Login Register Cart 0
Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Letter Article

Evaluation of a Series of 9,10-Anthraquinones as Antiplasmodial Agents

Author(s): Che Puteh Osman*, Nor Hadiani Ismail, Aty Widyawaruyanti, Syahrul Imran, Lidya Tumewu, Chee Yan Choo and Sharinah Ideris

Volume 16, Issue 3, 2019

Page: [353 - 363] Pages: 11

DOI: 10.2174/1570180815666180607085102

Price: $65

Abstract

Background: A phytochemical study on medicinal plants used for the treatment of fever and malaria in Africa yielded metabolites with potential antiplasmodial activity, many of which are Anthraquinones (AQ). AQs have similar sub-structure as naphthoquinones and xanthones, which were previously reported as novel antiplasmodial agents.

Objective: The present study aimed to investigate the structural requirements of 9,10- anthraquinones with hydroxy, methoxy and methyl substituents to exert strong antiplasmodial activity and to investigate their possible mode of action.

Methods: Thirty-one AQs were synthesized through Friedel-Crafts reaction and assayed for antiplasmodial activity in vitro against Plasmodium falciparum (3D7). The selected compounds were tested for toxicity and probed for their mode of action against β-hematin dimerization through HRP2 and lipid catalyses. The most active compounds were subjected to a docking study using AutoDock 4.2.

Results: The active AQs have similar common structural characteristics. However, it is difficult to establish a structure-activity relationship as certain compounds are active despite the absence of the structural features exhibited by other active AQs. They have either ortho- or meta-arranged substituents and one free hydroxyl and/or carbonyl groups. When C-6 is substituted with a methyl group, the activity of AQs generally increased. 1,3-DihydroxyAQ (15) showed good antiplasmodial activity with an IC50 value of 1.08 µM, and when C-6 was substituted with a methyl group, 1,3- dihydroxy-6-methylAQ (24) showed stronger antiplasmodial activity with an IC50 value of 0.02 µM, with better selectivity index. Compounds 15 and 24 showed strong HRP2 activity and mild toxicity against hepatocyte cells. Molecular docking studies showed that the hydroxyl groups at the ortho (23) and meta (24) positions are able to form hydrogen bonds with heme, of 3.49 Å and 3.02 Å, respectively.

Conclusion: The activity of 1,3-dihydroxy-6-methylAQ (24) could be due to their inhibition against the free heme dimerization by inhibiting the HRP2 protein. It was further observed that the anthraquinone moiety of compound 24 bind in parallel to the heme ring through hydrophobic interactions, thus preventing crystallization of heme into hemozoin.

Keywords: Anthraquinone, synthesis, antiplasmodial, malaria, Plasmodium falciparum, beta-hematin, HRP2.

« Previous Next »
Graphical Abstract

[1]
Chan-Bacab, M.J.; Pena-Rodriguez, L.M. Plant natural products with antileishmanicidal activity. Nat. Prod. Rep., 2001, 18, 674-688.
[2]
WHO. World malaria report 2017; WHO: Switzerland, 2017.
[3]
Pink, R.; Hudson, A.; Mouries, M-A.; Bendig, M. Opportunities and Challenges in antiparasitic drug discovery. Nat. Rev. Drug Dis., 2005, 4, 727-740.
[4]
Egan, T.J. Haemozoin (malaria pigment): A unique crystalline drug target. TARGETS, 2003, 2, 115-124.
[5]
Sullivan, D.J. Theories on malarial pigment formation and quinoline action. Int. J. Parasitol., 2002, 32, 1645-1653.
[6]
Cowman, A.F.; Foote, S.J. Chemotherapy and drug resistance in malaria. Int. J. Para., 1990, 20, 503-513.
[7]
Kumar, S.; Guha, M.; Choubey, V.; Maity, P.; Bandyopadhyay, U. Antimalarial drugs inhibiting hemozoin (β-hematin) formation: A mechanistic update. Life Sci., 2007, 80, 813-828.
[8]
Rathore, D.; Jani, D.; Nagarkatti, R.; Kumar, S. Heme detoxification and antimalarial drugs - known mechanisms and future prospects. Drug Dis. Today Therap. Strateg., 2006, 3, 153-158.
[9]
Egan, T.J.; Chen, J.Y-J.; de Villiers, K.A.; Mabotha, T.E.; Naidoo, K.J.; Ncokazi, K.K.; Langford, S.J.; McNaughton, D.; Pandiancherri, S.; Wood, B.R. Haemozoin (beta-haematin) biomineralization occurs by self-assembly near the lipid/water interface. FEBS Lett., 2006, 580, 5105-5110.
[10]
Sittie, A.A.; Lemmich, E.; Olsen, C.E.; Hviid, L.; Kharazmi, A.; Nkrumah, F.K.; Christensen, S.B. Structure-activity studies: In vitro antileishmanial and antimalarial activities of anthraquinones from Morinda lucida. Planta Medica., 1999, 65, 259-261.
[11]
Eyong, K.O.; Folefoc, G.N.; Kuete, V.; Beng, V.P.; Krohn, K.; Hussain, H.; Nkengfack, A.E.; Saeftel, M.; Sarite, S.R.; Hoerauf, A. New bouldiaquinone A: A naphthoquinone-anthraquinone ether coupled pigment, as a potential antimicrobial and antimalarial agent from New bouldia laevis. Phytochemistry, 2006, 67, 605-609.
[12]
Abegaz, B.M. Bezabih, M.; Msuta, T.; Brun, R.; Menche, D.; Muhlbacher, J.; Bringmann, G.; Gaboroquinones A and B and 4′-O-Demethylknipholone-4′-O-β-D-glucopyranoside, Phenylanthraquinones from the Roots of Bulbine frutescens. J. Nat. Prod., 2002, 65, 1117-1121.
[13]
Ajaiyeoba, E.O.; Ashidi, J.S.; Okpako, L.C.; Houghton, P.J.; Wright, C.W. Antiplasmodial compounds from Cassia siamea stem bark extract. Phytother. Res., 2008, 22, 254-255.
[14]
Abdissa, N.; Induli, M.; Akala, H.M.; Heydenreich, M.; Midiwo, J.O.; Ndakala, A.; Yenesew, A. Knipholone cyclooxanthrone and an anthraquinone dimer with antiplasmodial activities from the roots of Kniphofia foliosa. Phytochem. Lett., 2013, 6, 241-245.
[15]
Onegi, B.; Kraft, C.; Köhler, I.; Freund, M.; Jenett-Siems, K.; Siems, K.; Beyer, G.; Melzig, M.F.; Bienzle, U.; Eich, E. Antiplasmodial activity of naphthoquinones and one anthraquinone from Stereospermum kunthianum. Phytochemistry, 2002, 60, 39-44.
[16]
Kopa, T.K.; Tchinda, A.T.; Tala, M.F.; Zofou, D.; Jumbam, R.; Wabo, H.K.; Titanji, V.P.K.; Frédérich, M.; Tan, N-H.; Tane, P. Antiplasmodial anthraquinones and hemisynthetic derivatives from the leaves of Tectona grandis (Verbenaceae). Phytochem. Lett., 2014, 8, 41-45.
[17]
Endale, M.; Ekberg, A.; Alao, J.; Akala, H.; Ndakala, A.; Sunnerhagen, P.; Erdélyi, M.; Yenesew, A. Anthraquinones of the Roots of Pentas micrantha. Molecules, 2012, 18, 311.
[18]
Endale, M.; Alao, J.P.; Akala, H.M.; Rono, N.K.; Eyase, F.L.; Derese, S.; Ndakala, A.; Mbugua, M.; Walsh, D.S.; Sunnerhagen, P.; Erdelyi, M.; Yenesew, A. Antiplasmodial quinones from pentas longiflora and pentas lanceolata. Planta Med., 2012, 78, 31-35.
[19]
Lai, J-M.; Chang, J.T.; Wen, C-L.; Hsu, S-L. Emodin induces a reactive oxygen species-dependent and ATM-p53-Bax mediated cytotoxicity in lung cancer cells. European . J. Pharmacol., 2009, 623, 1-9.
[20]
Winter, R.W.; Cornell, K.A.; Johnson, L.L.; Ignatushchenko, M.V.; Hinrichs, D.J.; Roscoe, M.K. Potentiation of the antimalarial agents rufigallol. Antimicrobial . Agents Chemother., 1996, 40, 1408-1411.
[21]
Gutierrez, P.L. The metabolism of quinone-containing alkylating agents: Free radical production and measurement. Front. Biosci., 2001, 5, d629-d638.
[22]
Winter, R.W.; Cornell, K.A.; Johnson, L.L.; Isabelle, L.M.; Hinrichs, D.J.; Riscoe, M.K. Hydroxy-anthraquinones as antimalarial agents. Bioorgan. Med. Chem. Lett., 1995, 5, 1927-1932.
[23]
Ignatushchenko, M.V.; Winter, R.W.; Bachinger, H.P.; Hinrichs, D.J.; Riscoe, M.K. Xanthones as antimalarial agents; studies of a possible mode of action. FEBS Lett., 1997, 409, 67-73.
[24]
Osman, C.P.; Ismail, N.H.; Ahmad, R.; Ahmat, N.; Awang, K.; Jaafar, F.M. Anthraquinones with antiplasmodial activity from the roots of Rennellia elliptica Korth. (Rubiaceae). Molecules, 2010, 15, 7218-7226.
[25]
Singh, R. Geetanjali, isolation and synthesis of anthraquinones and related compounds of Rubia cordifolia. J. Serbian . Chem. Soc., 2005, 70, 937-942.
[26]
Brieger, G.; Pelletier, W.M. Oxygen alkylation in the ethyl acetoacetate synthesis. Tetrahedron Lett., 1965, 6, 3555-3558.
[27]
Inoue, K.; Ueda, S.; Nayeshiro, H.; Inouyet, H. Quinones of Streptocarpus dunnii. Phytochemistry, 1983, 22, 737-741.
[28]
Widyawaruyanti, A.S.; Kalauni, S.K.; Awale, S.; Nindatu, M.; Zaini, N.C.; Syafruddin, D.; Asih, P.B.S.; Tezuka, Y.; Kadota, S. New prenylated flavones from Artocarpus champeden and their antimalarial activity in vitro. J. Nat. Med., 2007, 61, 410-413.
[29]
Xuan, T.D.T.; Huy, N.T.; Uyen, D.T.; Sasai, M.; Shiono, T.; Harada, S.; Kamei, K. Inhibition assay of β-hematin formation initiated by lecithin for screening new antimalarial drugs. Analyt. Biochem., 2006, 349, 292-296.
[30]
Huy, N.T.; Uyen, D.T.; Sasai, M.; Trang, D.T.X.; Shiono, T.; Harada, S.; Kamei, K. A simple and rapid colorimetric method to measure hemozoin crystal growth in vitro. Analyt. Biochem., 2006, 354, 305-307.
[31]
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J. Immunolog. Methods, 1983, 65, 55-63.
[32]
Ismail, N.H.; Ali, A.M.; Aimi, N.; Kitajima, M.; Takayama, H.; Lajis, N.H. Anthraquinones from Morinda elliptica. Phytochemistry, 1997, 45, 1723-1725.
[33]
Ismail, N.H. Chemistry and biological activity of anthraquinones from Morinda elliptica (Rubiaceae). Thesis, Universiti Putra Malaysia, Serdang. 1998.
[34]
Saha, K. The synthesis and bioactivity study of anthraquinones and the isolation of bioactive compounds from leea indica (Burm, F.) Merr. Thesis, Universiti Putra Malaysia, Serdang. 2005.

Rights & Permissions Print Cite
Article Metrics
35
6
© 2024 Bentham Science Publishers | Privacy Policy