Synthesis, characterization, molecular docking, antimalarial, and antiproliferative activities of benzyloxy-4-oxopyridin benzoate derivatives

Marjan Mohebi , Neda Fayazi, Somayeh Esmaeili, Mahboubeh Rostami, Fereshteh Bagheri, Alireza Aliabadi, Parvin Asadi, Lotfollah Saghaie

Abstract


Background and purpose: Malaria and cancer are two major health issues affecting millions of lives annually. Maltol complexes and derivatives have been extensively investigated as chemotherapeutic and antimalarial activities. In this study, the design, synthesis, biological activities, and docking study of a novel series of pyridinones derivatives were reported.

Experimental approach: The chemical structures of synthesized compounds were approved by FTIR, 1HNMR, 13CNMR, and mass spectroscopies. The antimalarial activity was evaluated through β-hematin inhibition assay and the cytotoxicity activities were evaluated against PC12 and fibroblast cell lines via MTT and cell uptake assays. To theoretically investigate the ability of compounds to inhibit hemozoin formation, the synthesized compounds were docked in a heme sheet to explore their binding mode and possible interactions.

Findings/Results: β-Hematin inhibition assay showed acceptable activity for 7f, 7c, and 7d compounds and the molecular docking study showed 7h and 7f had effective interactions with the heme sheet. The cytotoxic study revealed compound 4b (IC50 = 18 µM) was significantly more active against PC12 cells than docetaxel (IC50 = 280 µM). The observations of cell uptake images were also shown both cell penetration and monitoring potential of synthesized compounds.

Conclusion and implications: The compounds showed a moderate ability to inhibition of heme polymerization and also good interaction with heme through molecular docking was observed. Additionally, some of them have a good cytotoxic effect on the study2 cell line. So further study on these compounds can lead to compounds that can be considered as anti-malarial and/or anticancer agents.

Keywords


Antimalarial activity; Anti-proliferative assay; β-hematin, Pyridinone derivatives.

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References


Chong CR, Sullivan DJ. Inhibition of heme crystal growth by antimalarials and other compounds: implications for drug discovery. Biochem Pharmacol. 2003;66(11):2201-2212.

DOI: 10.1016/j.bcp.2003.08.009.

Perez BC, Tixeira C, Figueiras M, Gut J, Rosenthal PJ, Gomes JRB, et al. Novel cinnamic acid/4-aminoquinoline conjugates bearing non-proteinogenic amino acids: towards the development of potential dual action antimalarials. Eur J Med Chem. 2012;54:887-899.

DOI: 10.1016/j.ejmech.2012.05.022.

Belete TM. Recent progress in the development of new antimalarial drugs with novel targets. Drug Des Devel Ther. 2020;14:3875-3889.

DOI: 10.2147/DDDT.S265602.

Egan TJ. Haemozoin formation. Mol Biochem Parasitol. 2008;157(2):127-136.

DOI: 10.1016/j.molbiopara.2007.11.005.

Fong KY, Wright DW. Hemozoin and antimalarial drug discovery. Future Med Chem. 2013;5(12):1437-1450.

DOI: 10.4155/fmc.13.113.

Phi LTH, Sari IN, Yang YG, Lee SH, Jun N, Kim KS, et al. Cancer stem cells (CSCs) in drug resistance and their therapeutic implications in cancer treatment. Stem Cells Int. 2018;2018:5416923.

DOI: 10.1155/2018/5416923.

Kamaludin NF, Zakaria SA, Awang N, Mohamad R, Pim NU. Cytotoxicity assessment of organotin(IV) (2-metoxyethyl) methyldithiocarbamate compounds in human leukemia cell lines. Orient J Chem. 2017;33(4):1756-1766.

DOI: 10.13005/ojc/330420.

Alama A, Viale M, Cilli M. In vitro cytotoxic activity of tri-n-butyltin(IV)lupinylsulfide hydrogen fumarate (IST-FS 35) and preliminary antitumor activity in vivo. Invest New Drugs. 2009;27:124-130.

DOI: 10.1007/s10637-008-9148-x.

Ito H. The formation of maltol and isomaltol through degradation of sucrose. Agric Biol Chem. 1977;41:1307-1308.

DOI: 10.1080/00021369.1977.10862669.

Yellamma K, Jyothi P. In silico approach for validation of maltol derivatives as acetylcholinesterase inhibitors. Int J Pharm Sci Rev Res. 2017;42(1):300-306.

Perokovic VP, Car Z, Usenik A, Opacak-Bernardi T, Juric A, Tomic S. Adamantyl pyran-4-one derivatives and their in vitro antiproliferative activity. Mol Diversity. 2020;24:253-263.

DOI: 10.1007/s11030-019-09948-1.

Jiang X, Guo J, Lv Y, Yao C, Zhang Ch, Mi Z, et al. Rational design, synthesis and biological evaluation of novel multitargeting anti-AD iron chelators with potent MAO-B inhibitory and antioxidant activity. Bioorg Med Chem. 2020;28(12):115550.

DOI: 10.1016/j.bmc.2020.115550.

Pergola PE, Kopyt NP. Oral ferric maltol for the treatment of iron-deficiency anemia in patients with CKD: a randomized trial and open-label extension. Am J Kidney Dis. 2021;78(6):846-856.e1.

DOI: 10.1053/j.ajkd.2021.03.020.

Sabet R, Fassihi A, Hemmateenejad B, Saghaei L, Miri R, Gholami M. Computer-aided design of novel antibacterial 3-hydroxypyridine-4-ones: application of QSAR methods based on the MOLMAP approach. J Comput Aided Mol Des. 2012;26(3):349-361.

DOI: 10.1007/s10822-012-9561-2.

Heppner DG, Kontoghiorghes G, Kontoghiorghes GJ, Eaton JW. Antimalarial properties of orally active iron chelators. Blood. 1988;72(1):358-361.

PMID: 3291984.

Jiang X, Zhou T, Bai R, Xie Y. Hydroxypyridinone-based iron chelators with broad-ranging biological activities. J Med Chem. 2020;63(23):14470-14501.

DOI: 10.1021/acs.jmedchem.0c01480.

Li W, Su X, Han Y, Xu Q, Zhang J, Wang Z, et al. Maltol, a Maillard reaction product, exerts anti-tumor efcacy in H22 tumor-bearing mice via improving immune function and inducing apoptosis. RSC Adv. 2015;5:101850-101859.

DOI: 10.1039/C5RA17960B.

Reddy VD, Dayal D, Szalda DJ, Cosenza SC, Reddy MVR. Syntheses, structures, and anticancer activity of novel organometallic ruthenium-maltol complexes. J Organomet Chem. 2012;700:180-187.

DOI: 10.1016/j.jorganchem.2011.12.011.

Kandioller W, Hartinger CG, Nazarov AA, Kasser J, John R, Jakupec MA, et al. Tuning the anticancer activity of maltol-derived ruthenium complexes by derivatization of the 3-hydroxy-4-pyrone moiety. J Organomet Chem. 2009;694:922-929.

DOI: 10.1016/j.jorganchem.2008.10.016.

Fayyazi N, Esmaeili S, Taheri S, Ribeiro FF, Scotti MT, Scotti L, et al. Pharmacophore modeling, synthesis, scaffold hopping and biological β-Hematin inhibition interaction studies for anti-malaria compounds. Curr Top Med Chem. 2019;19(30):2743-2765.‏

DOI: 10.2174/1568026619666191116160326.

Andayi WA, Egan TJ, Chibale K. Kojic acid derived hydroxypyridinone-chloroquine hybrids: synthesis, crystal structure, antiplasmodial activity and β-haematin inhibition. Bioorg Med Chem Lett. 2014;24(15):3263-3267.

DOI: 10.1016/j.bmcl.2014.06.012.

Andayi WA, Egan TJ, Gut J, Rosenthal PJ, Chibale K. Synthesis, antiplasmodial activity, and β-hematin inhibition of hydroxypyridone-chloroquine hybrids. ACS Med Chem Lett. 2013;4(7):642-646.

DOI: 10.1021/ml4001084.

Rablen PR. Is the acetate anion stabilized by resonance or electrostatics? A systematic structural comparison. J Am Chem Soc. 2000;122(2):357-368.

DOI: 10.1021/ja9928475.

Beddard G, Carlin S, Harris L, Porter G, Tredwell C. Quenching of chlorophyll fluorescence by Nitrobenzene. Photochem Photobiol. 1978;27(4):433-438.

DOI: 10.1111/j.1751-1097.1978.tb07625.x.

Chernysheva MV, Bulatova M, Ding X, Haukka M. Influence of substituents in the aromatic ring on the strength of halogen bonding in iodobenzene derivatives. Cryst Growth Des. 2020;20:7197-7210.

DOI: 10.1021/acs.cgd.0c00866.

Salvatella L. The alkyl group is a –I + R substituentEl grupo alquilo es un sustituyente –I + R. Educación Química. 2017;28(4):232-237.

DOI: 10.1016/j.eq.2017.06.004.

Priimagi A, Cavallo G, Metrangolo P, Resnati G. The halogen bond in the design of functional supramolecular materials: recent advances. Acc Chem Res. 2013;46(11):2686-2695.

DOI: 10.1021/ar400103r.

Sciortino A, Pecorella R, Cannas M, Messina F. Effect of halogen ions on the photocycle of fluorescent carbon nanodots. C J Carbon Res. 2019;5(4):64-73.

DOI: 10.3390/c5040064.

Hameed A, Masood S, Hameed A, Ahmed E, Sharif A, Abdullah MI. Anti-malarial, cytotoxicity and molecular docking studies of quinolinyl chalcones as potential anti-malarial agent. J Comput Aided Mol Des. 2019;33(7):677-688.

DOI: 10.1007/s10822-019-00210-2.

Alson SG, Jansen O, Cieckiewicz E, Rakotoarimanana H, Rafatro H, Degotte G, et al. In‐vitro and in-vivo antimalarial activity of caffeic acid and some of its derivatives. J Pharm Pharmacol. 2018;70(10):1349-1356.

DOI: 10.1111/jphp.12982 .

Serafim TL, Carvalho FS, Marques MP, Calheiros R, Silva T, Garrido J, et al. Lipophilic caffeic and ferulic acid derivatives presenting cytotoxicity against human breast cancer cells. Chem Res Toxicol. 2011;24(5):763-764.

DOI: 10.1021/tx200126r.

Sheikhmoradi V, Saberi S, Saghaei L, Pestehchian N, Fassihi A. Synthesis and antileishmanial activity of antimony (V) complexes of hydroxypyranone and hydroxypyridinone ligands. Res Pharm Sci. 2018;13(2):111-120.

DOI: 10.4103/1735-5362.223793.

Ugarte-Uribe B, Perez-Rentero S, Lucas R, Avinno A, Reina JJ, Alkorta I, et al. Synthesis, cell-surface binding, and cellular uptake of fluorescently labeled glucose-DNA conjugates with different carbohydrate presentation. Bioconjug Chem. 2010;21(7):1280-1287.

DOI: 10.1021/bc100079n.

Momany FA, Rone R. Validation of the general purpose QUANTA® 3.2/CHARMm® force field. J Comput Chem. 1992;13(7):888-900.

DOI: 10.1002/JCC.540130714.

Ghasemi JB, Aghaee E, Jabbari A. Docking, CoMFA and CoMSIA studies of a series of N-benzoylated phenoxazines and phenothiazines derivatives as antiproliferative agents. Bull Korean Chem Soc. 2013;34(3):899-906.

DOI: 10.5012/bkcs.2013.34.3.899.


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