Computational Design of Thioxanthone Derivatives as Potential Antimalarial Agents through  Plasmodium falciparum  Protein Inhibition

Faris Hermawan; Jumina Jumina; Harno Dwi Pranowo; Eti Nurwening Sholikhah; Muthia Rahayu Iresha

doi:10.22146/ijc.69448

Computational Design of Thioxanthone Derivatives as Potential Antimalarial Agents through Plasmodium falciparum Protein Inhibition

https://doi.org/10.22146/ijc.69448

Faris Hermawan⁽¹⁾, Jumina Jumina^(2*), Harno Dwi Pranowo⁽³⁾, Eti Nurwening Sholikhah⁽⁴⁾, Muthia Rahayu Iresha⁽⁵⁾

(1) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia; Austrian-Indonesian Centre (AIC) for Computational Chemistry, Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia
(2) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia
(3) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia; Austrian-Indonesian Centre (AIC) for Computational Chemistry, Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia
(4) Department of Pharmacology and Therapeutics, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia
(5) Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia; Austrian-Indonesian Centre (AIC) for Computational Chemistry, Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara, Yogyakarta 55281, Indonesia
(*) Corresponding Author

Abstract

Plasmodium falciparum (P. falciparum) is the most fatal among the other Plasmodium parasites that infect humans with the malaria disease. Currently, the resistance of P. falciparum against some antifolate drugs has become a severe problem. On the other hand, xanthone and thioxanthone derivatives have been reported to have remarkable antimalarial activity. However, molecular docking studies have not evaluated thioxanthone derivative compounds as antimalarial agents. Accordingly, this research investigated the binding pose and inhibition mechanism of several thioxanthone derivatives against P. falciparum proteins DHFR (PDB ID: 1J3K) and DHODH (PDB ID: 1TV5) through molecular docking study. The compound structures were geometrically optimized using Gaussian 09 software and docked to the receptors using AutoDock4 software. The results showed that the free binding energy of thioxanthone derivatives ranged between -6.77 to -7.50 and -8.45 to -9.55 kcal mol^–1 against pfDHFR and pfDHODH, respectively, with RMSD values of less than 2 Å. Compound F (4-iodo-3,4-dihydroxy-thioxanthone) gave the most substantial free binding energy against both proteins. Furthermore, the hydrogen bond interaction of compound F was the same as the native ligands of pfDHFR and pfDHODH. These results suggested that compound F has a more robust interaction in pfDHFR and pfDHODH. Thus, it is promising to further evaluate the compound as a candidate for a new antimalarial agent.

Keywords

antimalarial; thioxanthone; pfDHFR; pfDHODH; molecular docking

Full Text:

Full Text PDF

References

[1] World Health Organization, 2020, World Malaria Report 2020, World Health Organization, Geneva, Switzerland.

[2] Lalremruata, A., Jeyaraj, S., Engleitner, T., Joanny, F., Lang, A., Bélard, S., Mombo-Ngoma, G., Ramharter, M., Kremsner, P.G., Mordmuller, B., and Held, J., 2017, Species and genotype diversity of Plasmodium in malaria patients from Gabon analysed by next generation sequencing, Malar. J., 16, 398.

[3] Blasco, B., Leroy, D., and Fidock, D.A., 2017, Antimalarial drug resistance: Linking Plasmodium falciparum parasite biology to the clinic, Nat. Med., 23 (8), 917–928.

[4] Saifi, M.A., Beg, T., Harrath, A.H., Altayalan, F.S.H., and Al Quraishy, S., 2013, Antimalarial drugs: Mode of action and status of resistance, Afr. J. Pharm. Pharmacol., 7 (5), 148–156.

[5] Yuvaniyama, J., Chitnumsub, P., Kamchonwongpaisan, S., Vanichtanankul, J., Sirawaraporn, S., Taylor, P., Walkinshaw, M.D., and Yuthavong, Y., 2003, Insights into antifolate resistance from malarial DHFR-TS structures, Nat. Struct. Mol. Biol., 10, 357–365.

[6] Mishra, R., Mishra, B., and Hari, N.S.H.N., 2006, Dihydrofolate reductase enzym: A potent target for antimalarial research, Asian J. Cell Biol., 1 (1), 45–58.

[7] Phillips, M.A., and Rathod, P.K., 2010, Plasmodium dihydroorotate dehydrogenase: A promising target for novel antimalarial chemotherapy, Infect. Disord.: Drug Targets, 10 (3), 226–239.

[8] Vyas, V.K., and Ghate, M., 2011, Recent developments in the medicinal chemistry and therapeutic potential of dihydroorotate dehydrogenase (DHODH) inhibitors, Mini-Rev. Med. Chem., 11 (12), 1039–1055.

[9] Syahri, J., Yuanita, E., Nurohmah, B.A., Wathon, M.H., Syafri, R., Armunanto, R., and Purwono, B., 2017, Xanthone as antimalarial: QSAR analysis, synthesis, molecular docking and in-vitro antimalarial evaluation, Orient. J. Chem., 33 (1), 29–40.

[10] Wadood, A., and Ul-Haq, Z., 2013, In silico identification of novel inhibitors against Plasmodium falciparum dihydroorate dehydrogenase, J. Mol. Graphics Modell., 40, 40–47.

[11] Singh, I.V., and Mishra, S., 2019, Molecular docking studies of benzamide derivatives for PfDHODH inhibitor as potent antimalarial agent, Am. J. Biochem. Mol. Biol., 9 (1), 1–6.

[12] Syahri, J., Yuanita, E., Nurohmah, B.A., Armunanto, R., and Purwono, B., 2017, Chalcone analogue as potent antimalarial compounds against Plasmodium falciparum: Synthesis, biological evaluation, and docking simulation study, Asian Pac. J. Trop. Biomed., 7 (8), 675–679.

[13] Brandão, G.C., Missias, F.C.R., Arantes, L.M., Soares, L.F., Roy, K.K., Doerksen, R.J., de Oliveira, A.B., and Pereira, G.R., 2018, Antimalarial naphthoquinones. Synthesis via click chemistry, in vitro activity, docking to PfDHODH and SAR of lapachol–based compounds, Eur. J. Med. Chem., 145, 191–205.

[14] Mukesh, B., and Rakesh, K., 2011, Molecular docking: A review, Int. J. Res. Ayurveda Pharm., 2 (6), 1746–1751.

[15] Ojo, A.A., 2021, Exploring the potential of selected bioactive compound isolated from Piper guineense Schumach. & Thonn. Leaf toward identification of novel pfDHFR and pfDHODH inhibitors as antimalaria agents, J. Appl. Pharm. Sci., 11 (4), 153–158.

[16] Adane, L., Bhagat, S., Arfeen, M., Bhatia, S., Sirawaraporn, R., Sirawaraporn, W., Chakraborti, A.K., and Bharatam, P.V., 2014, Design and synthesis of guanylthiourea derivatives as potential inhibitors of Plasmodium falciparum dihydrofolate reductase enzyme, Bioorg. Med. Chem. Lett., 24 (2), 613–617.

[17] Vyas, V.K., Qureshi, G., Ghate, M., Patel, H., and Dalai, S., 2016, Identification of novel PfDHODH inhibitors as antimalarial agents via pharmacophore-based virtual screening followed by molecular docking and in vivo antimalarial activity, SAR QSAR Environ. Res., 27 (6), 427–440.

[18] Amanatie, A., Jumina, J., Mustofa, M., Hanafi, M., Kadidae, L.A., and Sahidin, I., 2017, Synthesis of 2-hidroxyxanthone from xanthone as a basic material for new antimalarial drugs, Asian J. Pharm. Clin. Res., 10 (12), 242–246.

[19] Lyles, J.T., Negrin, A., Khan, S.I., He, K., and Kennelly, E., 2014, In vitro antiplasmodial activity of benzophenones and xanthones from edible fruits of Garcinia species, J Planta Med., 80 (9), 676–681.

[20] Upegui, Y., Robledo, S.M., Gil Romero, J.F., Quinones, W., Archbold, R., Torres, F., Escobar, G., Nariño, B., and Echeverri, F., 2015, In vivo antimalarial activity of α‐mangostin and the new xanthone δ‐mangostin, Phytother. Res., 29 (8), 1195–1201.

[21] Auranwiwat, C., Limtharakul T., Pyne, S.G., Rattanajak, R., and Kamchonwongpaisan, S., 2021, A new xanthone and a biphenyl from the flower and twig extract of Garcinia mckeaniana, Nat. Prod. Res., 35 (20), 3404–3409.

[22] Charris, J., Dominguez, J., Lobo, G., and Riggione, F., 1999, Synthesis of some thiochromone derivatives and activity against Plasmodium falciparum in‐vitro, Pharm. Pharmacol. Commun., 5 (2), 107–110.

[23] Hung, J., McNamara, D.J., and Werbel, L.M., 1983, Synthesis of 3,4‐dihydrothioxanthene‐1,9‐dione analogs as potential antimalarial agents, J. Heterocycl. Chem., 20 (6), 1575–1580.

[24] Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Mennucci, B., Petersson, G.A., Nakatsuji, H., Caricato, M., Li, X., Hratchian, H.P., Izmaylov, A.F., Bloino, J., Zheng, G., Sonnenberg, J.L., Hada, M., Ehara, M., Toyota, K., Fukuda, R., Hasegawa, J., Ishida, M., Nakajima, T., Honda, Y., Kitao, O., Nakai, H., Vreven, T., Montgomery, J.A., Jr., Peralta, J.E., Ogliaro, F., Bearpark, M., Heyd, J.J., Brothers, E., Kudin, K.N., Staroverov, V.N., Kobayashi, R., Normand, J., Raghavachari, K., Rendell, A., Burant, J.C., Iyengar, S.S., Tomasi, J., Cossi, M., Rega, N., Millam, J.M., Klene, M., Knox, J. E., Cross, J.B., Bakken, V., Adamo, C., Jaramillo, J., Gomperts, R., Stratmann, R.E., Yazyev, O., Austin, A.J., Cammi, R., Pomelli, C., Ochterski, J.W., Martin, R.L., Morokuma, K., Zakrzewski, V.G., Voth, G. A., Salvador, P., Dannenberg, J. J., Dapprich, S., Daniels, A. D., Farkas, Ö., Foresman, J. B., Ortiz, J.V., Cioslowski, J., and Fox, D.J., 2013, Gaussian-09 Revision D.01, Gaussian, Inc., Wallingford, CT.

[25] Ramirez, D., and Cabello, J., 2018, Is it reliable the molecular docking top scoring position as the best solution without considering available structural data?, Molecules, 23 (5), 1038-1055.

[26] Yogaswara, R., Pulung M.L., Yuliani, S.H., and Istiyanto, E.P., 2020, Docking-guided 3D-QSAR studies of 4-aminoquinoline-1,3,5-triazines as inhibitors for Plasmodium falciparum dihdrofolate reductase, Indones. J. Chem., 20 (6), 1455–1460.

[27] Siswanto, I., Pranowo, H.D., and Mudasir, M., 2019, Docking of new designed compounds derived from 1,6-dihydro-1,3,5-triazine-2,4-diamine toward quadruple mutant plasmodium dihydrofolate reductase, Indones. J. Chem., 19 (3), 777–785.

[28] Scolastica, M., Ndakala, A.J., and Derese, S., 2108, Modeling and synthesis of antiplasmodial chromones, chromanones, and chalcone based on natural product of Kenya, Asian J. Nat. Prod. Biochem., 16 (1), 8–21.

[29] Singh, I.V., and Mishra, S., 2018, Molecular docking analysis of pyrimethamine derivatives with Plasmodium falciparum dihydrofolate reductase, Bioinformation, 14 (5), 232–235.

[30] Murthy, S.S., and Narsaiah, T.B., 2019, Molecular docking studies of phytocompounds with transcriptional factors in hepatocellular carcacinoma, Rasayan J. Chem., 12 (4), 2030–2038.

[31] Pavadai, E., Mazouni, F.E., Wittlin, S., de Kock, C., Phillips, M.A., and Chibale, K., 2016, Identification of new human malaria parasite Plasmodium falciparum dihroorotate dehydrogenase inhibitors by pharmacophore and structure-based virtual screening, J. Chem. Inf. Model., 56 (3), 548–562.

DOI: https://doi.org/10.22146/ijc.69448