  3. Bongomin F, Gago S, Oladele RO, Denning DW. Global and Multi-National Prevalence of Fungal Diseases-Estimate Precision. J Fungi (Basel). 2017;3(4):57. PubMed, PubMedCentral, CrossRef
  4. Lovering F, Bikker J, Humblet C. Escape from flatland: increasing saturation as an approach to improving clinical success. J Med Chem. 2009;52(21):6752-6756. PubMed, CrossRef
  5. Meyers J, Carter M, Mok NY, Brown N. On the origins of three-dimensionality in drug-like molecules. Future Med Chem. 2016;8(14):1753-1767. PubMed, PubMedCentral, CrossRef
  6. Geldenhuys WJ, Malan SF, Bloomquist JR, Marchand AP, Van der Schyf CJ. Pharmacology and structure-activity relationships of bioactive polycyclic cage compounds: a focus on pentacycloundecane derivatives. Med Res Rev. 2005;25(1):21-48. PubMed, CrossRef
  7. Palchykov V, Dil K, Manko N, Finiuk N, Novikevych О, Pokhodylo N. Cage arylsulfonamides and their antimicrobial properties. J Chem Technol. 2022;30(1):1-10. CrossRef
  8. Palchikov VA, Tarabara IN, Krishchik OV, Omelchenko IV, Shishkina SV, Shishkin OV, Kasyan LI. Exo-2,3-epoxybicyclo[2.2.1]heptan-endo-5,6-dicarboximides: versatile starting materials for the preparation of oxazaheterocyclic cage compounds. Monatsh Chem. 2014;145(7):1155-1163. CrossRef
  9. Egunlusi AO, Malan SF, Omoruyi SI, Ekpo OE, Palchykov VA, Joubert J. Open and rearranged norbornane derived polycyclic cage molecules as potential neuroprotective agents through attenuation of MPP +- and calcium overload-induced excitotoxicity in neuroblastoma SH-SY5Y cells. Eur J Med Chem. 2020;204:112617. PubMed, CrossRef
  10. Petrova T, Tarabara I, Palchikov V, Kasyan L, Kosenkov D, Okovytyy S, Gorb L, Shishkina S, Shishkin O, Leszczynski J. Ethanolysis of N-substituted norbornane epoxyimides: discovery of diverse pathways depending on substituent’s character. Org Biomol Chem. 2010;8(9):2142-2157. PubMed, CrossRef
  11. Kas’yan LI, Prid’ma SA, Turov AV, Pal’chikov VA, Kas’yan AO, Karat LD. Reaction of N-(2,3-Epoxypropyl)arenesulfonamides with (bicyclo[2.2.1]hept-5-en-endo-2-yl)methanamine. Russ J Org Chem. 2009;45(4):505-511. CrossRef
  12. Mykhailiuk PK. Saturated bioisosteres of benzene: where to go next? Org Biomol Chem. 2019;17(11):2839-2849. PubMed, CrossRef
  13. Zhong M, Peng E, Huang N, Huang Q, Huq A, Lau M, Colonno R, Li L. Discovery of functionalized bisimidazoles bearing cyclic aliphatic-phenyl motifs as HCV NS5A inhibitors. Bioorg Med Chem Lett. 2014;24(24):5731-5737. PubMed, CrossRef
  14. Shyyka OY, Pokhodylo NT, Palchykov VA, Finiuk NS, Stoika RS, Obushak MD. Cage-like amines in the green protocol of transannular thieno[2,3-d]pyrimidinone formation as promising anticancer agents. ChemHeterocycl Compd. 2020;56(6):793-799. CrossRef
  15. Kessenikh A, Gnuchikh E, Bazhenov S, Bermeshev M, Pevgov V, Samoilov V, Shorunov S, Maksimov A, Yaguzhinsky L, Manukhov I. Genotoxic effect of 2,2′-bis(bicyclo[2.2.1] heptane) on bacterial cells. PLoS One. 2020;15(8):e0228525. PubMed, PubMedCentral, CrossRef
  16. Milbeo P, Quintin F, Moulat L, Didierjean C, Martinez J, Bantreil X, Calmès M, Lamaty F. Synthesis, characterisation and cytotoxic activity evaluation of new metal-salen complexes based on the 1, 2-bicyclo[2.2.2]octane bridge. Tetrahedron Lett. 2021;63:152706. CrossRef
  17. Cantín A, Corma A, Díaz-Cabaña MJ, Jordá JL, Moliner M, Rey F. Synthesis and characterization of the all-silica pure polymorph C and an enriched polymorph B intergrowth of zeolite beta. Angew Chem Int Ed Engl. 2006;45(47):8013-8015. PubMed, CrossRef
  18. Johnson MR, Gauuan JF, Guo C, Guzzo PR, Le VD, Shenoy RA, Hamby J, Roark H, Stier M, Mangette JE. Synthesis and characterization of novel bi-and tricyclic α-amino acids. Synth Commun. 2011;41(18):2769-2793. CrossRef
  19. Sastre G, Cantin A, Diaz-Cabañas MJ, Corma A. Searching organic structure directing agents for the synthesis of specific zeolitic structures: An experimentally tested computational study. Chem Mater. 2005;17(3):545-552. CrossRef
  20. Kas’yan LI, Tarabara IN, Pal’chikov VA, Krishchik OV, Isaev AK, Kas’yan AO. Acylation of Aminopyridines and Related Compounds with Endic Anhydride. Russ J Org Chem. 2005; 41(10): 1530-1538. CrossRef
  21. Gunkara OT, Kulu I, Ocal N, Kaufmann DE. Synthesis of arylated norbornyl amino acid esters. Monatsh Chem. 2010;141(11):1237-1243. CrossRef
  22. Kas’yan LI, Pal’chikov VA, Tarabara IN, Krishchik OV, Kas’yan AO, Shishkina SV, Shishkin OV. Products of endic anhydride reaction with cyclic amines and their heterocyclization. Russ J Org Chem. 2006;42(11):1642-1652. CrossRef
  23. Pal’chikov VA, Tarabara IN, Kas’yan LI. Endic acid diamides. Synthesis and reactivity. Russ J Org Chem. 2007;43(7):984-989. CrossRef
  24. Desselle MR, Neale R, Hansford KA, Zuegg J, Elliott AG, Cooper MA, Blaskovich MA. Institutional profile: Community for Open Antimicrobial Drug Discovery – crowdsourcing new antibiotics and antifungals. Future Sci OA. 2017;3(2):FSO171. PubMed, PubMedCentral, CrossRef
  25. Lootsik M, Manko N, Stoika R, Gromyko O, Tistechok S, Lutsyk M. Honeybee chitosan-melanin complex: isolation and investigation of antimicrobial activity. Ukr Biochem J. 2020;92(6):143-153. CrossRef
  26. Liu X, Zu Y, Fu Y, Yao L, Gu C, Wang W, Efferth T. Antimicrobial activity and cytotoxicity towards cancer cells of Melaleuca alternifolia (tea tree) oil. Eur Food Res Technol. 2009;229(2):247-253. CrossRef
  27. Kuznietsova H, Byelinska I, Dziubenko N, Lynchak O, Milokhov D, Khilya O, Finiuk N, Klyuchivska O, Stoika R, Rybalchenko V. Suppression of systemic inflammation and signs of acute and chronic cholangitis by multi-kinase inhibitor 1-(4-Cl-benzyl)-3-chloro-4-(CF3-phenylamino)-1H-pyrrole-2,5-dione. Mol Cell Biochem. 2021;476(8):3021-3035. PubMed, CrossRef
  28. Finiuk NS, Ivasechko II, Klyuchivska OY, Ostapiuk YV, Hreniukh VP, Shalai YR, Matiychuk VS, Obushak MD, Babsky AM, Stoika RS. Apoptosis induction in human leukemia cells by novel 2-amino-5-benzylthiazole derivatives. Ukr Biochem J. 2019;91(2):29-39. CrossRef
  29. Tkachenko IV, Tarabara IN, Omelchenko IV, Palchykov VA. Grignard reagents and their N-analogues in the synthesis of tri- and tetracyclic cage-like lactams. J Het Chem. 2018; 55(10): 2381-2391. CrossRef
  30. Nair LG, Sannigrahi M, Bogen S, Pinto P, Chen KX, Prongay A, Tong X, Cheng KC, Girijavallabhan V, Njoroge FG. P4 capped amides and lactams as HCV NS3 protease inhibitors with improved potency and DMPK profile. Bioorg Med Chem Lett. 2010;20(2):567-570. PubMed, CrossRef
  31. Pat. Ukraine 86195. Method for synthesis of stereochemically pure cis-cyclopentane-1,3-dicarboxylic acid. (In Ukrainian).
  32. Hronowski LJ, Szarek WA. Synthesis of cyclopentane analogs of 1-(2′,3′-dideoxy-β-glycero-pentofuranosyl)pyrimidine nucleosides. Can J Chem. 1988;66(1):61-70. CrossRef
  33. 33. Arthi P, Haleel A, Srinivasan P, Prabhu D, Arulvasu C, Kalilur Rahiman A. Antibacterial, DNA interaction and cytotoxic activities of pendant-armed polyamine macrocyclic dinuclear nickel(II) and copper(II) complexes. Spectrochim Acta A Mol Biomol Spectrosc. 2014;129:400-414. PubMed, CrossRef
  34. Fan Y, Pauer AC, Gonzales AA, Fenniri H. Enhanced antibiotic activity of ampicillin conjugated to gold nanoparticles on PEGylated rosette nanotubes. Int J Nanomedicine. 2019;14:7281-7289. PubMed, PubMedCentral, CrossRef
  35. Bueno AB, Collado I, de Dios A, Domínguez C, Martín JA, Martín LM, Martínez-Grau MA, Montero C, Pedregal C, Catlow J, Coffey DS, Clay MP, Dantzig AH, Lindstrom T, Monn JA, Jiang H , Schoepp DD, Stratford RE, Tabas LB, Tizzano JP, Wright RA, Herin MF. Dipeptides as effective prodrugs of the unnatural amino acid (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740), a selective group II metabotropic glutamate receptor agonist. J Med Chem. 2005;48(16):5305-5320. PubMed, CrossRef
  36. Monn JA, Henry SS, Massey SM, Clawson DK, Chen Q, Diseroad BA, Bhardwaj RM, Atwell S, Lu F, Wang J, Russell M, Heinz BA, Wang XS, Carter JH, Getman BG, Adragni K, Broad LM, Sanger HE, Ursu D, Catlow JT, Swanson S, Johnson BG, Shaw DB, McKinzie DL, Hao J. Synthesis and Pharmacological Characterization of C4 β-Amide-Substituted 2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1 S,2 S,4 S,5 R,6 S)-2-Amino-4-[(3-methoxybenzoyl)amino]bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2794193), a Highly Potent and Selective mGlu 3 Receptor Agonist. J Med Chem. 2018;61(6):2303-2328. PubMed, CrossRef
  37.  Che JX, Wang ZL, Dong XW, Hu YH, Xie X, Hu YZ. Bicyclo[2.2.1]heptane containing N, N’-diarylsquaramide CXCR2 selective antagonists as anti-cancer metastasis agents. RSC Adv. 2018;8(20):11061-11069. PubMed, PubMedCentral, CrossRef
  38. Zaks-Makhina E, Kim Y, Aizenman E, Levitan ES. Novel neuroprotective K+ channel inhibitor identified by high-throughput screening in yeast. Mol Pharmacol. 2004;65(1):214-219. PubMed, CrossRef
  39. Manner S, Oltner VT, Oredsso S, Ellervik U, Frejd T. Spiro-bicyclo[2.2.2]octane derivatives as paclitaxel mimetics. Synthesis and toxicity evaluation in breast cancer cell lines. Org Biomol Chem. 2013;11(41):7134-7144. PubMed, CrossRef

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