<i>In silico</i> Investigation of the Antimalarial Activity of some Selected Alkaloids and Terpenoids Present in the Aerial Parts of <i>Andrographis paniculata</i>.

http://www.doi.org/10.26538/tjnpr/v7i8.33

Authors

  • Oladapo J. Olaosebikan Chemistry Programme, College of Agriculture, Engineering and Science, Bowen University, Iwo, Osun State, Nigeria.
  • Esther O. Faboro Chemistry Programme, College of Agriculture, Engineering and Science, Bowen University, Iwo, Osun State, Nigeria.
  • Olatomide A. Fadare Department of Chemistry, Obafemi Awolowo University, Faculty of Science, Ile-ife, Osun State, Nigeria
  • Adebomi A. Ikotun Chemistry Programme, College of Agriculture, Engineering and Science, Bowen University, Iwo, Osun State, Nigeria.

Keywords:

In silico studies, Andrographis paniculata, Antimalarial, Alkaloids, Terpenoids

Abstract

Most of the frontline drugs being used to treat malaria are gradually losing efficacy due to parasite resistance and this stipulates that new antimalarial drugs are discovered and developed either from plant origin or synthesis this study employed computational techniques to investigate the potential of phytochemicals from a medicinal plant (Andrographis paniculata) to act as potential inhibitors of Plasmodium falciparum Dihydroorotate Dehydrogenase (PfDHODH). In this study, the aerial parts of Andrographis paniculata were locally sourced and processed, and cold extraction was carried out using 100 % dichloromethane, ethyl acetate and methanol. The extracts were characterized using GC-MS analysis to identify the various phytochemicals present. Spectra analysis revealed the presence of secondary metabolites, majorly alkaloids and terpenoids. The GC-MS revealed 60 compounds which were docked against PfDHODH and screened using the known inhibitor, 5-methyl-7-(naphthalen-2-ylamino)-1H-{1,2,4}triazolo{1,5-
a}pyrimidine-3,8-diium, DSM1, as reference. 16 compounds were selected for druglikeness and in-silico pharmacokinetic property prediction and these were submitted to the online server, Admetlab 2.0. Based on the druglikeness assessment (Quantitative Estimate of Druglikeness, QED), 6 of the compounds were found to possess druglike qualities and these six were alkaloids and terpenoids, including Andrographolide. After considering other Pharmacokinetic parameters such as absorption, distribution, metabolism and toxicity, 4 compounds were eventually selected as potential PfDHODH inhibitors with optimum pharmacokinetic properties that are worth considering as lead compounds for an antimalarial drug discovery effort. The four compounds identified are 6-methoxy-2-methyl-quinoline-3-carboxylic acid-2-dimethylamino-ethylester (MET24_671), Andrographolide (MET25_998), 1-(6-purinyl)-2-pyrolidinecarboxylic acid (DCM14_463) and 2-ethylacridine (EA24_614) of which DCM14_463 was deemed the best.

References

Jarukamjorn K, Nemoto N. Pharmacological Aspects of Andrographis paniculata on Health and Its Major Diterpenoid Constituent Andrographolide. J. Health Sci. 2008; 54(4): 370-381.

Okhuarobo A, Falodun JE, Erharuyi O, Imieje V, Falodun A, Langer P. Harnessing the medicinal properties of Andrographis paniculata for diseases and beyond: a review of its phytochemistry and pharmacology. Asian Pac J Trop Dis 2014; 4(3):213-222.

Ukpanukpong RU, Bassey SO, Akindahunsi DO, Omang WA, Ugor JA. Antidirrheal and Antihepatic Effect of Andrographis paniculata Leaf Extract on Castor Oil Induced Diarrhea in Wistar Rats. The Pharm. chem. j. 2018; 5(1): 62-76.

https://www.sciencedirect.com/topics/agricultural-andbiologicalsciences/phytochemical. {online}. {cited 2023 May 3}.

Ikotun AA, Babajide EE, Omolekan TO, Ajaelu CJ. In vitro Antioxidant Activities of Some Re(I) Metal Carbonyls Synthesized from Isatin Derivatives. Trop. J. Nat. Prod. Res. 2022; 6(10): 1723-1726.

Afolayan FI, Ijidakinro OD. In silico antiparasitic investigation of compounds derived from Andrographis paniculata on some parasites validated drug targets. Afr. J. Bio. Sci. 2021; 3(3): 93-110.

Mishra SK, Sangwan NS, Sangwan RS. Andrographis paniculata (Kalmegh): A Review. Phcog. Rev 2007; 1(283): 283-298.

Zeng B, Wei A, Zhou Q, Yuan M, Lei K, Liu Y, Song J, Guo L, Ye Q. Andrographolide: A review of its pharmacology, pharmacokinetics, toxicity and clinical trials and pharmaceutical researches. Phytother Res. 2022; 36(1): 336-364.

Hossain S, Urbi Z, Karuniawati H, Mohiuddin, RB, Moh Qrimida, A, Allzrag AMM, Ming LC, Pagano E, Capasso R. Andrographis paniculata (Burm. f.) Wall. ex Nees: An Updated Review of Phytochemistry, Antimicrobial Pharmacology, and Clinical Safety and Efficacy. Life 2021;

(4): 348.

Kumar S, Singh, B, Bajpai, V. Andrographis paniculata(Burm.f.) Nees: Traditional uses, phytochemistry, pharmacological properties and quality control/quality assurance. J Ethnopharmacol, 2021; 275: 114054.

Jayakumar T, Hsieh CY, Lee JJ, Sheu JR. Experimental and Clinical Pharmacology of Andrographis paniculata and Its Major Bioactive Phytoconstituent Andrographolide. Evid Based Complement Alternat Med. 2013; 2013: 846740.

White NJ. Antimalarial drug resistance. J Clin Invest. 2004; 113(8): 1084-1092.

Wicht KJ, Mok S, Fidock DA. Molecular Mechanisms of Drug Resistance in Plasmodium falciparum Malaria. Annu Rev Microbiol. 2020; 74: 431-454.

Roux AT, Maharaj L, Oyegoke O, Akoniyon OP, Adeleke MA, Maharaj R and Okpeku M. Chloroquine and Sulfadoxine–Pyrimethamine Resistance in Sub-Saharan Africa-A Review. Front. Genet. 2021; 12: 668574.

Zhu L, van der Pluijm RW, Kucharski M, Nayak S, Tripathi J, White NJ, Day NPJ, Faiz A, Phyo AP, Amaratunga C, Lek D, Ashley EA, Nosten F, Smithuis F, Ginsburg H, von Seidlein L, Lin K, Imwong M, Chotivanich K, Mayxay M, Dhorda M, Nguyen HC, Nguyen TNT, Miotto O, Newton

PN, Jittamala P, Tripura R, Pukrittayakamee S, Peto TJ, Hien TT, Dondorp AM, Bozdech Z. Artemisinin resistance in the malaria parasite, Plasmodium falciparum, originates from its initial transcriptional response. Commun Biol. 2022; 5(1): 274.

Ward KE, Fidock DA, Bridgford JL. Plasmodium falciparum resistance to artemisinin-based combination therapies. Curr Opin Microbiol. 2022; 69: 102193.

da Silva C, Matias D, Dias B, Cancio B, Silva M, Viegas R, Chivale N, Luis S, Salvador C, Duarte D, Arnaldo P, Enosse S, Nogueira F. Anti-malarial resistance in Mozambique: Absence of Plasmodium falciparum Kelch 13 (K13) propeller domain polymorphisms associated with resistance to artemisinins. Malar J. 2023; 22(1): 160.

Hyde JE. Exploring the folate pathway in Plasmodium falciparum. Acta Trop. 2005; 94(3): 191-206.

Yuthavong Y. Antifolate Drugs. In: Hommel M, Kresmsner P (eds) Encyclopedia of Malaria. Springer, New York, NY; 2013. Vol 1-12.

Herraiz T, Guillén H, González-Peña D, Arán VJ. Antimalarial Quinoline Drugs Inhibit β-Hematin and Increase Free Hemin Catalyzing Peroxidative Reactions and Inhibition of Cysteine Proteases. Sci Rep. 2019; 9(1): 15398.

Kapishnikov S, Staalsø T, Yang Y, Lee J, Pérez-Berná AJ, Pereiro E, Yang Y, Werner S, Guttmann P, Leiserowitz L, Als-Nielsen J. Mode of action of quinoline antimalarialdrugs in red blood cells infected by Plasmodium falciparum revealed in vivo. Proc Natl Acad Sci U S A. 2019; 116(46):

-22952.

O’Neill, PM, Barton VE, Ward SA. The Molecular Mechanism of Action of Artemisinin—The Debate Continues. Molecules 2010; 15(3): 1705-1721.

Meshnick SR. Artemisinin antimalarials: mechanisms of action and resistance. Med Trop (Mars). 1998; 58(3 Suppl): 13-17.

Hasan MA, Mazumder MH, Chowdhury AS, Datta A, Khan MA. Molecular-docking study of malaria drug target enzyme transketolase in Plasmodium falciparum 3D7 portends the novel approach to its treatment. Source Code Biol Med. 2015; 10: 7.

Boateng RA, Tastan Bishop Ö, Musyoka TM. Characterisation of plasmodial transketolases and identification of potential inhibitors: an in silico study. Malar J. 2020; 19(1): 442.

Cassera MB, Zhang Y, Hazleton KZ, Schramm VL. Purine and pyrimidine pathways as targets in Plasmodium falciparum. Curr Top Med Chem. 2011; 11(16): 2103-2115.

Frame IJ, Deniskin R, Arora A, Akabas MH. Purine import into malaria parasites as a target for antimalarial drug development. Ann N Y Acad Sci. 2015; 1342(1): 19-28.

Hoelz LV, Calil FA, Nonato MC, Pinheiro LC, Boechat N. Plasmodium falciparum dihydroorotate dehydrogenase: a drug target against malaria. Future Med Chem. 2018; 10(15): 1853-1874.

Phillips MA, Rathod PK. Plasmodium dihydroorotate dehydrogenase: a promising target for novel anti-malarial chemotherapy. Infect Disord Drug Targets. 2010; 10(3): 226-239.

Hyde JE. Targeting purine and pyrimidine metabolism inhuman apicomplexan parasites. Curr Drug Targets 2007; 8(1): 31–47.

Phillips MA, Rathod PK, Rueckle T, Matthews D, Burrows JN, Charman SA. Medicinal Chemistry Case History: Discovery of the Dihydroorate Dehydrogenase Inhibitor DSM265 as an Antimalarial Drug Candidate. In Chackalamannil S, Rotella D, Ward SE, editors, Comprehensive Medicinal Chemistry III: Case Histories in Recent Drug Discovery. 3 ed. Vol. 8. Amsterdam The Netherlands: Elsevier. 2017. p. 544-557. Reference Module in Chemistry, Molecular Sciences and Chemical Engineering; 3).

Xu Y, Jiang H. Potential treatment of COVID-19 by inhibitors of human dihydroorotate dehydrogenase. Protein cell. 2020; 11(10): 699–702.

Faboro EO, Wei L, Liang S, McDonald AG, Obafemi CA. Phytochemical Analyzes from the Leaves of Bryophyllum pinnatum. European j. med. plants 2016; 14(3): 1-10.

O'Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR. Open Babel: An open chemical toolbox. J Cheminform. 2011; 3(33).

Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2010; 31(2): 455–461.

The PyMOL Graphics System, Version 2.0 Schrödinger, LLC. {Online}. 2023 {cited 2023 April 15}. Available from: Support | pymol.org.

Ouzebla D, Ourhriss N, Fadare OA, Belghiti ME, El Abdallaoui HE, Zeroual A. Efficient Synthesis of Acyclic Nucleosides by N-Alkylation Using K2CO3 Supported with Natural Phosphate (K2CO3@NP) as Catalyst and Docking Study Against VIH. Chem Afri. 2022; 6(1): 881-890.

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

Kyei LK, Gasu EN, Ampomah GB, Mensah JO, Borquaye LS. An In Silico Study of the Interactions of Alkaloids from Cryptolepis sanguinolenta with Plasmodium falciparum Dihydrofolate Reductase and DihydroorotateDehydrogenase. J Chem. 2022; 2022.

Mishra K, Dash AP, Dey N. Andrographolide: A Novel Antimalarial Diterpene Lactone Compound from Andrographis paniculata and Its Interaction with Curcumin and Artesunate. J Trop Med. 2011; 2011: 579518.

Kim SK, Karadeniz F. Biological importance and applications of squalene and squalane. Adv Food Nut Res. 2012; 65: 223–233.

Huang ZR, Lin YK, Fang JY. Biological and pharmacological activities of squalene and related compounds: potential uses in cosmetic dermatology. Molecules. 2009; 14(1): 540-54.

Islam MT, Ali ES, Uddin SJ, Shaw S, Islam MA, Ahmed MI, Chandra Shill M, Karmakar UK, Yarla NS, Khan IN, Billah MM, Pieczynska MD, Zengin G, Malainer C, Nicoletti F, Gulei D, Berindan-Neagoe I, Apostolov A, Banach M, Yeung AWK, El-Demerdash A, Xiao J, Dey P, Yele S, Jóźwik A, Strzałkowska N, Marchewka J, Rengasamy KRR, Horbańczuk J, Kamal MA, Mubarak MS, Mishra SK, Shilpi JA, Atanasov AG. Phytol: A review of

biomedical activities. Food Chem Toxicol. 2018; 121: 82-94.

Bickerton GR, Paolini GV, Besnard J, Muresan S, Hopkins AL. Quantifying the chemical beauty of drugs. Nat Chem. 2012; 4(2): 90-98.

Published

2023-08-31

How to Cite

Olaosebikan, O. J., Faboro, E. O., Fadare, O. A., & Ikotun, A. A. (2023). <i>In silico</i> Investigation of the Antimalarial Activity of some Selected Alkaloids and Terpenoids Present in the Aerial Parts of <i>Andrographis paniculata</i>.: http://www.doi.org/10.26538/tjnpr/v7i8.33. Tropical Journal of Natural Product Research (TJNPR), 7(8), 3787–3799. Retrieved from https://tjnpr.org/index.php/home/article/view/2460