Synthesis, Molecular Docking, and Evaluation of Some New Curcumin Analogs as Antimalarial Agents

Endang Astuti; Tri Joko Raharjo; Putra Boang Manalu; Ilham Satria Putra; Stephanus Satria Waskitha; Junita Solin

doi:10.22146/ijc.57646

Synthesis, Molecular Docking, and Evaluation of Some New Curcumin Analogs as Antimalarial Agents

https://doi.org/10.22146/ijc.57646

Endang Astuti^(1*), Tri Joko Raharjo⁽²⁾, Putra Boang Manalu⁽³⁾, Ilham Satria Putra⁽⁴⁾, Stephanus Satria Waskitha⁽⁵⁾, Junita Solin⁽⁶⁾

(1) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, 55281 Yogyakarta, Indonesia
(2) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, 55281 Yogyakarta, Indonesia
(3) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, 55281 Yogyakarta, Indonesia
(4) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, 55281 Yogyakarta, Indonesia
(5) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, 55281 Yogyakarta, Indonesia
(6) Department of Agronomy, Faculty of Agriculture, Universitas Gadjah Mada, Jl. Flora, Yogyakarta 55821, Indonesia
(*) Corresponding Author

Abstract

This research involves the synthesis, antimalarial evaluation, and molecular docking of several curcumin analogs. A total of six curcumin analog compounds were synthesized using aldol condensation using hydrochloric acid and sodium hydroxide catalysts. The synthesized compounds were elucidated using FTIR, ¹H-NMR, ¹³C-NMR, and LC-MS/MS. Subsequently, all curcumin analogs were tested as an antimalarial agent against Plasmodium falciparum 3D7 strain, and their mechanism of action was evaluated through a molecular docking study. Six curcumin analogs, i.e. 2,6-bis(2-hydroxybenzylidene)cyclohexanone; 2,6-bis(2-hydroxybenzylidene)cyclopentanone; 1.5-bis(2-hydroxyphenyl)penta-1,4-diene-3-one; 2,6-bis(3-hydroxybenzylidene)cyclo-hexanone; 2,6-bis(3-hydroxybenzylidene)cyclopentanone; and 1,5-bis(3-hydroxy-phenyl)penta-1,4-diene-3-one have been successfully synthesized. In addition, 2,6-bis(2-hydroxybenzylidene) cyclopentanone demonstrated the lowest IC₅₀ value and binding affinity of 0.04 µM and -7.6 kcal/mol, respectively. Based on molecular docking studies, this compound also showed the most potent antimalarial activity targeted at PfATP6.

Keywords

curcumin analogs; antiplasmodium; aldol condensation; molecular docking

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References

[1] Ministry of Health Republic of Indonesia, 2015, Indonesia Health Profile, Ministry of Health RI, Jakarta, Indonesia.

[2] Arnou, B., Montingny, C., Morth, J.P., Nissen, P., Jaxel, C., Møller, J.V., and le Maire, M., 2011, The Plasmodium falciparum Ca²⁺ ATPase PfATP6 Insensitive to artemisinin, but a potential drug target, Biochem. Soc. Trans., 39 (3), 823–831.

[3] Soni, R., Sharma, D., Rai, P., Sharma, B., and Bhatt, T.K., 2017, Signalling strategies of malaria parasite for its survival, proliferation, and infection during erythrocytic stage, Front. Immunol., 8, 349.

[4] Brochet, M., and Billker, O., 2016, Calcium signalling in malaria parasites, Mol. Microbiol., 100 (3), 397–408.

[5] Ji, H.F., and Shen, L., 2009, Interactions of curcumin with the PfATP6 model and the implications for its antimalarial mechanism, Bioorg. Med. Chem. Lett., 19 (9), 2453–2455.

[6] Moncoq, K., Trieber, C.A., and Young, H.S., 2007, The Molecular Basis for Cyclopiazonic Acid inhibition of the Sarcoplasmic Reticulum Calcium Pump, J. Biol. Chem., 282 (13), 9784–9757.

[7] Coma-Cros, E.M., Biosca, A., Lantero, E., Manca, M.L., Caddeo, C., Gutiérrez, L., Ramírez, M., Borgheti-Cardoso, L.N., Manconi, M., and Fernández-Busquets, X., 2018, Antimalarial activity of orally administered curcumin incorporated in Eudragit®-containing liposomes, Int. J. Mol. Sci., 19 (5), 1361.

[8] Kim, Y.J., Lee, H.J., and Shin, Y., 2013, Optimization and validation of high-performance liquid chromatography method for individual curcuminoids in tumeric by heat-refluxed extraction, J. Agric. Food Chem., 61 (46), 10911–10918.

[9] Manohar, S., Khan, S.I., Kandi, S.K., Raj, K., Sun, G., Yang, X., Molina, A.D.C., Ni, N., Wang, B., and Rawat, D.S., 2013, Synthesis antimalarial activity and cytotoxic potential of new monocarbonyl analogues of curcumin, Bioorg. Med. Chem. Lett., 23 (1), 112–116.

[10] Kumavat, S.D., Chaudhari, Y.S., Borole, P., Mishra, P., Shenghani, K., and Duvvuri, P., 2013, Degradation studies of curcumin, IJPRR, 3 (2), 50-55.

[11] Pana, A.M., Badea, V., Bănică, R., Bora, A., Dudas, Z., Cseh, L., and Costisor, O., 2014, Network reaction of 2,6-bis(2-hydroxybenzylidene)cyclohexanone by external stimuli, J. Photochem. Photobiol., A, 283, 22–28.

[12] Persittamaia, I., 2018, Sintesis dan Uji Aktivitas Antibakteri Senyawa Analog Kurkumin 2,6-bis-(3’-hidroksibenziliden)-sikloheksanon, Undergraduate Thesis, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta.

[13] Thomas, J.A., Collins, C.R., Das, S., Hackett, F., Graindorge, A., Bell, D., Deu, E., and Blackman, M.J., 2016, Development and application of a simple plaque assay for the human malaria parasite Plasmodium falciparum, PLoS One, 11 (6), e0157873.

[14] Basco, L.K., 2007, Field Application of in vitro Assays for the Sensitivity of Human Malaria Parasites to Antimalarial Drugs, World Health Organization, France.

[15] Pranowo, H.D., and Hetadi, A.K.R., 2011, Pengantar Kimia Komputasi, Lubuk Agung, Bandung, Indonesia.

[16] Forli, S., Huey, R., Pique, M.E., Sanner, M.F., Goodsell, D.S., and Olson, A.J., 2016, Computational protein–ligand docking and virtual drug screening with the AutoDock suite, Nat. Protoc., 11 (5), 905–919.

[17] Mena-Ulecia, K., Tiznado, W., and Caballero, J., 2015, Study of the differential activity of thrombin inhibitors using docking, QSAR, molecular dynamics, and MM-GBSA, PLOS One, 10 (11), e0142774.

[18] Kamaraj, C., Kaushik, N.K., Mohanakrishnan, D., Elango, G., Bagavan, A., Zahir, A.A., Rahuman, A.A., and Sahal, D., 2012, Antiplasmodial potential of medicinal plant extracts from Malaiyur and Javadhu hills of South India, Parasitol. Res., 111 (2), 703–715.

[19] Dohutia, C., Chetia, D., Gogoi, K., Bhattacharyya, D.R., and Sarma, K., 2017, Molecular docking, synthesis, and in vitro antimalarial evaluation of certain novel curcumin analogues, Braz. J. Pharm. Sci., 53 (4), e00084.

[20] Chen, D., Oezguen, N., Urvil, P., Ferguson, C., Dann, S.M., and Savidge, T.C., 2016, Regulation of protein-ligand binding affinity by hydrogen bond pairing, Sci. Adv., 2 (3), e1501240.

[21] Makwana, K.M., and Mahalakshmi, R., 2015, Implications of aromatic-aromatic interactions: From protein structures to peptide models, Protein Sci., 24 (12), 1920–1933.

DOI: https://doi.org/10.22146/ijc.57646