Sains Malaysiana 53(8)(2024): 1901-1912

http://doi.org/10.17576/jsm-2024-5308-14

Sintesis, Aktiviti Antimalaria dan Pendekatan Dinamik Molekul Kompleks Logam Salofen

 (Synthesis, Antimalarial Activity, and Molecular Dynamic Approaches of Salophen Metal Complexes)

  AMATUL HAMIZAH ALI¹, NUR HAFIZAH MUKHTAR¹, NG YEE LING², NUR AQILAH ZAHIRAH NORAZMI¹, HANI KARTINI AGUSTAR³, LAU YEE LING², NURUL HUDA ABD KARIM¹, SITI FAIRUS MOHD YUSOFF¹, MOSTAFA YOUSEFZADEH BORZEHANDANI^4,5 & NURUL IZZATY HASSAN^1,*

¹Department of Chemical Sciences, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, 43600 UKM Bangi, Selangor, Malaysia

²Department of Parasitology, Faculty of Medicine, Universiti Malaya, 50603 Kuala Lumpur, Malaysia

³Department of Earth Sciences and Environment, Faculty of Science and Technology, Universiti Kebangsaan Malaysia,43600 UKM Bangi, Selangor, Malaysia

⁴Integrated Chemical BioPhysics Research, Faculty of Science, Universiti Putra Malaysia, 43400 UPM Serdang,Selangor, Malaysia

⁵Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia

Received: 14 December 2023/Accepted: 14 June 2024

Abstrak

Malaria masih merupakan salah satu penyakit berjangkit yang utama di kawasan beriklim tropika. Pelbagai ubat antimalaria telah diperkenalkan sebelum ini seperti klorokuina, primakuina dan artemisinin. Namun, keberkesanan ubat antimalaria menjadi rumit disebabkan oleh penyebaran parasit Plasmodium yang ada kerintangan terhadap ubat sedia ada. Oleh demikian, penerokaan kompleks logam salofen berasaskan ligan bes Schiff yang berpotensi sebagai agen antimalaria dijalankan. Empat ligan berasaskan salofen a-d dan lapan kompleks logam salofen 1a-4a dan 1b-4b telah disintesis melalui tindak balas kondensasi bes Schiff. Aktiviti antimalaria sebatian ini telah diuji dengan asai Plasmodium laktat dehidrogenase terhadap Plasmodium falciparum 3D7 yang menunjukkan bahawa 1a, 3a dan 4b masing-masing (IC₅₀ = 14.74, 19.38 dan 12.13 µM) mempunyai kesan perencatan aktif terhadap parasit secara in vitro. Analisis dok molekul mendedahkan bahawa sebatian 1a, 3a dan 4b menunjukkan nilai pengikatan yang baik pada protein PfDHFR-TS iaitu nilai masing-masing adalah -9.7, -8.9 dan -9.5 kcal. mol^-1. Tambahan pula, simulasi dinamik molekul mendedahkan bahawa sebatian 1a dan 3a ditempatkan di dalam poket reseptor protein dengan sebatian dikelilingi oleh beberapa permukaan berpolar. Bagaimanapun, sebatian 4b membentuk sistem kompleks reseptor-ligan dengan konformasi yang paling stabil apabila kompleks diletakkan di dalam poket reseptor hidrofobik. Oleh itu, PfDHFR-TS dianggap sebagai sasaran protein parasit yang khusus untuk kompleks logam salofen. Kesimpulannya, kompleks logam salofen didapati mempunyai potensi tinggi untuk dibangunkan sebagai agen antimalaria dan mampu menjadi struktur templat kepada pembentukan ubat antimalaria bagi melawan kes kerintangan.

Kata kunci: Aktiviti antimalaria; dok molekul; dinamik molekul; kompleks logam salofen; PfDHFR-TS

Abstract

Malaria is still one of the main infectious diseases in tropical climates. Various antimalarial drugs have been introduced before, such as chloroquine, primaquine, and artemisinin. However, the effectiveness of antimalarial drugs is complicated by the spread of Plasmodium parasites’s resistance. This study was carried out to explore metal complexes based on Schiff base ligands with good potential as antimalarial agents. Four salophen-based ligands a-d, and eight salophen metal complexes 1a-4a and 1b-4b were synthesized via Schiff base condensation reaction. Antimalarial properties of these compounds were investigated by plasmodium lactate dehydrogenase assay against Plasmodium falciparum 3D7, which showed that 1a, 3a, and 4b possessed active parasite inhibitory effect in vitro study (IC₅₀: 14.74, 19.38, and 12.13 µM, respectively). Molecular docking analysis showed that compounds 1a, 3a, and 4b showed good binding affinity values, i.e. -9.7, -8.9, and -9.5 kcal/mol on PfDHFR-TS. Furthermore, the molecular simulations showed that 1a and 3a accommodated in the receptor’s pocket where some polar surfaces surrounded the compounds. However, 4b built the highest conformational stable receptor-ligand complex system when positioned in the receptor’s hydrophobic pocket. Thus, PfDHFR-TS is a specific parasite protein target for the salophen metal complex. In conclusion, this study found that the salophen metal complex has a high potential to be developed as an antimalarial agent and can be a template structure for forming antimalarial drugs to fight resistance cases.

Keywords: Antimalarial activities; molecular docking; molecular dynamics; PfDHFR-TS; salophen metal complexes

REFERENCES

Aispuro-Pérez, A., López-Ávalos, J., García-Páez, F., Montes-Avila, J., Picos-Corrales, L.A., Ochoa-Terán, A., Bastidas, P., Montaño, S., Calderón-Zamora, L., Osuna-Martínez, U. & Sarmiento-Sánchez, J.I. 2020. Synthesis and molecular docking studies of imines as α-glucosidase and α-amylase inhibitors. Bioorganic Chemistry 94: 103491.

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. 2014. Spread of artemisinin resistance in Plasmodium falciparum malaria. New England Journal of Medicine 371(5): 411-423.

Azizian, H., Bahrami, H., Pasalar, P. & Amanlou, M. 2010. Molecular modeling of Helicobacter pylori arginase and the inhibitor coordination interactions. Journal of Molecular Graphics and Modelling 28(7): 626-635.

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.

Brown, R.W. & Hyland, C.J. 2015. Medicinal organometallic chemistry - an emerging strategy for the treatment of neglected tropical diseases. MedChemComm 6(7): 1230-1243.

Chong, J.H., Ardakani, S.J., Smith, K.J. & MacLachlan, M.J. 2009. Triptycene‐based metal salphens-exploiting intrinsic molecular porosity for gas storage. Chemistry - A European Journal 15(44): 11824-11828.

Dueke-Eze, C.U., Fasina, T.M., Oluwalana, A.E., Familoni, O.B., Mphalele, J.M. & Onubuogu, C. 2020. Synthesis and biological evaluation of copper and cobalt complexes of (5-substituted-salicylidene) isonicotinichydrazide derivatives as antitubercular agents. Scientific African 9: e00522.

Essmann, U., Perera, L., Berkowitz, M.L., Darden, T., Lee, H. & Pedersen, L.G. 1995. A smooth particle mesh Ewald method. The Journal of Chemical Physics 103(19): 8577-8593.

Fonkui, T.Y., Ikhile, M.I., Ndinteh, D.T. & Njobeh, P.B. 2018. Microbial activity of some heterocyclic Schiff bases and metal complexes: A review. Tropical Journal of Pharmaceutical Research 17(12): 2507-2518.

Garberoglio, G. 2012. OBGMX: A web‐based generator of GROMACS topologies for molecular and periodic systems using the universal force field. Journal of Computational Chemistry 33(27): 2204-2208.

Garcia, J., Carvalho, A., das Neves, R.P., Malheiro, R., Rodrigues, D.F., Figueiredo, P.R., Bovolini, A., Duarte, J.A., Costa, V.M. & Carvalho, F. 2022. Antidotal effect of cyclosporine A against α-amanitin toxicity in CD-1 mice, at clinical relevant doses. Food and Chemical Toxicology 166: 113198.

Gasteiger, J. & Marsili, M. 1980. Iterative partial equalization of orbital electronegativity-a rapid access to atomic charges. Tetrahedron 36(22): 3219-3228.

Han, M. & Zhang, J.Z. 2010. Class I phospho-inositide-3-kinases (PI3Ks) isoform-specific inhibition study by the combination of docking and molecular dynamics simulation. Journal of Chemical Information and Modeling 50(1): 136-145.

Kaminski, G.A., Friesner, R.A., Tirado-Rives, J. & Jorgensen, W.L. 2001. Evaluation and reparametrization of the OPLS-AA force field for proteins via comparison with accurate quantum chemical calculations on peptides. The Journal of Physical Chemistry B 105(28): 6474-6487.

Kementerian Kesihatan Malaysia (KKM). 2020. Sambutan Hari Malaria Peringkat Kebangsaan Tahun 2020. https://www.moh.gov.my/index.php/database_stores/attach_download/337/1499 Diakses pada 1 Jun 2022.

Koenderink, J.B., Kavishe, R.A., Rijpma, S.R. & Russel, F.G. 2010. The ABCs of multidrug resistance in malaria. Trends in Parasitology 26(9): 440-446.

Kondaparla, S., Manhas, A., Dola, V.R., Srivastava, K., Puri, S.K. & Katti, S.B. 2018. Design, synthesis and antiplasmodial activity of novel imidazole derivatives based on 7-chloro-4-aminoquinoline. Bioorganic Chemistry 80: 204-211.

Kooijman, E.E., Tieleman, D.P., Testerink, C., Munnik, T., Rijkers, D.T.S., Burger, K.N.J. & de Kruijff, B. 2007. An electrostatic/hydrogen bond switch as the basis for the specific interaction of phosphatidic acid with proteins. Journal of Biological Chemistry 282(15): 11356-11364. doi:10.1074/jbc.M609737200

Li, H., Xi, D., Niu, Y., Wang, C., Xu, F., Liang, L. & Xu, P. 2019. Design, synthesis and biological evaluation of cobalt (II)-Schiff base complexes as ATP-noncompetitive MEK1 inhibitors. Journal of Inorganic Biochemistry 195: 174-181.

Liu, M., Yang, H., Li, D., Yao, Q., Wang, H., Zhang, Z. & Dou, J. 2021. Zn and Cu complexes of o-van-gly Schiff base: Syntheses, crystal structures, fluorescence sensing and anticancer properties. Inorganica Chimica Acta 522: 120384.

Makler, M.T. & Hinrichs, D.J. 1993. Measurement of the lactate dehydrogenase activity of Plasmodium falciparum as an assessment of parasitemia. The American Journal of Tropical Medicine and Hygiene 48(2): 205-210.

Mark, P. & Nilsson, L. 2001. Structure and dynamics of the TIP3P, SPC, and SPC/E water models at 298 K. The Journal of Physical Chemistry A 105(43): 9954-9960.

Morris, G.M., Huey, R., Lindstrom, W., Sanner, M.F., Belew, R.K., Goodsell, D.S. & Olson, A.J. 2009. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. Journal of Computational Chemistry 30(16): 2785-2791.

Neafsey, D.E., Waterhouse, R.M., Abai, M.R., Aganezov, S.S., Alekseyev, M.A., Allen, J.E., Amon, J., Arcà, B., Arensburger, P., Artemov, G. & Assour, L.A. 2015. Highly evolvable malaria vectors: The genomes of 16 Anopheles mosquitoes. Science 347(6217): 1258522.

Norazmi, N.A.Z., Mukhtar, N.H., Ali, A.H., Abd Karim, N.H., Yusoff, S.F.M., Agustar, H.K., Abd Razak, M.R.M. & Hassan, N.I. 2022. In vitro antimalarial activity of metal complexes of tetraazamacrocyclic ligands against Plasmodium falciparum K1 strain. Sains Malaysiana 51(4): 1123-1130.

Opo, F.A.D.M., Rahman, M.M., Ahammad, F., Ahmed, I., Bhuiyan, M.A. & Asiri, A.M. 2021. Structure based pharmacophore modeling, virtual screening, molecular docking and ADMET approaches for identification of natural anti-cancer agents targeting XIAP protein. Scientific Reports 11(1): 4049.

Ouji, M., Augereau, J.M., Paloque, L. & Benoit-Vical, F. 2018. Plasmodium falciparum resistance to artemisinin-based combination therapies: A sword of Damocles in the path toward malaria elimination. Parasite 25: 24.

Páll, S. & Hess, B. 2013. A flexible algorithm for calculating pair interactions on SIMD architectures. Computer Physics Communications 184(12): 2641-2650.

Pulcini, S., Staines, H.M., Lee, A.H., Shafik, S.H., Bouyer, G., Moore, C.M., Daley, D.A., Hoke, M.J., Altenhofen, L.M., Painter, H.J. & Mu, J. 2015. Mutations in the Plasmodium falciparum chloroquine resistance transporter, PfCRT, enlarge the parasite’s food vacuole and alter drug sensitivities. Scientific Reports 5(1): 14552.

Rathi, P.C., Ludlow, R.F. & Verdonk, M.L. 2019. Practical high-quality electrostatic potential surfaces for drug discovery using a graph-convolutional deep neural network. Journal of Medicinal Chemistry 63(16): 8778-8790.

Saikumari, N. 2021. Synthesis and characterization of amino acid Schiff base and its copper (II) complex and its antimicrobial studies. Materials Today: Proceedings 47: 1777-1781.

Saini, G., Dalal, V., Savita, B.K., Sharma, N., Kumar, P. & Sharma, A.K. 2019. Molecular docking and dynamic approach to virtual screen inhibitors against Esbp of Candidatus Liberibacter asiaticus. Journal of Molecular Graphics and Modelling 92: 329-340.

Savir, S., Liew, J.W.K., Vythilingam, I., Lim, Y.A.L., Tan, C.H., Sim, K.S., Lee, V.S., Maah, M.J. & Tan, K.W. 2021. Nickel (II) complexes with polyhydroxybenzaldehyde and O, N, S tridentate thiosemicarbazone ligands: Synthesis, cytotoxicity, antimalarial activity, and molecular docking studies. Journal of Molecular Structure 1242: 130815.

Senthamarai, T., Chandrashekhar, V.G., Gawande, M.B., Kalevaru, N.V., Zbořil, R., Kamer, P.C., Jagadeesh, R.V. & Beller, M. 2020. Ultra-small cobalt nanoparticles from molecularly-defined Co–salen complexes for catalytic synthesis of amines. Chemical Science 11(11): 2973-2981.

Shaikh, I., Jadeja, R.N., Patel, R., Mevada, V. & Gupta, V.K. 2021. 4-Acylhydrazone-5-pyrazolones and their zinc (II) metal complexes: synthesis, characterization, crystal feature and antimalarial activity. Journal of Molecular Structure 1232: 130051.

Trager, W. & Jensen, J.B. 1976. Human malaria parasites in continuous culture. Science 193(4254): 673-675.

Trott, O. & Olson, A.J. 2010. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry 31(2): 455-461.

Van Der Spoel, D., Lindahl, E., Hess, B., Groenhof, G., Mark, A.E. & Berendsen, H.J. 2005. GROMACS: Fast, flexible, and free. Journal of Computational Chemistry 26(16): 1701-1718.

Wang, Y.Y., Xu, F.Z., Zhu, Y.Y., Song, B., Luo, D., Yu, G., Chen, S., Xue, W. & Wu, J. 2018. Pyrazolo [3, 4-d] pyrimidine derivatives containing a Schiff base moiety as potential antiviral agents. Bioorganic & Medicinal Chemistry Letters 28(17): 2979-2984.

World Health Organization (WHO). 2022. World Malaria Report. Geneva. https://www.who.int/teams/global-malaria-programme/reports/world-malaria-report-2022. Diakses 1 Jun 2023.

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.

*Corresponding author; email: drizz@ukm.edu.my