Synthesis and In vitro Leishmanicidal Activities of Six Quercetin Derivatives

Mohajeri, Maryam; Saghaei, Lotfollah; Ghanadian, Mustafa; Saberi, Sedighe; Pestechian, Nader; Ostadhusseini, Ehsan

Synthesis and In vitro Leishmanicidal Activities of Six Quercetin Derivatives

Document Type : Original Article

Authors

¹ Department of Medicinal Chemistry, Isfahan Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran

² Department of Pharmacognosy, School of Pharmacy and Pharmaceutical Sciences, Isfahan Pharmaceutical Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran

³ Department of Medical Mycoparasitology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

Abstract

Background: Today, leishmaniasis is a widespread, infectious parasitic disease caused by Leishmania spp. Natural-derived compounds are likely to provide a valuable source of new pharmaceuticals, and among them, quercetin derivatives may have antileishmanial effects. The antileishmanial activity of 3,5,7,3',4'-pentahydroxyflavonol (quercetin) derivatives is partly attributed to the position and pKa of phenolic or catechol hydroxyl groups. Therefore, to optimize their leishmanicidal effect, the structural features of quercetin and its derivatives were improved by acylation or alkylation of hydroxyl groups and changing their pKa and consequently their activities. Materials and Methods: In this study, during a regioselective method, quercetin derivatives were synthesized. The structures of synthesized compounds were confirmed by mass, IR, ¹H-, and ¹³C-NMR spectral data. The antileishmanial activities of compounds 1–6 were compared with glucantime as the standard drug against promastigotes of Leishmania major using standard cell-based leishmanicidal assay. Results: In this study, during a regioselective method, two 7-O-quercetin derivatives (5 and 6), and three quercetin acetate derivatives (2, 3, and 4) were synthesized. In detail, the IC₅₀values found against L. major were (1) 2.5 ± 0.92; (2) 2.85 ± 0.99; (3) 15.5 ± 1.95; (4) 13.5 ± 3.5; (5) 2.6 ± 0.57; and (6) 1.3 ± 0.35 μM while IC₅₀value of glucantime as the standard drug was 88.5 ± 9.47 μM. Conclusions: The present study showed an effective antileishmanial activity of quercetin semisynthetic compounds (1–6) against in vitro promastigotes of L. major. Among them, quercetin analogs with more lipophilic and iron-chelating activity showed more antiparasite activity.

Keywords

References

1.	Chen M, Christensen SB, Theander TG, Kharazmi A. Antileishmanial activity of licochalcone A in mice infected with Leishmania major and in hamsters infected with leishmania donovani. Antimicrob Agents Chemother 1994;38:1339-44. [PUBMED]
2.	Singh N, Kumar M, Singh RK. Leishmaniasis: Current status of available drugs and new potential drug targets. Asian Pac J Trop Med 2012;5:485-97. [PUBMED]
3.	Rocha LG, Almeida JR, Macêdo RO, Barbosa-Filho JM. A review of natural products with antileishmanial activity. Phytomedicine 2005;12:514-35.
4.	Croft SL, Seifert K, Yardley V. Current scenario of drug development for leishmaniasis. Indian J Med Res 2006;123:399-410. [PUBMED]
5.	Ouellette M, Drummelsmith J, Papadopoulou B. Leishmaniasis: Drugs in the clinic, resistance and new developments. Drug Resist Updat 2004;7:257-66. [PUBMED]
6.	Tasdemir D, Kaiser M, Brun R, Yardley V, Schmidt TJ, Tosun F, et al. Antitrypanosomal and antileishmanial activities of flavonoids and their analogues: In vitro, in vivo, structure-activity relationship, and quantitative structure-activity relationship studies. Antimicrob Agents Chemother 2006;50:1352-64. [PUBMED]
7.	Bhakuni DS, Satish S, Shukla YN, Tandon JS. Chemical constituents of Diospyros buxifolia, D. tomentosa, D. ferra, D. lotus, Rhus parviflora, Polygonum recumbens, Balanites aegyptiaca and Pyrus pashia. Phytochemistry. 1971;10:2829-31.
8.	Mattarei A, Biasutto L, Rastrelli F, Garbisa S, Marotta E, Zoratti M, et al. Regioselective O-derivatization of quercetin via ester intermediates. An improved synthesis of rhamnetin and development of a new mitochondriotropic derivative. Molecules 2010;15:4722-36. [PUBMED]
9.	Park HR, Yoon H, Kim MK, Lee SD, Chong Y. Synthesis and antiviral evaluation of 7-O-arylmethylquercetin derivatives against SARS-associated coronavirus (SCV) and hepatitis C virus (HCV). Arch Pharm Res 2012;35:77-85. [PUBMED]
10.	Zhong D, Liu M, Cao Y, Zhu Y, Bian S, Zhou J, et al. Discovery of metal ions chelator quercetin derivatives with potent anti-HCV activities. Molecules 2015;20:6978-99. [PUBMED]
11.	Asghari G, Zahabi F, Eskandarian A, Yousefi H, Asghari M. Chemical composition and leishmanicidal activity of Pulicaria gnaphalodes essential oil. Res J Pharm 2014;1:27-33.
12.	Sen G, Mukhopadhyay S, Ray M, Biswas T. Quercetin interferes with iron metabolism in Leishmania donovani and targets ribonucleotide reductase to exert leishmanicidal activity. J Antimicrob Chemother 2008;61:1066-75. [PUBMED]
13.	Huynh C, Andrews NW. Iron acquisition within host cells and the pathogenicity of Leishmania. Cell Microbiol 2008;10:293-300. [PUBMED]
14.	Ben-Othman R, Flannery AR, Miguel DC, Ward DM, Kaplan J, Andrews NW, et al. Leishmania-mediated inhibition of iron export promotes parasite replication in macrophages. PLoS Pathog 2014;10:e1003901.
15.	Soteriadou K, Papavassiliou P, Voyiatzaki C, Boelaert J. Effect of iron chelation on the in-vitro growth of Leishmania promastigotes. J Antimicrob Chemother 1995;35:23-9. [PUBMED]
16.	Iniesta V, Gómez-Nieto LC, Corraliza I. The inhibition of arginase by N (omega)-hydroxy-l-arginine controls the growth of Leishmania inside macrophages. J Exp Med 2001;193:777-84.
17.	Manjolin LC, dos Reis MB, do Carmo Maquiaveli C, Santos-Filho OA, da Silva ER. Dietary flavonoids fisetin, luteolin and their derived compounds inhibit arginase, a central enzyme in Leishmania (Leishmania) amazonensis infection. Food chemistry. 2013;141:2253-62.
18.	Fonseca-Silva F, Inacio JD, Canto-Cavalheiro MM, Almeida-Amaral EE. Reactive oxygen species production and mitochondrial dysfunction contribute to quercetin induced death in Leishmania amazonensis. PLoS One 2011;6:e14666. [PUBMED]
19.	Mittra B, Saha A, Chowdhury AR, Pal C, Mandal S, Mukhopadhyay S, et al. Luteolin, an abundant dietary component is a potent anti-leishmanial agent that acts by inducing topoisomerase II-mediated kinetoplast DNA cleavage leading to apoptosis. Mol Med 2000;6:527-41. [PUBMED]

Advanced Biomedical Research