Synthesis and Docking Study of 2–Aryl-4,5-diphenyl-1H-imidazole Derivatives as Lead Compounds for Antimalarial Agent

https://doi.org/10.22146/ijc.67777

Ika Septiana(1), Bambang Purwono(2*), Chairil Anwar(3), Beta Achromi Nurohmah(4), Jufrizal Syahri(5)

(1) Department of Chemistry, Faculty Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, PO BOX BLS 21, Yogyakarta 55281, Indonesia
(2) Department of Chemistry, Faculty Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, PO BOX BLS 21, Yogyakarta 55281, Indonesia
(3) Department of Chemistry, Faculty Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, PO BOX BLS 21, Yogyakarta 55281, Indonesia
(4) Department of Chemistry, Faculty Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, PO BOX BLS 21, Yogyakarta 55281, Indonesia
(5) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Muhammadiyah Riau, Pekanbaru 28156, Indonesia
(*) Corresponding Author

Abstract


Series of 2-aryl-4,5-diphenyl-1H-imidazole derivatives of 2-(4-hydroxy-3-methoxyphenyl)-4,5-diphenyl-1H-imidazole (1), 2-(4,5-dimethoxyphenyl)-4,5-diphenyl-1H-imidazole (2) and 2-(4-methoxyphenyl)-4,5-diphenyl-1H-imidazole (3) were produced and evaluated for their in vitro antimalarial activities against the chloroquine-sensitive Plasmodium falciparum 3D7 strain. A molecular docking study was also carried out against the crystal protein of Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) (PDB ID: 1J3I.pdb) to predict the interaction between the compounds and protein. The physicochemical and pharmacokinetic parameters were computationally performed to predict the parameters of the absorption, distribution, metabolism, excretion, and toxicity (ADMET). Imidazoles were synthesized from aryl aldehyde derivatives with benzyl and ammonium acetate in glacial acetic acid using microwave-assisted-organic synthesis. Compounds 1, 2, and 3 were produced in 64.33, 50.56, and 70.55% yields, respectively. The IC50 of compounds 1, 2, and 3 against chloroquine-sensitive Plasmodium falciparum 3D7 strain was found to be 1.14, 5.28, and 2.42 µM, respectively. The molecular docking study agreed with the in vitro data by showing the lowest CDOCKER energy for compound 1 (-47.48 kcal/mol), followed by 3 (-43.79 kcal/mol) and 2 (-41.47 kcal/mol). The physicochemical and pharmacokinetic parameters showed that imidazoles 1, 2, and 3 obeyed Lipinski rules of five to propose as lead compounds for the antimalarial agents.

Keywords


antimalarial; imidazole; 3D7 strain; molecular docking

Full Text:

Full Text PDF


References

[1] WHO, 2020, World Malaria Report: 20 Years of Global Progress and Challenges, World Health Organization, Geneva, Switzerland, CC BY-NC-SA 3.0 IGO.

[2] Milner Jr., D.A., 2018, Malaria Pathogenesis, Cold Spring Harb. Perspect. Med., 8 (1), a025569.

[3] Cui, L., Mharakurwa, S., Ndiaye, D., Rathod, P.K., and Rosenthal, P.J., 2015, Antimalarial drug resistance: Literature review and activities and findings of the ICEMR network, Am. J. Trop. Med. Hyg., 93 (3 Suppl.), 57–68.

[4] Kumar, M., Kumar, D., and Raj, V., 2017, Studies on Imidazole and its derivatives with particular emphasis on their chemical/biological applications as bioactive molecules/intermediated to bioactive molecule, Curr. Synth. Syst. Biol., 5 (1), 1000135.

[5] dos Santos Nascimento, M.V.P., Mattar Munhoz, A.C., De Campos Facchin, B.M., Fratoni, E., Rossa, T.A., Mandolesi Sá, M., Campa, C.C., Ciraolo, E., Hirsch, E., and Dalmarco, E.M., 2019, New pre-clinical evidence of anti-inflammatory effect and safety of a substituted fluorophenyl imidazole, Biomed. Pharmacother., 111, 1399–1407.

[6] Abrigach, F., Rokni, Y., Takfaoui, A, Khoutoul, M., Doucet, H., Asehraou, A., and Touzan, R., 2018, In vitro screening, homology modeling and molecular docking studies of some pyrazole and imidazole derivatives, Biomed. Pharmacother., 103, 653–661.

[7] Guda, R., Kumar, G., Korra, R., Balaji, S., Dayakar, G., Palabindela, R., Myadaraveni, P., Yellu, N.R., and Kasula, M., 2017, EGFR, HER2 target based molecular docking analysis, in vitro screening of 2, 4, 5-trisubstituted imidazole derivatives as potential antioxidant and cytotoxic agents, J. Photochem. Photobiol., B, 176, 69–80.

[8] Le Manach, C., Gonzàlez Cabrera, D., Douelle, F., Nchinda, A.T., Younis, Y., Taylor, D., Wiesner, L., White, K.L., Ryan, E., March, C., Duffy, S., Avery, V.M., Waterson, D., Witty, M.J., Wittlin, S., Charman, S.A., Street, L.J., and Chibale, K., 2014, Medicinal chemistry optimization of antiplasmodial imidazopyridazine hits from high throughput screening of a SoftFocus kinase library: Part 1, J. Med. Chem., 57 (6), 2789–2798.

[9] Kondaparla, S., Manhas, A., Dola, R.V., Srivastava, K., Puri, S.K., and Katti, S.B., 2018, Design, synthesis and antiplasmodial activity of novel imidazole derivatives based on 7-chloro-4-aminoquinoline, Bioorg. Chem., 80, 204–211.

[10] Sharma, K., Shrivastava, A., Mehra, R.N., Deora, G.S., Alam, M.M., Zaman, M.S., and Akhter, M., 2017, Synthesis of novel benzimidazole acrylonitriles for inhibition of Plasmodium falciparum growth by dual target inhibition, Arch. Pharm., 351 (1), e1700251.

[11] Syahri, J., Nasution, H., Nurohmah, B.A., Purwono, B., and Yuanita E., 2020, Aminoalkylated chalcone: Synthesis, biological evaluation, and docking simulation as potent antimalarial agents, J. Appl. Pharm. Sci., 10 (6), 001–005.

[12] Purwono, B., Nurohmah, B.A., Fathurrohman, P.Z., and Syahri, J., 2021, Some 2-arylbenzimidazole derivatives as an antimalarial agent: Synthesis, activity assay, molecular docking and pharmacological evaluation, Rasayan J. Chem., 14 (1), 94–100.

[13] Patel, K., Karthikeyan, C., Moorthy, N.S.H.N., Deora, G.S., Solomon, V.R., Lee, H., and Trivedi, P., 2012, Design, synthesis and biological evaluation of some novel 3-cinnamoyl-4-hydroxy-2H-chromen-2-ones as antimalarial agents, Med. Chem. Res., 21 (8), 1780–1784.

[14] Singh, R.K., Bhatt, A., and Kant, R., 2016, Design and synthesis of some novel imidazole derivatives as potent antimicrobial & antimalarial agents, Pharm. Lett., 8 (7), 188–194.

[15] Batista, R., De Jesus Silva Júnior A., and 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.

[16] Syahri, J., Nasution, H., Nurohmah, B.A., Purwono, B., Yuanita, E., Zakaria, N.H., and Hassan, I., 2020, Design, synthesis and biological evaluation of aminoalkylated chalcones as antimalarial agent, Sains Malays., 49 (11), 2667–2677.

[17] Yang, H., Lou, C., Sun, L., Li, J., Cai, Y., Wang, Z., Li, W., Liu, G., and Tang, Y., 2019, admetSAR 2.0: Web-service for prediction and optimization of chemical ADMET properties, Bioinformatics, 35 (6), 1067–1069.

[18] Xiong, G., Wu, Z., Yi, J., Fu, L., Yang, Z., Hsieh, C., Yin, M., Zeng, X., Wu, C., Lu, A., Chen, X., Hou, T., and Cao, D., 2021, ADMETlab 2.0: An integrated online platform for accurate and comprehensive predictions of ADMET properties, Nucleic Acids Res., 49 (W1), W5–W14.

[19] Yang, H., Sun, L., Wang, Z., Li, W., Liu, G., and Tang, Y., 2018, ADMETopt: A web server for ADMET optimization in drug design via scaffold hopping, J. Chem. Inf. Model., 58 (10), 2051–2056.

[20] Li, J.T., Chen, B.H., Li, Y.W., and Sun, X.L., 2012, Efficient improved synthesis of 2–aryl-4,5-diphenylimidazole by heating, Int. J. Adv. Pharm., Biol. Chem., 1 (3), 287–292.

[21] Shelke, K.F., Sapkal, S.B., Sonal, S.S., Madje, B.R., Shingate, B.B., and Shingare, M.S., 2009, An efficient synthesis of 2,4,5-Triaryl-1H-Imidazole derivatives catalyzed by boric acid in aqueous media under ultrasound-irradiation, Bull. Korean Chem. Soc., 30 (5), 1057–1060.

[22] Hadni, H., and Elhallaoui, M., 2019, Molecular docking and QSAR studies for modeling the antimalarial activity of hybrids 4-anilinoquinoline-triazines derivatives with the wild-type and mutant receptor pf-DHFR, Heliyon, 5 (8), e02357.

[23] Finch, A., and Pillans, P., 2014, Importance of P-glycoprotein and its role in drug-drug interactions, Aust. Prescr., 37 (4), 137–139.

[24] Glaeser, H., 2011, “Importance of P-glycoprotein for drug-drug interactions” in Drug Transporters. Handbook of Experimental Pharmacology, Eds. Fromm, M., and Kim, R., Springer, Berlin, Heidelberg, 201, 285–297.

[25] Wu, Z., Lei, T., Shen, C., Wang, Z., Cao, D., and Hou, T., 2019, ADMET evaluation in drug discovery. 19. Reliable prediction of human Cytochrome P450 inhibition using artificial intelligence approaches, J. Chem. Inf. Model., 59 (11), 4587–4601.

[26] Han, Y., Zhang, J., Hu, C.Q., Zhang, X., Ma, B., and Zhang, P., 2019, In silico ADME and toxicity prediction of ceftazidime and its impurities, Front. Pharmacol., 10, 434.



DOI: https://doi.org/10.22146/ijc.67777

Article Metrics

Abstract views : 3802 | views : 3180


Copyright (c) 2021 Indonesian Journal of Chemistry

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

 


Indonesian Journal of Chemistry (ISSN 1411-9420 /e-ISSN 2460-1578) - Chemistry Department, Universitas Gadjah Mada, Indonesia.

Web
Analytics View The Statistics of Indones. J. Chem.