Plasmodium falciparum is the cause of malaria and has become resistant to the drugs used to treat the disease. Therefore, the development for novel compounds with antimalarial activity has become urgent. Plant species, such as naphthoquinone-rich Eleutherine plicata, may provide novel substances that exhibit antimalarial activity and serve as an alternative for the treatment of this disease. From this plant species, ethanol extracts were obtained, fractionated, and the isolated substances eleutherin, and isoleutherin were characterized by nuclear magnetic resonance. There in vitro activity against Plasmodium falciparum was examined using the traditional Microtest method using the extract, fractions, and isolated molecules. Eleutherin and isoleutherin showed the best activity toward the parasite with IC50 values of 10.45 and 8.70 µg/mL, respectively. Characterization of the binding mode of the compounds with a target enzyme and identification of the molecular interactions were revealed via molecular docking results. Eleutherin and isoeleutherin interacted with highly conserved residues from the binding cavity of the cytochrome bc1 complex, a protein found in mitochondria. Therefore, the eleutherin and isoeleutherin naphthoquinones showed antiplasmodial activity with a similar mechanism to that of atovaquone were able to interact with the cytochrome bc1 complex, and showed promise for antimalarial treatments.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
Alves TMA, Kloos H, Zani CL (2003) Eleutherinone, a novel fungitoxic naphthoquinone from Eleutherine bulbosa (Iridaceae). Mem Inst Oswaldo Cruz. https://doi.org/10.1590/S0074-02762003000500021
Alves FS, de AR do Rego J, da Costa ML et al. (2019) Spectroscopic methods and in silico analyses using density functional theory to characterize and identify piperine alkaloid crystals isolated from pepper (Piper nigrum L.). J Biomol Struct Dyn. https://doi.org/10.1080/07391102.2019.1639547
Becke AD (1993) Density‐functional thermochemistry. III. The role of exact exchange. J Chem Phys. 98:5648–5652. https://doi.org/10.1063/1.464913
Birth D, Kao W-C, Hunte C (2014a) Structural analysis of atovaquone-inhibited cytochrome bc1 complex reveals the molecular basis of antimalarial drug action. Nat Commun 5:4029. https://doi.org/10.1038/ncomms5029
Birth D, Kao W, Hunte C (2014b) Structural analysis of mitochondrial cytochrome bc1 complex with atovaquone bound reveals the molecular basis of antimalarial drug action. Malar J 13: https://doi.org/10.1186/1475-2875-13-s1-p103
Lambros C, Vanderberg JP (1979) Synchronization of Plasmodium falciparum erythrocytic stages in culture. J Parasitol 65:418–420
Carvalho LH, Krettli AU (1991) Antimalarial chemotherapy with natural products and chemically defined molecules. Mem Inst Oswaldo Cruz. https://doi.org/10.1590/S0074-02761991000600041
Couto CLL, Moraes DFC, Cartágenes M, do SS et al. (2016) Eleutherine bulbous (Mill.) Urb.: a review study. J Med Plants Res. 10:286–297. https://doi.org/10.5897/JMPR2016.6106
Cowman AF, Healer J, Marapana D, Marsh K (2016) Malaria: biology and disease. Cell 167:610–624
da Costa KS, Galúcio JM, da Costa CHS, et al. (2019) Exploring the potentiality of natural products from essential oils as inhibitors of odorant-binding proteins: a structure- and ligand-based virtual screening approach to find novel mosquito repellents. ACS Omega acsomega. 9b03157. https://doi.org/10.1021/acsomega.9b03157
Das S, Tripathy S, Chattopadhayay S et al. (2017) Progressive increase in point mutations associates chloroquine resistance: even after withdrawal of chloroquine use in India. Int J Parasitol Drugs drug Resist 7:251–261. https://doi.org/10.1016/j.ijpddr.2017.06.002
Dennington R, Keith TA, Millam JM (2016) GaussView Version 6 Semichem Inc., Shawnee Mission, KS
Dolabela MF, Martins MT, Brandao DLDN et al. (2015a) Method for producing a plant extract and fraction, pharmaceutical compositions and use there of, United States, Patent Application Publication, Pub. No.: US 2015/0132421 A1, Pub. Date: 14 May 2015
Dolabela MF, Póvoa MM, Brandão GC, et al. (2015b) Aspidosperma species as sources of anti-malarials: uleine is the major anti-malarial indole alkaloid from Aspidosperma parvifolium (Apocynaceae). Malar J. https://doi.org/10.1186/s12936-015-0997-4
Frisch MJ, Trucks GW, Schlegel HB, et al. (2016) Gaussian 16, Revision B.01. Gaussian, Inc., Wallingford, CT
Gallo FR, Palazzino G, Federici E et al. (2010) Polyketides from Eleutherine bulbosa. Nat Prod Res. 24:1578–1586. https://doi.org/10.1080/14786419.2010.500007
Geleta G, Ketema T (2016) Severe malaria associated with Plasmodium falciparum and P. vivax among children in Pawe Hospital, Northwest Ethiopia. Malar Res Treat 2016:1–7. https://doi.org/10.1155/2016/1240962
Hara H, Maruyama N, Yamashita S, et al. (2011) Elecanacin, a novel new naphthoquinone from the bulb of Eleutherine americana. Chem Pharm Bull. https://doi.org/10.1248/cpb.45.1714
Hong J-H, Yu ES, Han A-R et al. (2008) Isoeleutherin and eleutherinol, naturally occurring selective modulators of Th cell-mediated immune responses. Biochem Biophys Res Commun 371:278–282. https://doi.org/10.1016/j.bbrc.2008.04.060
Imperatore C, Persico M, Senese M et al. (2019) Exploring the antimalarial potential of the methoxy-thiazinoquinone scaffold: Identification of a new lead candidate. Bioorg Chem. 85:240–252. https://doi.org/10.1016/j.bioorg.2018.12.031
Junior M, Leite F, Santos C, et al. (2019) In silico study to identify new antituberculosis molecules from natural sources by hierarchical virtual screening and molecular dynamics simulations. Pharmaceuticals. https://doi.org/10.3390/PH12010036
Kessl JJ, Lange BB, Merbitz-Zahradnik T et al. (2003) Molecular basis for atovaquone binding to the cytochrome bc1 complex. J Biol Chem. 278:31312–31318. https://doi.org/10.1074/jbc.M304042200
Klotz LO, Hou X, Jacob C (2014) 1,4-naphthoquinones: from oxidative damage to cellular and inter-cellular signaling. Molecules. https://doi.org/10.3390/molecules190914902
Kusuma IW, Arung ET, Rosamah E et al. (2010) Antidermatophyte and antimelanogenesis compound from Eleutherine americana grown in Indonesia. J Nat Med. 64:223–226. https://doi.org/10.1007/s11418-010-0396-7
López LIL, Flores SDN, Belmares SYS, Galindo AS (2014) Naphthoquinones: biological properties and synthesis of lawsone and derivatives - a structured review. VITAE 21:248–258
Moreira DRM, De Sá MS, Macedo TS et al. (2015) Evaluation of naphthoquinones identified the acetylated isolapachol as a potent and selective antiplasmodium agent. J Enzyme Inhib Med Chem. https://doi.org/10.3109/14756366.2014.958083
Nam MW, Zhao J, Lee MS et al. (2015) Enhanced extraction of bioactive natural products using tailor-made deep eutectic solvents: application to flavonoid extraction from Flos sophorae. Green Chem. https://doi.org/10.1039/c4gc01556h
Neves Cruz J, da Costa KS, de Carvalho TAA, de Alencar NAN (2019a) Measuring the structural impact of mutations on cytochrome P450 21A2, the major steroid 21-hydroxylase related to congenital adrenal hyperplasia. J Biomol Struct Dyn. https://doi.org/10.1080/07391102.2019.1607560
Neves Cruz J, Oliveira M, Gomes Silva S et al. (2019b) Insight into the interaction mechanism of nicotine, NNK and NNN with cytochrome P450 2A13 based on molecular dynamics simulation. J Chem Inf Model ACS 9b00741. https://doi.org/10.1021/acs.jcim.9b00741
Newman DJ, Cragg GM (2016) Natural products as sources of new drugs from 1981 to 2014. J Nat Prod 79:629–661
Paramapojn S, Ganzera M, Gritsanapan W, Stuppner H (2008) Analysis of naphthoquinone derivatives in the Asian medicinal plant Eleutherine americana by RP-HPLC and LC-MS. J Pharm Biomed Anal 47:990–993. https://doi.org/10.1016/j.jpba.2008.04.005
Phillips MA, Burrows JN, Manyando C et al. (2017) Malaria. Nat Rev Dis Prim 3: https://doi.org/10.1038/nrdp.2017.50
Rahmatullah M, Rahman T, Jahan R (2012) Anti-malarial plants used in folk medicine in Bangladesh. In: M. K. Rai, Geoffrey A. Cordell, Jose L. Martinez, Mariela Marinoff LR (eds) Medicinal Plants: Biodiversity and Drugs, 1st edn. CRC Press, pp 241–290
Ramos RS, Macêdo WJC, Costa JS et al. (2019) Potential inhibitors of the enzyme acetylcholinesterase and juvenile hormone with insecticidal activity: study of the binding mode via docking and molecular dynamics simulations. J Biomol Struct Dyn 1–31. https://doi.org/10.1080/07391102.2019.1688192
René Thomsen MHC, Thomsen R, Christensen MH (2006) MolDock: a new technique for high-accuracy molecular docking. J Med Chem. 49:3315–3321. https://doi.org/10.1021/jm051197e
Rieckmann KH, Campbell GH, Sax LJ, Mrema JE (1978) Drug sensitivity of Plasmodium falciparum. an in-vitro microtechnique. Lancet 1:22–23. https://doi.org/10.1016/s0140-6736(78)90365-3
Rodrigues SV, Viana LM, Baumann W (2006) UV/Vis spectra and solubility of some naphthoquinones, and the extraction behavior of plumbagin from Plumbago scandens roots in supercritical CO2. Anal Bioanal Chem. 385:895–900. https://doi.org/10.1007/s00216-006-0502-6
Siciliano G, Alano P (2015) Enlightening the malaria parasite life cycle: Bioluminescent Plasmodium in fundamental and applied research. Front Microbiol 6:1–8. https://doi.org/10.3389/fmicb.2015.00391
Singh B, Daneshvar C (2013) Human infections and detection of Plasmodium knowlesi. Clin Microbiol Rev 5: https://doi.org/10.1128/CMR.00079-12
Siregar JE, Kurisu G, Kobayashi T et al. (2015) Direct evidence for the atovaquone action on the Plasmodium cytochrome bc1 complex. Parasitol Int. 64:295–300. https://doi.org/10.1016/j.parint.2014.09.011
Talapko Škrlec, Alebić et al. (2019) Malaria: the past and the present. Microorganisms 7:179. https://doi.org/10.3390/microorganisms7060179
Tewierik LM, Dimitriadis C, Donner CD et al. (2006) Total synthesis of enantiopure 1,3-dimethylpyranonaphthoquinones including ventiloquinones E, G, L and eleutherin. Org Biomol Chem. 4:3311–3318. https://doi.org/10.1039/b607366b
Vaidya AB, Mather MW (2009) Mitochondrial evolution and functions in malaria parasites. Annu Rev Microbiol 63:249–267. https://doi.org/10.1146/annurev.micro.091208.073424
Wang Z, Shrestha S, Li X et al. (2015) Prevalence of K13-propeller polymorphisms in Plasmodium falciparum from China-Myanmar border in 2007-2012. Malar J. 14:168. https://doi.org/10.1186/s12936-015-0672-9
WHO (2018) World Malaria Report. World Health Organization, Geneva
This study was financed in part by the Coordination of Superior Level Staff Improvement (CAPES) and National Council for Scientific and Technological Development (CNPq).
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Vale, V.V., Cruz, J.N., Viana, G.M.R. et al. Naphthoquinones isolated from Eleutherine plicata herb: in vitro antimalarial activity and molecular modeling to investigate their binding modes. Med Chem Res 29, 487–494 (2020). https://doi.org/10.1007/s00044-019-02498-z
- Eleutherine plicata
- Antimalarial activity
- Molecular modeling