Design of heterocyclic and macrocyclic enzyme inhibitors as potential drug molecules
According to the materials of report at the meeting of the Presidium of the NAS of Ukraine, May 28, 2025
DOI:
https://doi.org/10.15407/visn2025.08.074Keywords:
calix[4]arenes, phosphonic acids, thiazoles, rhodanines, aurones, chalcones, benzoic acids, photoactive compounds, hybrid compounds, protein tyrosine phosphatases, glutathione S-transferases, cholinesterases, xanthine oxidase, α-glucosidase.Abstract
Natural and synthetic organic molecules are potential molecular tools for regulating enzyme activity and can be directed at therapeutically important targets. The search for and investigation of effective enzyme inhibitors form the basis and open up opportunities for the creation of new drugs. The report highlights our approaches to the design of novel inhibitors of protein tyrosine phosphatases, glutathione S-transferases, cholinesterases, xanthine oxidase, and α-glucosidase. The mechanistic features of the interactions of the bioactive compounds with key amino acid residues involved in ligand-protein complexes formation have been established. The obtained results can be used for understanding the relationship between the structure and activity of an inhibitor against a target, which is important for the development of new drug molecules aimed at the treatment of metabolic, oncological, and neurodegenerative diseases.
Cite this article:
Kobzar O.L. Design of heterocyclic and macrocyclic enzyme inhibitors as potential drug molecules (according to the materials of report at the meeting of the Presidium of the NAS of Ukraine, May 28, 2025). Visn. Nac. Akad. Nauk Ukr. 2025. (8): 74—84. https://doi.org/10.15407/visn2025.08.074
References
Vovk A.I., Kalchenko V.I., Cherenok S.O., Kukhar V.P., Muzychka O.V., Lozynsky M.O. Calix[4]arene methylenebisphopsphonic acids as calf intestine alkaline phosphatase inhibitors. Org. Biomol. Chem. 2004. 2(21): 3162—3166. https://doi.org/10.1039/B409526J
Vovk A.I., Kononets L.A., Tanchuk V.Yu., Cherenok S.O., Drapailo A.B., Kalchenko V.I., Kukhar V.P. Inhibition of Yersinia protein tyrosine phosphatase by phosphonate derivatives of calixarenes. Bioorg. Med. Chem. Lett. 2010. 20(2): 483—487. https://doi.org/10.1016/j.bmcl.2009.11.126
Trush V.V., Cherenok S.O., Tanchuk V.Yu., Kukhar V.P., Kalchenko V.I., Vovk A.I. Calix[4]arene methylenebisphosphonic acids as inhibitors of protein tyrosine phosphatase 1B. Bioorg. Med. Chem. Lett. 2013. 23(20): 5619—5623. https://doi.org/10.1016/j.bmcl.2013.08.040
Trush V.V., Kharchenko S.G., Tanchuk V.Yu., Kalchenko V.I., Vovk A.I. Phosphonate monoesters on a thiacalix[4]arene framework as potential inhibitors of protein tyrosine phosphatase 1B. Org. Biomol. Chem. 2015. 13(33): 8803—8806. https://doi.org/10.1039/c5ob01247c
Trush V., Cherenok S., Tanchuk V., Kalchenko V., Vovk A. Evaluation of inhibition of protein tyrosine phosphatase 1B by calixarene-based α-ketophosphonic acids. Chem. Biol. Lett. 2015. 2(1): 1—5. http://www.pubs.iscience.in/journal/index.php/cbl/article/view/253
Kobzar O.L., Cherenok S.O., Kosterin S.O., Kalchenko V.I., Vovk A.I. Biologically active calixarene phosphonic acids. Ukr. Bioorg. Acta. 2022. 17(2): 3—13. https://doi.org/10.15407/bioorganica2022.02.003
Buldenko V., Kobzar O., Trush V., Drapailo A., Kalchenko V., Vovk A. Sulfonyl-bridged calix[4]arene as an inhibitor of protein tyrosine phosphatases. Fr.-Ukr. J. Chem. 2017. 5(2): 144—151. https://doi.org/10.17721/fujcV5I2P144-151
Buldenko V.M., Trush V.V., Kobzar O.L., Drapailo A.B., Vyshnevsky S.G., Kalchenko V.I., Vovk A.I. The assessment of sulfonylcalix[4]arene derivatives as inhibitors of protein tyrosine phosphatases. J. Org. Pharm. Chem. 2018. 16(3): 24—29. https://doi.org/10.24959/ophcj.18.947
Buldenko V.M., Trush V.V., Kobzar O.L., Drapailo A.B., Kalchenko V.I., Vovk A.I. Calixarene-based phosphinic acids as inhibitors of protein tyrosine phosphatases. Bioorg. Med. Chem. Lett. 2019. 29(6): 797—801. https://doi.org/10.1016/j.bmcl.2019.01.026
Kobzar O.L., Shulha Yu.V., Buldenko V.M., Drapailo A.B., Kalchenko V.I., Vovk A.I. Inhibition of glutathione S-transferases by calix[4]arene-based phosphinic acids. Ukr. Bioorg. Acta. 2022. 17(1): 86—91. https://doi.org/10.15407/bioorganica2022.01.086
Silenko O., Cherenok S., Shulha Yu., Kobzar O., Rusanov E., Karpichev Y., Vovk A., Kalchenko V. Thiacalix[4]arene phosphoric acids. Synthesis, structure, and inhibition of glutathione S-transferases. Phosphorus Sulfur Relat. Elem. 2021. 197(5-6): 538—541. https://doi.org/10.1080/10426507.2021.2011877
Silenko O., Cherenok S., Kobzar O., Shulha Yu., Rusanov E., Karpichev Y., Drapailo A., Vovk A., Kalchenko V. Synthesis and structure of thiacalix[4]arene phosphoric acids and their ability to inhibit protein tyrosine phosphatases. Phosphorus Sulfur Relat. Elem. 2025. 1—12. https://doi.org/10.1080/10426507.2025.2490167
Kobzar О.L., Shulha Yu.V., Buldenko V.M., Mrug G.P., Kolotylo M.V., Stanko O.L., Onysko P.P., Vovk A.I. Alkyl and aryl α-ketophosphonate derivatives as photoactive compounds targeting glutathione S-transferases. Phosphorus Sulfur Relat. Elem. 2021. 196(7): 672—678. https://doi.org/10.1080/10426507.2021.1901703
Vovk A.I., Mischenko I.M., Cherenok S.O., Tanchuk V.Y., Kalchenko V.I., Kukhar V.P. Phosphorylated calix[4]arenes as inhibitors of glutathione S-transferase. Phosphorus Sulfur Relat. Elem. 2011. 186(4): 961—963. https://doi.org/10.1080/10426507.2010.514313
Cherenok S.O., Yushchenko O.A., Tanchuk V.Y., Mischenko I.M., Samus N.V., Ruban O.V., Matvieiev Y.I., Karpenko J.A., Kukhar V.P., Vovk A.I., Kalchenko V.I. Calix[4]arene-α-hydroxyphosphonic acids. Synthesis, stereochemistry, and inhibition of glutathione S-transferase. ARKIVOC. 2012: 278—298. https://doi.org/10.3998/ark.5550190.0013.421
Kobzar O., Shulha Yu., Buldenko V., Cherenok S., Silenko O., Kalchenko V., Vovk A. Inhibition of glutathione S-transferases by photoactive calix[4]arene α-ketophosphonic acids. Bioorg. Med. Chem. Lett. 2022. 77(1): 129019. https://doi.org/10.1016/j.bmcl.2022.129019
Kobzar O.L., Sinenko V.O., Shulha Yu.V., Buldenko V.M., Hodyna D.M., Pilyo S.G., Brovarets V.S., Vovk A.I. Synthesis and evaluation of new thiazole-containing rhodanine-3-alkanoic acids as inhibitors of protein tyrosine phosphatases and glutathione S-transferases. Ukr. Bioorg. Acta. 2020. 15(2): 33—40. https://doi.org/10.15407/bioorganica2020.02.033
Los O.V., Sinenko V.O., Kobzar O.L., Zhirnov V.V., Vovk A.I., Brovarets V.S. Synthesis and in vitro anticancer potential of new thiazole-containing derivatives of rhodanine. Chem. Heterocycl. Comp. 2023. 59(6): 484—493. https://doi.org/10.1007/s10593-023-03220-z
Velihina Y., Geses R., Zhirnov V., Kobzar O., Bui B., Pilyo S., Vovk A., Shen H.-Y., Brovarets V. Design, synthesis and evaluation of the anti-breast cancer activity of 1,3-oxazolo[4,5-d]pyrimidine and 1,3-oxazolo[5,4-d]pyrimidine derivatives. RSC Med. Chem. 2023. 14(4): 692—699. https://doi.org/10.1039/D2MD00377E
Pilyo S.G., Kozachenko O.P., Zhirnov V.V., Kachaeva M.V., Kobzar O.L., Vovk A.I., Brovarets V.S. Synthesis and anticancer activity of 5-sulfonyl derivatives of 1,3-oxazole-4-carboxylates. Ukr. Bioorg. Acta. 2020. 15(2): 13—21. hpps://doi.org/10.15407/bioorganica2020.02.013
Kovalishyn V., Severin O., Kachaeva M., Kobzar O., Keith K.A., Harden E.A., Hartline C.B., James S.H., Vovk A., Brovarets V. In silico design and experimental validation of novel oxazole derivatives against varicella zoster virus. Mol. Biotechnol. 2021. 66(4): 707—717. https://doi.org/10.1007/s12033-023-00670-w
Ocheretniuk A.D., Kobzar O.L., Mischenko I.M., Vovk A.I. N-Phenacylthiazolium salts as inhibitors of cholinesterases. Fr.-Ukr. J. Chem. 2017. 5(2): 1—14. https://doi.org/10.17721/fujcV5I2P1-14
Ocheretniuk A.D., Kobzar O.L., Kozachenko O.P., Brovarets V.S., Vovk A.I. Synthesis and the activity assessment of adamantyl-containing thiazolium inhibitors of butyrylcholinesterase. J. Org. Pharm. Chem. 2017. 15(4): 48—55. https://doi.org/10.24959/ophcj.17.926
Kobzar O., Ocheretniuk A., Buldenko V., Babiy L., Kozachenko O., Brovarets V., Vovk A. O-substituted N(3)-benzyl analogs of vitamin B1 as inhibitors of acetylcholinesterase or butyrylcholinesterase. Curr. Chem. Lett. 2020. 9(1): 51—62. https://doi.org/10.5267/j.ccl.2019.7.002
Muzychka O.V., Kobzar O.L., Popova A.V., Frasinyuk M.S., Vovk A.I. Carboxylated aurone derivatives as potent inhibitors of xanthine oxidase. Bioorg. Med. Chem. 2017. 25(14): 3606—3613. https://doi.org/10.1016/j.bmc.2017.04.048
Kobzar O.L., Mischenko I.M., Tatarchuk A.V., Vdovin V.S., Lukashov S.S., Yarmoluk S.M., Vovk A.I. Nitro-substituted aurones as xanthine oxidase inhibitors. Ukr. Bioorg. Acta. 2021. 16(2): 12—17. https://doi.org/10.15407/bioorganica2021.02.012
Kobzar O.L., Tatarchuk A.V., Mrug G.P., Bondarenko S.P., Demydchuk B.A., Frasinyuk M.S., Vovk A.I. Carboxylated chalcones and related flavonoids as inhibitors of xanthine oxidase. Med. Chem. Res. 2023. 32(8): 1804—1815. https://doi.org/10.1007/s00044-023-03109-8
Kobzar O.L., Tatarchuk A.V., Kachaeva M.V., Pilyo S.G., Sukhoveev O.V., Sukhoveev V.V., Brovarets V.S., Vovk A.I. Azomethine derivatives of p-aminobenzoic acid as antioxidants and xanthine oxidase inhibitors. Dopov. Nac. Akad. Nauk Ukr. 2020. 6: 74—82. https://doi.org/10.15407/dopovidi2020.06.074
Beiko A.V., Kobzar O.L., Kachaeva M.V., Pilyo S.G., Tanchuk V.Yu., Vovk A.I. Inhibition of xanthine oxidase by pyrazolone derivatives bearing a 4-(furan-2-yl)benzoic acid moiety. J. Org. Pharm. Chem. 2023. 21(4): 27—35. https://doi.org/10.24959/ophcj.23.298726
Beiko A.V., Kobzar O.L., Kachaeva M.V., Pilyo S.G., Kozachenko O.P., Vovk A.I. Rhodanine-based 4-(furan-2-yl)benzoic acids as inhibitors of xanthine oxidase. Ukr. Bioorg. Acta. 2023. 18(2): 31—40. https://doi.org/10.15407/bioorganica2023.02.031
Kobzar O., Beiko A., Merzhyievskyi D., Shablykin O., Brovarets V., Tanchuk V., Vovk A. Design, synthesis, and xanthine oxidase inhibitory activity of 4‐(5‐aminosubstituted‐4‐cyanooxazol‐2‐yl)benzoic acids. ChemMedChem. 2024. 19(21): e202400478. https://doi.org/10.1002/cmdc.202400478
Myshko A.S., Mrug G.P., Bondarenko S.P., Kondratyuk K.M., Kobzar O.L., Buldenko V.M., Kozytskiy A.V., Vovk A.I., Frasinyuk M.S. Trapping of thermally generated ortho- and para-quinone methides by imidazoles and pyrazoles: a simple route to green synthesis of benzopyrone-azole hybrids and their evaluation as α-glucosidase inhibitors. RSC Adv. 2024. 14(38): 27809—27815. https://doi.org/10.1039/D4RA05230G
Myshko A.S., Mrug G.P., Bondarenko S.P., Demydchuk B.A., Kobzar O.L., Buldenko V.M., Vovk A.I., Frasinyuk M.S. Divergent synthesis of novel 3(5)‐aminoazole–benzopyrone hybrids and their evaluation as α‐glucosidase inhibitors. ChemMedChem. 2025. 20(5): e202400525. https://doi.org/10.1002/cmdc.202400525
