IN SILICO PREDICTION AND MOLECULAR DOCKING STUDIES OF BIOLOGICAL ACTIVITY OF HYDROACRIDINE (QUINOLINE) DERIVATIVES
№4

Keywords

9-chloroacridine(quinoline)-N-aryl)pyrrolidine-2,5-diones, docking studies, cholinesterase inhibitors, anti-inflammatory activity, anticonvulsant activity.

How to Cite

Smetanin , N., Tokarieva, S., Varenichenko , S., Farat , O., & Markov, V. (2021). IN SILICO PREDICTION AND MOLECULAR DOCKING STUDIES OF BIOLOGICAL ACTIVITY OF HYDROACRIDINE (QUINOLINE) DERIVATIVES. Ukrainian Chemistry Journal, 87(5), 38-52. https://doi.org/10.33609/2708-129X.87.05.2021.38-52

Abstract

To find biological activity among easily available 2-[(4S,4’S/4R,4’R)-2’,5’-dioxo-2,3,5,6,7,8-hexahydro-1H-spiro[acridine-4,3’-pyrrolidin]-4’-yl]-N-aryl-acetamide, (4S/4R)-4-[(3R/3S)-1-(2-aryl)-2,5-dioxopyrrolidin-3-yl]-1,2,3,4,5,6,7,8-octahydroacridine-4-carbonitrile, (3S/4R)-3-[(3R/4S)-9-chloroacridine(quinoline)-4-yl]-1-N-aryl)pyrrolidine-2,5-diones. Methods: Organic synthesis, spectral methods, and molecular docking. We investigated by molecular docking the potential biological activity of previously synthesized compounds containing acridine and pyrrolidine-2,5-diones fragments in their structure, as well as synthesized in this work N’-hydroxy-1,2,3,4,5,6,7,8-octahydroacridine-4-carboximidamide. Based on the literature data, 3 directions of searching for the biological activity of the synthesized compounds have been chosen: cholinesterase inhibitors, anti-inflammatory, and anticonvulsant agents. As inhibitors of acetylcholinesterase and butylcholinesterase, substances with good binding free energy and hydrogen bonds with the desired amino acid residues of the Glu-His-Ser triad have been found among the tested compounds. The indicators of synthesized products have exceeded the literature data. The docking data for anti-inflammatory activity has revealed compounds with values above the docking data of the reference drugs - celecoxib and indomethacin. The compounds tested have shown moderate activity as anticonvulsant agents. 3-(7-bromo-9-chloro-1,2,3,4-tetrahydroacridin-4-yl)-1-(3-nitrophenyl)pyrrolidine-2,5-dione is potentially promising as an acetylcholinesterase inhibitor due to its high binding free energy (-13.7 kcal/mol) and hydrogen bonds with two amino acid residues Ser200, His440. Compound (4S/4R)-4-[(3R/3S)-1-(3-nitrophenyl)-2,5-dioxopyrrolidin-3-yl]-1,2,3,4,5,6,7,8-octahydroacridine-4-carbonitrile has proved to be the best as an anti-inflammatory agent. The presence of a pyrrolidine-2,5-diones fragment increases the indicators of the biological activity of the synthesized compounds in comparison with just acridine derivatives.

https://doi.org/10.33609/2708-129X.87.05.2021.38-52
№4

References

Chen R., Huo L., Jaiswal Y., Huang J., Zhong Zh., Zhong J., Williams L., Xia X., Liang Y., Yan Zh. Design, Synthesis, Antimicrobial, and Anticancer Activities of Acridine Thiosemicarbazides Derivatives. Molecules. 2019. 24(11): 2065.

Rupar J.S., Dobričić V.D., Aleksić M.M., Brborić J.S., Čudina O.A. A review of published data on acridine derivatives with different biological activities. Kragujevac Journal of Science. 2018. 40: 83–101.

Ali I., Lone M.N., Alothman Z.A., Alwarthan A. Insights into the pharmacology of new heterocycles embedded with oxopyrrolidine rings DNA binding, molecular docking, and anticancer studies. Journal of Molecular Liquids. 2017. 234: 391–402.

Obniska J., Sałat K., Librowski T., Kamiń­ski K., Lipkowska A., Wiklik B., Rybka S., Rapacz A. Antinociceptive properties of N-Mannich bases derived from 3-substituted pyrrolidine-2,5-dione in the formalin model of persistent pain in mice. Pharmacological Reports. 2015. 67(1): 63–68.

Pardeshi S.D., Sonar J.P., Dokhe S.A., Zine A.M., Thore S.N. Synthesis and anti-microbial activity of novel pyrrolidine containing chalcones and pyrazolines. IJCPS. 2016. 5: 34–40.

Abass S.J.: Synthesis and characterization of some new pyrrolidine-2,5-dione derivatives using anthranilic acid. Journal of Kerbala University. 2015. 13(2): 236–42.

Tsai Y.F., Yang S.C., Hwang T.L. Formyl peptide receptor modulators: a patent review and potential applications for inflammatory diseases. Expert Opinion on Therapeutic Patents. 2016. 26(10): 1139–56.

Socała K., Mogilski S., Pierуg M., Nieo­czym D., Abram M., Szulczyk B., Lubelska A., Latacz G., Doboszewska U., Wla P. and Kamiński K. KA-11, a novel pyrrolidine-2, 5-dione derived broad-spectrum anticonvulsant: its antiepileptogenic, antinociceptive properties and in-vitro characterization. ACS chemical neuroscience. 2018. 10(1): 636–48.

Jan M.S., Ahmad S., Hussain F., Ahmad A., Mahood F., Rashid U., Abid O-U-R, Ullah F., Ayaz M., Sadiq A. Design, synthesis, in-vitro, in-vivo and in-silico studies of pyrrolidine-2, 5-dione derivatives as multitarget anti-inflammatory agents. Eur J Med Chem. 2020. 186: 111–863.

Markov V.I., Farat O.K., Varenichenko S.A., Velikaya E.V. Rearrangement of 5’,6’,7’,8’-tetrahydro-1’H-spiro(cyclohe­xane-1,2’-quinazolin)-4’(3’H)-one during Vilsmeier reaction. Mendeleev Commun. 2012. 22: 101–102.

Farat O.K., Markov V.I., Varenichenko S.A., Dotsenko V.V., Mazepa A.V. The Vil­smeier-Haack formylation of 2,3-dihydro-4H-1,3-benzoxazin-4-ones and isomeric 1,2-dihydro-4H-3,1-benzoxazin-4- ones: an effective approach to functionalized 2H-/4H-Chromenes and Tetrahydroacridines. Tetrahedron. 2015. 71: 5554.

Zaliznaya E.V., Smetanin N.V., Varenichenko S.A., Mazepa A.V., Farat O.K., Mar­kov V.I. Synthesis of new hexahydro-5H-indolo[3,2-c]acridines and indolylbutanoic acids by Fischer cyclization of arylhydrazones. Chemistry of Heterocyclic Compounds. 2018. 2: 138–145.

Zaliznaya E.V., Farat O.K., Varenichenko S.A., Mazepa A.V., Markov V.I. Functionalization of tetra- and octahydroacridine derivatives through Michael addition. Tetrahedron Lett. 2016. 57 (31): 3485–3487.

Smetanin N.V., Varenichenko S.A., Zali­znaya E.V., Mazepa A.V., Farat O.K., Mar­kov V.I. Functionalization of N-arylmaleimides by sp3 C-H bonds of hydroacridines(qinolines). Voprosy Khimii i Khi­micheskoi Tekhnologii. 2020. 6: 165–170.

Sussman J.L., Harel M., Frolow F., Oefner C., Goldman A., Toker L., Silman I. Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein. Science. 1991. 253(5022): 872–879.

Kharlamova A.D., Lushchekina S.V., Pet­rov K.A., Kots E.D., Nachon F., Villard-Wandhammer M., Zueva I.V., Krejci E., Reznik V.S., Zobov V.V., Nikolsky E.E., Masson P.. Slow-binding inhibition of acetylcholinesterase by an alkylammonium derivative of 6-methyluracil: mechanism and possible advantages for myasthenia gravis treatment. Biochem. J. 2016. 473(9): 1225.

Morris G.M., Huey R., Lindstrom W., Sanner M.F., Belew R.K., Goodsell D.S., Olson A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem. 2009. 30 (16): 2785–91.

Makhaeva G.F., Rudakova E.V., Kovaleva N.V., Lushchekina S.V., Boltneva N.P., Proshin A.N., Shchegolkov E.V., Burgart J.V., Saloutin V.I. Cholinesterase and carbo­xylesterase inhibitors as pharmacological agents. Izvestiya Akademii nauk. Seriya khemicheskaya. 2019. 5: 967–984 [In Russian].

Ahmad A., Ullah F., Sadiq A., Ayaz M., Jan M.S, Shahid M., Wadood A., Mah­mood F., Rashid U., Ullah R., Sahibzada M-U-K, Alqahtani A.S., Mahmood H.M. Comparative Cholinesterase, α-Glucosidase Inhibitory, Antioxidant, Mole­cular Docking, and Kinetic Studies on Potent Succinimide Derivatives. Drug Design, Development and Therapy. 2020. 14: 2165–2178.

Muhammad S.J., Sajjad A., Fida H., Ashfaq A., Fawad M., Umer R., Obaid-ur-Rahman A., Farhat U., Muhammad A., Abdul S. Design, synthesis, in-vitro, in-vivo and in-silico studies of pyrrolidine-2,5-dione derivatives as multitarget anti-inflammatory agents. European Journal of Medicinal Chemistry. 2019. 45: 555–563.

Maru A. Molecular docking study of new-Mannich bases derived from pyrollidine-2,5-dione as anticonvulsant agents. International Journal of Pharmaceutical Sciences and Research, 2020. 11(3): 1243–1248.

Pedretti A., Villa L., Vistoli G. VEGA – An open platform to develop chemobioinformatics applications, using plugin architecture and script programming. J.C.A.M.D. 2004. 18: 167–173.

Hu M.-K., Lu C.-F. A facile synthesis of bis-tacrine isosteres. Tetrahedron Lett. 2000. 41 (11): 1815–1818.

Zigeuner G., Gübitz G. Über das tetra­hydro[spirocyclohexan-1,2(1H)-chi­na­zolin]-4-(3H)-on. Monatshefte Chem. 1970. 101: 1547–1558.

Son J. K., Kim S. III, Janng Y. A modified Niementowski reaction for the synthesis of 4-hydroxyquinoline and its related compounds. Heterocycles. 2001. 55 (10): 1981–1986.

Downloads

Download data is not yet available.