Synthesis of New Indazole Analogs of Curcumin as Antioxidant and Anti-inflammatory Candidates: An  In Vitro  Investigation

Hariyanti Hariyanti; Hayun Hayun; Arry Yanuar; Azminah Azminah

doi:10.22146/ijc.82443

Synthesis of New Indazole Analogs of Curcumin as Antioxidant and Anti-inflammatory Candidates: An In Vitro Investigation

https://doi.org/10.22146/ijc.82443

Hariyanti Hariyanti^(1*), Hayun Hayun⁽²⁾, Arry Yanuar⁽³⁾, Azminah Azminah⁽⁴⁾

(1) Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Science, Universitas Muhammadiyah Prof. Dr. HAMKA, Jl. Delima II/IV, Jakarta Timur 13460, Indonesia
(2) Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Indonesia, Jl. Lingkar Kampus Raya, Pondok Cina, Depok 16424, Indonesia
(3) Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Indonesia, Jl. Lingkar Kampus Raya, Pondok Cina, Depok 16424, Indonesia
(4) Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Surabaya, Jl. Ngagel Jaya Selatan 169, Surabaya 60284, Indonesia
(*) Corresponding Author

Abstract

The development of analog curcumin compounds by modifying the structure of monocarbonyl into an analog indazole of curcumin (AIC) is recognized to have a great potential. Still, only a few reports have been available. Rarely occurring in nature, indazole molecules are typically created through chemical synthesis. Therefore, this study aimed to synthesize six new AIC compounds with a particular focus on testing in vitro antioxidant activity using the DPPH and FRAP methods, as well as anti-inflammatory activity using the protein denaturation method. The results showed that the compounds formed had high anti-inflammatory activity but low antioxidant activity. All synthesis products produced higher anti-inflammatory activity than standard diclofenac sodium and curcumin compounds. Specifically, compound 3a showed the highest anti-inflammatory activity with an IC₅₀ = 0.548 ± 0.062 μM. Therefore, it was concluded that compound 3a has the potential to be further studied for anti-inflammatory activity.

Keywords

analog indazole curcumin; anti-inflammatory; antioxidant; in vitro

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References

[1] Bayomi, S.M., El-Kashef, H.A., El-Ashmawy, M.B., Nasr, M.N.A., El-Sherbeny, M.A., Badria, F.A., Abou-zeid, L.A., Ghaly, M.A., and Abdel-Aziz, N.I., 2013, Synthesis and biological evaluation of new curcumin derivatives as antioxidant and antitumor agents, Med. Chem. Res., 22 (3), 1147–1162.

[2] Bayomi, S.M., El-Kashef, H.A., El-Ashmawy, M.B., Nasr, M.N.A., El-Sherbeny, M.A., Abdel-Aziz, N.I., El Sayed, M.A.A., Suddek, G.M., El-Messery, S.M., and Ghaly, M.A., 2015, Synthesis and biological evaluation of new curcumin analogs as antioxidant and antitumor agents: Molecular modelling study, Eur. J. Med. Chem., 101, 584–594

[3] Urošević, M., Nikolić, L., Gajić, I., Nikolić, V., Dinić, A., and Miljković, V., 2022, Curcumin: Biological activities and modern pharmaceutical forms, Antibiotics, 11 (2), 135.

[4] Peng, Y., Ao, M., Dong, B., Jiang, Y., Yu, L., Chen, Z., Hu, C., and Xu, R. 2021, Anti-inflammatory effects of curcumin in the inflammatory diseases: Status, limitations, and countermeasures, Drug Des., Dev. Ther., 15, 4503–4525.

[5] Shen, L., Liu, C.C., An, C.Y., and Ji, H.F., 2016, How does curcumin work with poor bioavailability? Clues from experimental and theoretical studies, Sci. Rep., 6 (1), 20872.

[6] Chopra, H., Dey, P.S., Das, D., Bhattacharya, T., Shah, M., Mubin, S., Maishu, S.P., Akter, R., Rahman, M.H., Karthika, C., Murad, W., Qusty, N., Qusti, S., Alshammari, E.M., Batiha, G.E., Altalbawy, F.M.A., Albooq, M.I.M., and Alamri, B.M., 2021, Curcumin nanoparticles as promising therapeutic agents for drug targets, Molecules, 26 (16), 4998.

[7] Ubeyitogullari, A., and Ciftci, O.N., 2019, A novel and green nanoparticle formation approach to forming low-crystallinity curcumin nanoparticles to improve curcumin’s bioaccessibility, Sci. Rep., 9 (1), 19112.

[8] Hariyanti, H., Yanuar, A., Kusmardi, K., and Hayun, H., 2020, (7E)‐3‐(4‐Methoxyphenyl)‐7‐[(4‐methoxyphenyl)methylidene]‐4,5,6,7‐tetrahydro‐3aH‐indazole, Molbank, 2020 (4), M1162.

[9] Hariyanti, H., Kusmardi, K., Yanuar, A., and Hayun, H., 2022, Synthesis and in vitro cytotoxic activity of novel indazole analogs of curcumin against MCF-7, HeLa, WiDr, and vero cell lines, J. Appl. Pharm. Sci., 12 (4), 179–184.

[10] Zhang, S.G., Liang, C.G., and Zhang, W.H., 2018, Recent advances in indazole-containing derivatives: Synthesis and biological perspectives, Molecules, 23 (11), 2783.

[11] Gaikwad, D.D., Chapolikar, A.D., Devkate, C.G., Warad, K.D., Tayade, A.P., Pawar, R.P., and Domb, A.J., 2015, Synthesis of indazole motifs and their medicinal importance: An overview, Eur. J. Med. Chem., 90, 707–731.

[12] Shrivastava, A., Chakraborty, A.K., Upmanyu, N., and Singh, A., 2016, Recent progress in chemistry and biology of indazole and its derivatives: A brief review, Austin J. Anal. Pharm. Chem., 3 (4), 1076.

[13] Cheekavolu, C., and Muniappan, M., 2016, in vivo and in vitro anti-inflammatory activity of indazole and its derivatives, J. Clin. Diagn. Res., 10 (9), FF01–FF06.

[14] Pérez-Villanueva, J., Yépez-Mulia, L., González-Sánchez, I., Palacios-Espinosa, J.F., Soria-Arteche, O., Sainz-Espuñes, T.D.R., Cerbón, M.A., Rodríguez-Villar, K., Rodríguez-Vicente, A.K., Cortés-Gines, M., Custodio-Galván, Z., and Estrada-Castro, D.B., 2017, Synthesis and biological evaluation of 2H-indazole derivatives: Towards antimicrobial and anti-Inflammatory dual agents, Molecules, 22 (11), 1864.

[15] Fakri Mustafa, Y., Riyadh Khalil, R., Tareq Mohammed, E., Bashir, M.K., and Khudhayer Oglah, M., 2021, Effects of structural manipulation on the bioactivity of some coumarin-based products, Arch. Razi Inst., 76 (5), 1297–1305.

[16] Wongrakpanich, S., Wongrakpanich, A., Melhado, K., and Rangaswami, J., 2018, A Comprehensive Review of Non-Steroidal Anti-Inflammatory Drug Use in The Elderly, Aging Dis., 9 (1), 143–150.

[17] Hariyanti, H., Kusmardi, K., Yanuar, A., and Hayun, H., 2021, Ligand-based pharmacophore modeling, virtual screening, and molecular docking studies of asymmetrical hexahydro-2H-indazole analogs of curcumin (AIACs) to discover novel estrogen receptors alpha (ERα) inhibitor, Indones. J. Chem., 21 (1), 137–147.

[18] Jasim, S.F., and Mustafa, Y.F., 2022, Synthesis and antidiabetic assessment of new coumarin-disubstituted benzene conjugates: An in silico–in virto study, J. Med. Chem. Sci., 5 (6), 887–899.

[19] Derbel, H., Elleuch, J., Mahfoudh, W., Michaud, P., Fendri, I., and Abdelkafi, S., 2023, In vitro antioxidant and anti-inflammatory activities of bioactive proteins and peptides from Rhodomonas sp., Appl. Sci., 13 (5), 3202.

[20] Rahmawati, N., Saputri, F.C., Hariyanti, H., and Hayun, H., 2020, Synthesis and preliminary in vitro anti-inflammatory evaluation of Mannich bases derivatives of 4’-methoxy-substituted of asymmetrical cyclovalone analogs, Indones. J. Pharm., 31 (1), 35–41.

[21] Sari, I.P., Yanuar, A., Hariyanti, H., Yanuar, A., and Hayun, H., 2021, New decahydroacridine-1,8-diones derived from 3-aminocyclohex-2-en-1-one: Synthesis, characterization, antioxidant, in-vitro, and in-silico anti-inflammatory activity, Rasayan J. Chem., 15 (2), 1241–1248.

[22] Jasim, S.F., and Mustafa, Y.F., 2022, Synthesis, ADME study, and antimicrobial evaluation of novel naphthalene-based derivatives, J. Med. Chem. Sci., 5 (5), 793–807.

[23] Francenia Santos-Sánchez, N., Salas-Coronado, R., Villanueva-Cañongo, C., and Hernández-Carlos, B., 2019, “Antioxidant Compounds and Their Antioxidant Mechanism” in Antioxidants, Eds. Shalaby, E., IntechOpen, Rijeka, Croatia, 1–28.

[24] Alam, M.N., Bristi, N.J., and Rafiquzzaman, M., 2013, Review on in vivo and in vitro methods evaluation of antioxidant activity, Saudi Pharm. J., 21 (2), 143–152.

[25] Sardjiman, S.S., Reksohadiprodjo, M.S., Hakim, L., van der Goot, H., and Timmerman, H., 1997, 1,5-Diphenyl-1,4-pentadiene-3-ones and cyclic analogs as antioxidative agents. Synthesis and structure-activity relationship, Eur. J. Med. Chem., 32 (7-8), 625–630

[26] Leelaprakash, G., and Mohan Dass, S., 2011, Invitro anti-inflammatory activity of methanol extract of Enicostemma axillare, Int. J. Drug Dev. Res., 3 (3), 189–196.

[27] Yang, H., Du, Z., Wang, W., Song, M., Sanidad, K., Sukamtoh, E., Zheng, J., Tian, L., Xiao, H., Liu, Z., and Zhang, G. 2017, Structure-activity relationship of curcumin: Role of the methoxy group in anti-inflammatory and anticolitis effects of curcumin, J. Agric. Food Chem., 65 (22), 4509–4515.

DOI: https://doi.org/10.22146/ijc.82443