In vitro and in silico Activity of Iridoids Against Leishmania amazonensis

Author(s): Maria Helena Vendruscolo, Gustavo Machado das Neves, Luciano Porto Kagami, Luiz Carlos Rodrigues Junior, Maria Luísa Nunes Diehl, Simone Cristina Baggio Gnoatto, Sérgio Augusto de Loreto Bordignon, Pedro Roosevelt Torres Romão, Vera Lucia Eifler-Lima, Gilsane Lino von Poser*

Journal Name: Current Drug Discovery Technologies

Volume 16 , Issue 2 , 2019

DOI : 10.2174/1570163814666171002102058

  Journal Home
Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Leishmaniasis reaches millions of people around the world. The control of the disease is difficult due to the restricted access to the diagnosis and medication, and low adherence to the treatment. Thus, more efficient drugs are needed and natural products are good alternatives. Iridoids, natural products with reported leishmanicidal activity, can be exploited for the development of anti- Leishmania drugs. The aim of this study was to isolate and to investigate the in vitro activity of iridoids against Leishmania amazonensis and to compare the activity in silico of these compounds with those reported as active against this parasite.

Methods: Iridoids were isolated by chromatographic methods. The in vitro activity of asperuloside (1) and geniposide (2) from Escalonia bifida, galiridoside (3) from Angelonia integerrima and theveridoside (4) and ipolamiide (5) from Amphilophium crucigerum was investigated against promastigote forms of Leishmania amazonensis. Molecular modeling studies of 1-5 and iridoids cited as active against Leishmania spp. were performed.

Results: Compounds 1-5 (5-100 µM) did not inhibit the parasite survival. Physicochemical parameters predicted for 1-5 did not show differences compared to those described in literature. The SAR and the pharmacophoric model confirmed the importance of maintaining the cyclopentane[C]pyran ring of the iridoid, of oxygen-linked substituents at the C1 and C6 positions and of bulky substituents attached to the iridoid ring to present leishmanicidal activity.

Conclusion: The results obtained in this study indicate that iridoids are a promising group of secondary metabolites and should be further investigated in the search for new anti-Leishmania drugs.

Keywords: Iridoids, Escalonia bifida, Angelonia integerrima, Amphilophium crucigerum, Leishmania, leishmanicidal activity, molecular modeling, pharmacophore.

[1]
Alvar J, Vélez ID, Bern C, et al. Leishmaniasis worldwide and global estimates of its incidence. PLoS One 2012; 7: e35671.
[2]
World Health Organization. Leishmania.2016. Available: http://www.who.int/gho/neglected_diseases/leishmaniasis/e/(cited: 2nd Aug 2017).
[3]
Ready PD. Epidemiology of visceral leishmaniasis. Clin Epidemiol 2014; 6: 147-54.
[4]
Ministério da Saúde. Orientações para uso racional do medicamento anfotericina B lipossomal utilizado para tratamento de pacientes com as leishmanioses. 2014. Available: http://portalsaude.saude.gov.br/index.php/o-ministerio/principal/leia-mais-o-ministerio/727-secretaria-svs/vigilancia-de-a-a-z/leishmaniose-visceral-lv/l1-leishmaniose-visceral-lv/14190-orientacoes-para-uso-racional-do-medicamento-anfotericina-b-lipossomal/ (cited: 16th jan 2017).
[5]
Tandon JS, Srivastava V, Guru PY. Iridoids: A new class of leishmanicidal agents from Nyctanthes arbortristis. J Nat Prod 1991; 54(4): 1102-4.
[6]
Mittal N, Gupta N, Goyal N, Roy U, Rastogi AK. Protective effect of picroliv from Picrorhiza kurroa against Leishmania donovani infections in Mesocricetus auratus. Life Sci 1998; 63(20): 1823-34.
[7]
Castillo D, Arevalo J, Herrera F, et al. Spirolactone iridoids might be responsible for the antileishmanial activity of a Peruvian traditional remedy made with Himatanthus sucuuba (Apocynaceae). J Ethnopharmacol 2007; 112: 410-4.
[8]
Sharma U, Singh D, Kumar P, Dobhal MP, Singh S. Antiparasitic activity of plumericin & isoplumericin isolated from Plumeria bicolor against Leishmania donovani. Indian J Med Res 2011; 135(5): 709-16.
[9]
Kirmizibekmez H, Atay I, Kaiser M, et al. Antiprotozoal activity of Melampyrum arvense and its metabolites. Phytother Res 2011; 25: 142-6.
[10]
Atay I, Kirmizibekmez H, Kaiser M, Akaydin G, Yesilada E, Tasdemir D. Evaluation of in vitro antiprotozoal activity of Ajuga laxmannii and its secondary metabolites. Pharm Biol 2016; 54(9): 1808-14.
[11]
Schuster D, Wolber G. Identification of bioactive natural products by pharmacophore-based virtual screening. Curr Pharm Des 2010; 16: 1666-81.
[12]
Rahim F. An in vitro development of selective inhibitor for histamine receptors. Biotechnology 2010; 9: 157-63.
[13]
Adibpour N, Rahim F, Rezaeei S, Ebrahimi A. in vitro designing selective inhibitor of drugs, medicinal plants compounds and experimental ligands for pteridine reductase targeting visceral leishmaniasis. Afr J Microbiol Res 2012; 6(5): 917-26.
[14]
Gangwar S, Baig MS, Shah P, Biswas S, Batra S, Siddiqi MI. Identification of novel inhibitors of dipeptidylcarboxypeptidase of Leishmania donovani via ligand-based virtual screening and biological evaluation. Chem Biol Drug Des 2012; 79(2): 149-56.
[15]
Kaur J, Kumar P, Tyagi S, Pathak R, Batra S, Singh P. in vitro screening, structure-activity relationship, and biologics evaluation of selective pteridine reductase inhibitors targeting visceral leishmaniasis. Antimicrob Agents Chemother 2011; 55(2): 659-66. a
[16]
Kaur J, Tiwari R, Kumar A, Singh N. Bioinformatic analysis of Leishmania donovani long-chain fatty acid-CoA ligase as a novel drug target. Mol Biol Int 2011; 2011: 278051.
[17]
Pomel S, Rodrigo J, Hendra F, Cave C, Loiseau PM. in vitro analysis of a therapeutic target in Leishmania infantum: The guanosine-diphospho-D-mannose pyrophosphorylase. Parasite 2012; 19(1): 63-70.
[18]
Macalino SJY, Gosu V, Hong S, Choi S. Role of computer-aided drug design in modern drug discovery. Arch Pharm Res 2015; 38: 1686-701.
[19]
Wermuth G, Ganellin CR, Lindberg P, Mitscher LA. Glossary of terms used in medicinal chemistry (IUPAC recommendations 1998). Pure Appl Chem 1998; 70(5): 1129-43.
[20]
Kaserer T, Beck KR, Akram M, Odermatt A, Schuster D. Pharmacophore models and pharmacophore-based virtual screening: Concepts and applications exemplified on hydroxysteroid dehydrogenases. Molecules 2015; 20: 22799-832.
[21]
Romão PRT, Tovar J, Fonseca SG, et al. Glutathione and the redox control system trypanothione/trypanothione reductase are involved in the protection of Leishmania spp. against nitrosothiol-induced cytotoxicity. Braz J Med Biol Res 2006; 39(3): 355-63.
[22]
Dagnino AP, Barros FM, Ccana-Ccapatinta GV, Prophiro JS, Poser GL, Romão PR. Leishmanicidal activity of lipophilic extracts of some Hypericum species. Phytomedicine 2015; 22: 71-6.
[23]
Sadowski J, Gasteiger J, Klebe G. Comparison of automatic three-dimensional model builders using 639 X-Ray structures. J Chem Inf Comput Sci 1994; 34: 1000-8.
[24]
WAVEFUNCTION WAVEFUNCTION Spartan'14 11 2014, 4 ed San Diego, California.
[25]
Cruciani G, Pastor M, Guba W. VolSurf: A new tool for the pharmacokinetic optimization of lead compounds. Eur J Pharm Sci 2000; 11(Suppl. 2): S29-39.
[26]
Daina A, Michielin O, Zoete V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep 2017; 7: 42717.
[27]
Tasdemir D, Güner N, Perozzo R, et al. Anti-protozoal and plasmodial FabI enzyme inhibiting metabolites of Scrophularia lepidota roots. Phytochemistry 2005; 66: 355-62.
[28]
Shukla AK, Patra S, Dubey VK. Iridoid glucosides from Nyctanthes arbortristis result in increased reactive oxygen species and cellular redox homeostasis imbalance in Leishmania parasite. Eur J Med Chem 2012; 54: 49-58.
[29]
Kirmizibekmez H, Çaliş I, Perozzo R, et al. Inhibiting activities of the secondary metabolites of Phlomis brunneogaleata agains parasitic protozoa and plasmodial enoyl-ACP Reductase, a crucial enzyme in fatty acid biosynthesis. Planta Med 2004; 70: 711-7.
[30]
Theobald DL, Wuttke DS. THESEUS: Maximum likelihood superpositioning and analysis of macromolecular structures. Bioinformatics 2006; 22: 2171-2.
[31]
Krieger E, Vriend G. YASARA View – molecular graphics for all devices – from smartphones to workstations. Bioinformatics 2014; 30(20): 2981-2.
[32]
ACCELRYS - Discovery studio modeling environment 2013, 40 ed San Diego, California: Accelrys Software Inc .
[33]
Amoa-Bosompem M, Ohashi M, Mosore M-T, et al. in vitro anti-Leishmania activity of tetracyclic iridoids from Morinda lucida, benth. Trop Med Health 2016; 44(25): 1-5.
[34]
Abdel-Mageed WM, Backheet EY, Khalifa AA, Ibraheim ZZ, Ross SA. Antiparasitic antioxidant phenylpropanoids and iridoid glycosides from Tecoma mollis. Fitoterapia 2012; 83: 500-7.
[35]
Vaidya HB, Ahmed AA, Goyal RK, Cheema SK. Glycogen phosphorylase-a is a common target from anti-diabetic effect of iridoid and secoiridoid glycosides. J Pharm Pharm Sci 2013; 16(4): 530-40.
[36]
Almeida-Souza F, Cardoso FO, Souza BVCS, Valle TZ. Morinda citrifolia Linn. reduces parasite load and modulates cytokines and extracellular matrix proteins in C57BL/6 mice infected with Leishmania (Leishmania) amazonensis. PLoS Negl Trop Dis 2016a; 10(8): 1-17.
[37]
Beig M, Oellien F, Garoff L, Noack S, Krauth-Siegel RL, Selzer PM. Trypanothione Reductase: A target protein for a combined in vitro and in vitro screening approach. PLoS Negl Trop Dis 2014; 9(6): 1-19.
[38]
Shukla AN, Patra S, Dubey VK. Deciphering molecular mechanism underlying antileishmanial activity of Nyctanthes arbortristis, an Indian medicinal plant. J Ethnopharmacol 2011; 134: 996-8.
[39]
Almeida-Souza F, Souza CSF, Taniwaki NN. Morinda citrifolia Linn. fruit (Noni) juice induces an increase in NO production and death of Leishmania amazonensis amastigotes in peritoneal macrophages from BALB/c. Nitric Oxide 2016b; 58: 51-8.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 16
ISSUE: 2
Year: 2019
Published on: 24 June, 2019
Page: [173 - 183]
Pages: 11
DOI: 10.2174/1570163814666171002102058
Price: $65

Article Metrics

PDF: 40
HTML: 4



Related Article(s)

Most Downloaded Article(s)