Sains Malaysiana 49(11)(2020): 2667-2677

http://dx.doi.org/10.17576/jsm-2020-4911-06

Design, Synthesis and Biological Evaluation of Aminoalkylated Chalcones as Antimalarial Agent

(Reka Bentuk, Sintesis dan Penilaian Biologi ke atas Aminoteralkil Kalkon sebagai Agen Antimalaria)

JUFRIZAL SYAHRI¹*, HASMALINA NASUTION¹, BETA ACHROMI NUROHMAH², BAMBANG PURWONO², EMMY YUANITA³, NUR HANIS ZAKARIA⁴ & NURUL IZZATY HASSAN⁴

¹Department of Chemistry, Universitas Muhammadiyah Riau, Jalan Tuanku Tambusai Ujung Nomor 1, Pekanbaru, Indonesia

²Department of Chemistry, Universitas Gadjah Mada, Jalan Kaliurang Sekip Utara Bulaksumur 21, 55281, Yogyakarta, Indonesia

³Department of Chemistry, Universitas Mataram, Jalan Majapahit 62A, Mataram, Indonesia

⁴Department of Chemical Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 UKM Bangi, Selangor Darul Ehsan, Malaysia

Diserahkan: 10 April 2020/Diterima: 28 Mei 2020

Abstract

Aminoalkylated chalcone compounds (4a-4c) have been designed using Quantitative Structure-Activity Relationship (QSAR) analysis, synthesized and evaluated for theirin vitro antimalarial activity. The best QSAR model obtained was log IC₅₀ = 705.132 (qC7) - 65.573 (qC3) - 24.845 (qC4) - 4.634 (qC13) - 220.479 and statistical analysis showed R² of 0.937, suggesting that the QSAR model was able to predict the actual antimalarial activity by 93.7% accuracy. The addition of secondary amines to the chalcone compounds was successfully carried out using the Mannich reaction, which was confirmed by spectroscopic analysis. The in vitro antimalarial activity of the synthesized compounds were screened against the 3D7 strain of Plasmodium falciparum (CQ sensitive). All of the compounds exhibited strong activity with IC₅₀ values ranging from 0.54 ± 0.649 to 1.12 ± 0.369 µM. The molecular docking studies investigated interactions of the prepared compounds to the binding site of wild-type Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (Pf-DHFR-TS) (PDB ID: IJ3I) and quadruple mutant Pf-DHFR-TS (PDB ID: IJ3K). Some hydrogen bond and π – π interactions were observed with the side chain of Ala16, Asp54, Cys15, Leu164, Tyr170, and Met55 in both the wild and mutant Pf-DHFR types. It has also been found that all the tested compounds were obeyed the Lipinski’s rule. This study proposed that compound 4b can be developed as the new lead of the antimalarial agent.

Keywords: Antimalarial; chalcone; Mannich reaction; molecular docking; QSAR

Abstrak

Sebatian aminoteralkil kalkon (4a-4c) telah direka bentuk menggunakan analisis Hubungan Struktur-Aktiviti Kuantitatif (QSAR) telah disintesis dan dinilai untuk aktiviti antimalaria secara in vitro. Model QSAR terbaik yang diperoleh adalah log IC₅₀ = 705.132 (qC7)-65.573 (qC3)-24.845 (qC4)-4.634 (qC13)-220.479 dan analisis statistik menunjukkan R² sebanyak 0.937, seterusnya mencadangkan bahawa model QSAR ini berupaya untuk meramalkan aktiviti antimalaria sebenar dengan ketepatan 93.7%. Penambahan amina sekunder telah dijalankan menggunakan tindak balas Mannich dan disahkan melalui analisis spektroskopi. Kesemua sebatian disaring menentang strain Klorokuina-sensitif (3D7) Plasmodium falciparum. Semua sebatian menunjukkan aktiviti baik dengan nilai IC₅₀ antara 0.54 ± 0.649 sehingga 1.12 ± 0.369 μM. Interaksi sebatian ini juga dikaji melalui kajian dok pada tapak pengikatan protein jenis liar Pf-DHFR-TS (PDB ID: IJ3I) dan mutan Pf-DHFR-TS (PDB ID: IJ3K). Ikatan hidrogen dan interaksi π-π sebatian dengan rantai sisi asid amino Ala16, Asp54, Cys15, Leu164, Tyr170 dan Met55 jelas diperhatikan pada kedua-dua protein tersebut. Sebatian yang dikaji ini juga didapati mematuhi peraturan Lipinski. Potensi aktiviti antimalaria yang ditunjukkan oleh sebatian 4b mampu dibangunkan sebagai sebatian utama.

Kata kunci: Antimalaria; kajian dok; kalkon; QSAR; tindak balas Mannich

RUJUKAN

Ashley, E.A., Dhorda, M., Fairhurst, R.M., Amaratunga, C., Lim, P., Suon, S., Sreng, S., Anderson, J.M., Mao, S., Sam, B., Sopha, C., Chuor, C.M., Nguon, C., Sovannaroth, S., Pukrittayakamee, S., Jittamala, P., Chotivanich, K., Chutasmit, K., Suchatsoonthorn, C., Runcharoen, R., Hien, T.T., Thuy-Nhien, N.T., Thanh, N.V., Phu, N.H., Htut, Y., Han, K.T., Aye, K.H., Mokuolu, O.A., Olaosebikan, R.R., Folaranmi, O.O., Mayxay, M., Khanthavong, M., Hongvanthong, B., Newton, P.N., Onyamboko, M.A., Fanello, C.I., Tshefu, A.K., Mishra, N., Valecha, N., Phyo, A.P., Nosten, F., Yi, P., Tripura, R., Borrmann, S., Bashraheil, M., Peshu, J., Faiz, M.A., Ghose, A., Hossain, M.A., Samad, R., Rahman, M.R., Hasan, M.M., Islam, A., Miotto, O., Amato, R., Maclnnis, B., Stalker, J., Kwiatkowski, D.P., Bozdech, Z., Jeeyapant, A., Cheah, P.Y., Sakulthaew, T., Chalk, J., Intharabut, B., Silamut, K., Lee, S.J., Vihokhern, B., Kunasol, C., Imwong, M., Tarning, J., Taylor, W.J., Yeung, S., Woodrow, C.J., Flegg, JA, Das, D., Smith, J., Venkatesan, M., Plowe, C.V., Stepniewska, K., Guerin, P.J., Dondorp, A.M., Day, N.P. & White, N.J. 2014. Spread of artemisinin resistance in Plasmodium falciparum malaria. The New England Journal of Medicine 371(5): 411-423.

Batista, R., de Jesus Silva Júnior, A. & de Oliveira, A.B. 2009. Plant-derived antimalarial agents: New leads and efficient phytomedicines. part II. non-alkaloidal natural products. Molecules 14(8): 3037-3072.

Bhasin, V.K. & Nair, L. 2003. ACT now-with caution-for malaria treatments. The Lancet Infectious Diseases 3(10): 609.

Cáceres-Castillo, D., Carballo, R.M., Quijano-Quiñones, R., Mirón-López, G., Graniel-Sabido, M., Moo-Puc, R.E. & Mena-Rejón, G.J. 2020. Synthesis, in vitro antigiardial activity, SAR analysis and docking study of substituted chalcones. Medicinal Chemistry Research 29(3): 431-441.

Chen, M., Theander, T.G., Christensen, S.B., Hviid, L., Zhai, L. & Kharazmi, A. 1994. Licochalcone A, a new antimalarial agent, inhibits in vitro growth of the human malaria parasite Plasmodium falciparum and protects mice from P. yoelii infection. Antimicrobial Agents and Chemotherapy 38(7): 1470-1475.

Cui, L., Wang, Z., Miao, J., Miao, M., Chandra, R., Jiang, H., Su, X.Z. & Cui, L. 2012. Mechanisms of in vitro resistance to dihydroartemisinin in Plasmodium falciparum. Molecular Microbiology 86(1): 111-128.

Dan, W. & Dai, J. 2020. Recent developments of chalcones as potential antibacterial agents in medicinal chemistry. European Journal of Medicinal Chemistry 187: 111980.

Elkhalifa, D., Siddique, A.B., Qusa, M., Cyprian, F.S., El Sayed, K., Alali, F., Al Moustafa, A.E. & Khalil, A. 2020. Design, synthesis, and validation of novel nitrogen-based chalcone analogs against triple negative breast cancer. European Journal of Medicinal Chemistry 187: 111954.

Frimayanti, N., Yam, M.L., Lee, H.B., Othman, R., Zain, S.M. & Rahman, N.A. 2011. Validation of quantitative structure-activity relationship (QSAR) model for photosensitizer activity prediction. International Journal of Molecular Sciences 12(12): 8626-8644.

Golbraikh, A., Shen, M., Xiao, Z., Xiao, Y.D., Lee, K.H. & Tropsha, A. 2003. Rational selection of training and test sets for the development of validated QSAR models. Journal of Computer-Aided Molecular Design 17(2-4): 241-253.

Jain, S.V., Ghate, M., Bhadoriya, K.S., Bari, S.B., Chaudhari, A. & Borse, J.S. 2012. 2D, 3D-QSAR and docking studies of 1, 2, 3-thiadiazole thioacetanilides analogues as potent HIV-1 non-nucleoside reverse transcriptase inhibitors. Organic and Medicinal Chemistry Letters 2(1): 22.

Jayaram, B., Singh, T., Mukherjee, G., Mathur, A., Shekhar, S. & Shekhar, V. 2012. Sanjeevini: A freely accessible web-server for target directed lead molecule discovery. BMC Bioinformatics 13: S7.

Jyoti, G.R., Kumar, Y., Cheema, H.S., Kapkoti, D.S., Darokar, M.P., Khan, F. & Bhakuni, R.S. 2019. Synthesis, molecular modelling studies of indolyl chalcone derivatives and their antimalarial activity evaluation. Natural Product ResearchDOI: 10.1080/14786419.2019.1696788T.

Kalita, J., Chetia, D. & Rudrapal, M. 2019. Molecular docking, dug-likeness studies and ADMET prediction of quinoline imines for antimalarial activity. Journal of Medicinal Chemistry and Drug Design 2(1): 1-7.

Khan, S.A., Asiri, A.M., Al-Ghamdi, N.S.M., Asad, M., Zayed, M.E., Elroby, S.A., Aqlan, F.M., Wani, M.Y. & Sharma, K. 2019. Microwave assisted synthesis of chalcone and its polycyclic heterocyclic analogues as promising antibacterial agents: in vitro, in silico and DFT studies. Journal of Molecular Structure 1190: 77-85.

Lipinski, C.A., Lombardo, F., Dominy, B.W. & Feeney, P.J. 1997. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews 23(1-3): 3-25.

Modak, V.P., Pathak, H., Thayer, M., Singer, S.J. & Wyslouzil, B.E. 2013. Experimental evidence for surface freezing in supercooled n-alkane nanodroplets. Physical Chemistry Chemical Physics 15(18): 6783-6795.

Motta, L.F. & Almeida, W.P. 2011. Quantitative structure-activity relationships (QSAR) of a series of ketone derivatives as anti-Candida albicans. International Journal of Drug Discovery 3(2): 100-117.

Quaglio, D., Zhdanovskaya, N., Tobajas, G., Cuartas, V., Balducci, S., Christodoulou, M.S., Fabrizi, G., Gargantilla, M., Priego, E.M., Carmona Pestaña, A. & Passarella, D. 2019. Chalcones and chalcone-mimetic derivatives as Notch inhibitors in a model of T-cell acute lymphoblastic leukemia. ACS Medicinal Chemistry Letters 10(4): 639-643.

Rammohan, A., Bhaskar, B.V., Venkateswarlu, N., Gu, W. & Zyryanov, G.V. 2020. Design, synthesis, docking and biological evaluation of chalcones as promising antidiabetic agents. Bioorganic Chemistry 95: 103527.

Rieckmann, K.H., Campbell, G.H., Sax, L.J. & Ema, J.E. 1978. Drug sensitivity of Plasmodium falciparum: an in-vitro microtechnique. The Lancet 311(8054): 22-23.

Shin, J., Jang, M.G., Park, J.C., Do Koo, Y., Lee, J.Y., Park, K.S., Chung, S.S. & Park, K. 2018. Antidiabetic effects of trihydroxychalcone derivatives via activation of AMP-activated protein kinase. Journal of Industrial and Engineering Chemistry 60: 177-184.

Sibley, C.H. 2015. Understanding artemisinin resistance. Science 347(6220): 373-374.

Suwito, H., Jumina Mustofa, Pudjiastuti, P., Fanani, M.Z., Kimata-Ariga, Y., Katahira, R., Kawakami, T., Fujiwara, T., Hase, T., Sirat, H.M. & Puspaningsih, N.N.T. 2014. Design and synthesis of chalcone derivatives as inhibitors of the ferredoxin - ferredoxin-NADP+ reductase interaction of Plasmodium falciparum: Pursuing new antimalarial agents. Molecules 19(12): 21473-21488.

Syahri, J., Yuanita, E., Nurohmah, B.A., Armunanto, R. & Purwono, B. 2017a. Chalcone analogue as potent anti-malarial compounds against Plasmodium falciparum: Synthesis, biological evaluation, and docking simulation study. Asian Pacific Journal of Tropical Biomedicine 7(8): 675-679.

Syahri, J., Rullah, K., Armunanto, R., Yuanita, E., Nurohmah, B.A., Aluwi, M.F.F.M., Wai, L.K. & Purwono, B. 2017b. Synthesis, biological evaluation, QSAR analysis, and molecular docking of chalcone derivatives for antimalarial activity. Asian Pacific Journal of Tropical Disease 7(1): 8-13.

Syahri, J., Purwono, B. & Armunanto, R. 2016. Design of new potential antimalaria compound based on QSAR analysis of chalcone derivatives. International Journal of Pharmaceutical Sciences Review and Research 36(2): 71-76.

Triglia, T., Thompson, J., Caruana, S.R., Delorenzi, M., Speed, T. & Cowman, A.F. 2001. Identification of proteins from Plasmodium falciparumthat are homologous to reticulocyte binding proteins in Plasmodium vivax. Infection and Immunity 69(2): 1084-1092.

Tuncel, S., Trivella, A., Atilla, D., Bennis, K., Savoie, H., Albrieux, F., Delort, L., Billard, H., Dubois, V., Ahsen, V. & Caldefie-Chézet, F. 2013. Assessing the dual activity of a chalcone-phthalocyanine conjugate: Design, synthesis, and antivascular and photodynamic properties. Molecular Pharmaceutics 10(10): 3706-3716.

Ur-Rashid, H., Xu, Y., Ahmad, N., Muhammad, Y. & Wang, L. 2019. Promising anti-inflammatory effects of chalcones via inhibition of cyclooxygenase, prostaglandin E2, inducible NO synthase and nuclear factor κB activities. Bioorganic Chemistry 87: 335-365.

Vinoth, R., Rangarajan, T.M., Singh, R.P. & Singh, M. 2019. Synthesis of novel chalcones through palladium-catalyzed CO cross-coupling reaction of bromo-chalcones with ethyl acetohydroxamate and their antiplasmodial evaluation against Plasmodium falcipuram in vitro. Bioorganic Chemistry 86: 631-640.

Wang, J., Huang, L., Cheng, C., Li, G., Xie, J., Shen, M., Chen, Q., Li, W., He, W., Qiu, P. & Wu, J. 2019a. Design, synthesis and biological evaluation of chalcone analogues with novel dual antioxidant mechanisms as potential anti-ischemic stroke agents. Acta Pharmaceutica Sinica B 9(2): 335-350.

Wang, L., Yang, X., Zhang, Y., Chen, R., Cui, Y. & Wang, Q. 2019. Anti-inflammatory chalcone-isoflavone dimers and chalcone dimers from Caragana jubata. Journal of Natural Products 82(10): 2761-2767.

Wilhelm, A., Kendrekar, P., Noreljaleel, A.E., Abay, E.T., Bonnet, S.L., Wiesner, L., de Kock, C., Swart, K.J. & van der Westhuizen, J.H. 2015. Syntheses and in vitro antiplasmodial activity of aminoalkylated chalcones and analogues. Journal of Natural Products 78(8): 1848-1858.

World Health Organization (WHO). 2019 Malaria Vaccines. Geneva, Switzerland: WHO Press.

World Health Organization (WHO). 2018. World Malaria Report. Geneva, Switzerland: WHO Press.

Yang, J.L., Ma, Y.H., Li, Y.H., Zhang, Y.P., Tian, H.C., Huang, Y.C., Li, Y., Chen, W. & Yang, L.J. 2019. Design, synthesis, and aanticancer activity of novel trimethoxyphenyl-derived chalcone-benzimidazolium salts. ACS Omega 4(23): 20381-20393.

Yuvaniyama, J., Chitnumsub, P., Kamchonwongpaisan, S., Vanichtanankul, J., Sirawaraporn, W., Taylor, P., Walkinshaw, M.D. & Yuthavong, Y. 2003. Insights into antifolate resistance from malarial DHFR-TS structures. Nature Structural & Molecular Biology 10(5): 357-365.

Zhang, J., Zhang, J., Hao, G., Xin, W., Yang, F., Zhu, M. & Zhou, H. 2019. Design, synthesis, and structure-activity relationship of 7-propanamide benzoxaboroles as potent anticancer agents. Journal of Medicinal Chemistry 62(14): 6765-6784.

*Pengarang untuk surat-menyurat; email: jsyachri@umri.ac.id