• View in gallery

    A, Structure of diethylcarbamazine (DEC). B, The proposed Michael-type addition of glutathione to chalcones mediated by glutathione-S-transferase.

  • View in gallery

    Various substituted chalcones exploited in the study.

  • 1

    Reed DJ, 1995. Molecular and Cellular Mechanisms of Toxicity. Boca Raton, FL: CRC Press.

  • 2

    Ottesen EA, Vijayaseksran V, Kumaraswami V, Pillai SVP, Sadanandam A, Sheila F, Prabhakar R, Tripathy SP, 1990. A controlled trial of ivermectin and diethylcarbamazine in lymphatc filariasis. N Engl J Med 322 :1113–1117.

    • Search Google Scholar
    • Export Citation
  • 3

    Nathan ST, Methew N, Kalyanasundaram M, Balaraman K, 2005. Structure of glutathione S-transferase of the filarial parasite Wuchereria bancrofti: a target for drug development against adult worm. J Mol Model 11 :194–199.

    • Search Google Scholar
    • Export Citation
  • 4

    Bennett JL, Williams JF, Dave V, 1988. Pharmacology of ivermectin. Parasitol Today 4 :226–228.

  • 5

    Ginger CD, 1986. Advances in filarial chemotherapy and screening. Parasitol Today 2 :38–40.

  • 6

    Loiseau PM, 1993. In vitro antifilarial evaluation of phenoxycyclohexane derivatives. Ann Trop Med Parasitol 87 :469–476.

  • 7

    Singh SN, Bhatnagar S, Fatma N, Chauhan PMS, Chatterjee RK, 1997. Antifilarial activity of a synthetic marine alkaloid aplysinospin. Trop Med Int Health 2 :535–543.

    • Search Google Scholar
    • Export Citation
  • 8

    Townsend LB, Wise DS, 1990. The synthesis and chemistry of certain antihelmintic benzimidazole. Parasitol Today 6 :107–112.

  • 9

    Mannervik B, Danielson UH, 1988. Glutathione transferases, structure and catalytic activity. CRC Crit Rev Biochem 23 :283–337.

  • 10

    Gomez FJS, Gayarre J, Avellano MI, Sala DP, 2007. Direct evidence for the covalent modification of glutathione S-transferase Pf-1 by electrophilic prostaglandins: implications for enzyme inactivation and cell survival. Arch Biochem Biophys 457 :150–159.

    • Search Google Scholar
    • Export Citation
  • 11

    Ibarraa CMP, Grillob ML, Belloc M, Nucettellic TK, Atkinsa Bammlerd WM, 2003. Exploration of in vitro pro-drug activation and futile cycling by glutathione S-transferases: thiol ester hydrolysis and inhibitor maturation. Arch Biochem Biophys 414 :303–311.

    • Search Google Scholar
    • Export Citation
  • 12

    Nielsen SF, Larsen M, Bosen T, Schonning K, Kromann H, 2005. Cationic chalcone antibiotics. design, synthesis, and mechanism of action. J Med Chem 48 :2667–2677.

    • Search Google Scholar
    • Export Citation
  • 13

    Mishra N, Arora P, Kumar B, Mishra LC, Bhattacharya A, Awasthi SK, Bhasin VK, 2008. Synthesis of novel susbtituted 1,3-diaryl propenone derivatives and their antimalarial activity in vitro. Eur J Med Chem 43 :1530–1535.

    • Search Google Scholar
    • Export Citation
  • 14

    Awasthi SK, Mishra N, Kumar B, Sharma M, Mishra LC, Bhattacharya A, Bhasin VK, Potent antimalarial activity of newly synthesized substituted chalcone analogs in vitro. Med Chem Res. DOI: 10.1007/s00044-008-9137-9.

    • Search Google Scholar
    • Export Citation
  • 15

    Robinson PT, Hubbard RB IV, Ehlers TJ, Arbiser JL, Goldsmith DJ, Bowen PJ, 2005. Synthesis and biological evaluation of aromatic enones related to curcumin. Bioorg Med Chem 13 :4007–4013.

    • Search Google Scholar
    • Export Citation
  • 16

    Vaya J, Belinky PA, Aviram M, 1997. Antioxidant constituents from licorice roots: isolation, structure elucidation and antioxidative capacity toward LDL oxidation. Free Radic Biol Med 23 :302–313.

    • Search Google Scholar
    • Export Citation
  • 17

    Khatib S, Nerya O, Musa R, Shmuel M, Tamir S, Vaya J, 2005. Chalcones as potent tyrosinase inhibitors: the importance of a 2,4-substituted resorcinol moiety. Bioorg Med Chem 13 :433–441.

    • Search Google Scholar
    • Export Citation
  • 18

    Chen M, Theander TG, Christensen BS, Hviid L, Zhai L, Kharazmi A, 1994. Licochalcone A, a new antimalarial agent, inhibits in vitro growth of the human malaria parasite Plasmodium falciparum and protects mice from P. yoelii infection. Antimicrob Agents Chemother 38 :1470–1475.

    • Search Google Scholar
    • Export Citation
  • 19

    Li R, Kenyon GL, Cohen FE, Chen X, Gong B, Dominguez JN, Davidson E, Kurzban G, Miller RE, Nuzum EO, Rosenthal PJ, McKerrow JH, 1995. In vitro antimalarial activity of chalcones and their derivatives. J Med Chem 38 :5031–5037.

    • Search Google Scholar
    • Export Citation
  • 20

    Gupta S, Rathaur S, 2005. Filarial glutathione S-transferase: its induction by xenobiotics and potential as drug target. Acta Biochim Pol 52 :493–500.

    • Search Google Scholar
    • Export Citation
  • 21

    Gupta S, Singh A, Yadav M, Singh K, Rathaur S, 2007. MALDI mass sequencing and characterization of filarial glutathione-S-transferase. Biochem Biophys Res Commun 356 :381–385.

    • Search Google Scholar
    • Export Citation
  • 22

    Bradford MM, 1976. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72 :248–254.

    • Search Google Scholar
    • Export Citation
  • 23

    Mosmann TR, Coffman RL, 1989. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 7 :145–173.

    • Search Google Scholar
    • Export Citation
  • 24

    Habig WH, Pabst MJ, Jakoby WB, 1974. Glutathione-S-transferase: the first enzymatic step in mercapturic acid formation. J Biol Chem 249 :7130–7139.

    • Search Google Scholar
    • Export Citation
  • 25

    Ellman GL, 1959. Tissue sulfhydryl groups. Arch Biochem Biophys 82 :70–77.

  • 26

    Jaiswal AK, 2004. Nrf2 signalling in activation of gene expression, free radical coordinated. Biol Med (Paris) 36 :1199–1207.

  • 27

    Liu YC, Hsieh CW, Wu CC, Wung BS, 2007. Chalcone inhibits the activation of NF-γ B and STAT3 in endothelial cells via endogenous electrophile. Life Sci 80 :1420–1430.

    • Search Google Scholar
    • Export Citation
  • 28

    Huang J, Tan PH, Tan BK, Bay BH, 2004. GST-pi expression correlates with oxidative stress and apoptosis in breast cancer. Oncol Rep 12 :921–925.

    • Search Google Scholar
    • Export Citation
  • 29

    Forkert PG, Costa DD, Mestrah ME, 1999. Expression and inducibility of Alpha, Pi and Mu glutathione-S-transferase protein and mRNA in murine lung. Am J Respir Cell Mol Biol 20 :143–152.

    • Search Google Scholar
    • Export Citation
  • 30

    Nguyen T, Yang CS, Pickett CB, 2004. The pathways and molecular mechanisms regulating Nrf2 activation in response to chemical stress. Free Radic Biol Med 37 :433–441.

    • Search Google Scholar
    • Export Citation
  • 31

    Kawalek JC, Rew RS, Heavner J, 1984. Glutathione S-transferase a possible drug metabolizing enzyme in Haemouchus contoras: comparative activity of cambendazole resistant and susceptible strain. Int J Parasitol 14 :173–175.

    • Search Google Scholar
    • Export Citation
  • 32

    Brophy PM, Campbell AM, van Eldik AJ, Teesdale-Spittle PH, Liebau E, Wang MF, 2000. β-Carbonyl substituted glutathione conjugates as inhibitors of O. volvulus GST2. Bioorg Med Chem Lett 10 :979–981.

    • Search Google Scholar
    • Export Citation
  • 33

    Brophy PM, Barrett J, 1990. Glutathione transferase in helminths. Parasitol 100 :345–349.

  • 34

    Rathaur S, Yadav M, Gupta S, Anandharaman V, Reddy MVR, 2008. Filarial glutathione-S-transferase: a potential vaccine candidate against lymphatic filariasis. Vaccine 26 :4094–4100.

    • Search Google Scholar
    • Export Citation

 

 

 

 

Antifilarial Activity of 1,3-Diarylpropen-1-One: Effect on Glutathione-S-Transferase, a Phase II Detoxification Enzyme

View More View Less
  • 1 Chemical Biology Laboratory, Department of Chemistry, University of Delhi, Delhi, India; Department of Biochemistry, Faculty of Science, Banaras Hindu University, Varanasi, India

Chalcone derivatives were evaluated for their antifilarial activity on Setaria cervi using glutathione-S-transferase (GST) as a drug target. The compounds 1-(4-benzotriazol-1-yl-phenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (5), and 3-(4-methoxyphenyl)-1-(4-pyrrolidin-1-yl-phenyl) prop-2-en-1-one (7) showed a significant suppression (P < 0.01) in GST activity of adult female parasite extract at 3 μM concentration in vitro. However, GST activity was detected along with depletion in GSH level. Except Compounds 1 and 2, all exhibited a significant effect on the motility and viability of adult parasites. Compounds 3-(4-chlorophenyl)-1-(4-piperidin-1-yl-phenyl)prop-2-en-1-one (3), 1-(4-benzotriazol-1-yl-phenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (5), and 3-(4-methoxyphenyl)-1-(4-pyrrolidin-1-yl-phenyl) prop-2-en-1-one (7) exhibited major irreversible effects on viability and resulted in parasite death and also inhibited the GST activity by 84–100% in vitro. We report for the first time the antifilarial activity of chalcones on GST of adult parasites. This study also strengthens our previous findings where GST is reported as a potential drug target for antifilarials.

The main problem regarding the chemotherapy of filariasis is that no safe and effective drug is available yet to combat adult human filarial worms. One of the main reasons is that filarial parasites exhibit a very strong antioxidant system, which protects them from the reactive oxygen species (ROS) produced by the normal metabolism or by immune cells of the host.1 This protective mechanism also prolongs their existence in mammalian hosts for many years.

To date, diethylcarbamazine (DEC) is the only effective drug on the market to treat filariasis (Figure 1A).2 The drug removes almost all microfilariae from the blood and has an incapacitating, if not lethal, effect on adult worms. Moreover, DEC is also reported to be metabolized or excreted within 24 hours of administration, which reduces the efficacy of this drug in major infection.3 Furthermore, ivermectin4 and semisynthtetic macrocyclic lactones have shown a significant effect on microfilariae but not on adult worms. It is well documented that organic arsenic compounds have long been known as good macrofilaricides.5 However, severe toxicity to the host prevented their use as antifilarial drugs. In addition to this, a large number of phenoxycyclohexane and aplysinoposin derivatives 6,7 have been used, but most of the compounds showed very poor adulticidal effects. Furthermore, benzimidazole8 substituted compounds showed interesting results against intestinal helminths, but they did not have any effect on treatment of tissue-dwelling helminths. Moreover, discovery of new drugs against filarial parasite has been hampered because of the dynamics of filariasis transmission and the long life span of the adult worm. Thus, the search for broad-range macrofilaricidal agents remains in need.

Glutathione-S-transferase (GST; EC 2.5.1.18) belongs to the Phase II detoxification system and is an ubiquitous family of multi-functional enzymes that play a major role in metabolism of xenobiotics by catalyzing nucleophilic conjugation of glutathione (γ-glutamyl cysteinyl glycine) with electrophilic substrates, producing less reactive chemical species.9 GSTs provide drug resistance by two possible mechanisms, including GST-dependent metabolism of DNA alkylators or other therapeutic agents and direct interaction of GSTs with signal transduction proteins, which inhibits c-Jun N-terminal kinase and prevents drug-induced apoptosis. 10 The interaction between drugs and reduced glutathione (GSH) has also been of great interest because some carboxylated drugs or compounds are activated by forming thiol esters with GSH, which was further hydrolyzed by GST, leading them to detoxification. 11 Thus, this GSH/GST system is a primary cellular mechanism that provides optimal conditions for the detoxification of reactive intermediates formed from xenobiotics.

Chalcone, a biosynthetic product of the shikimate pathway, is the precursor of various flavones and a key intermediate for combinatorial assembly of different heterocyclic scaffolds. Chalcones (1,3-diphenyl-2-propen-1-one) constitute an important group of natural products, and some of them exhibit a wide spectrum of biological significance such as antibacterials, antifungals, antivirals, antitumorals, antioxidants, tyrosine inhibitors, and antimalarials activities. 1219

To evaluate the efficacy of some newly synthesized chalcones derivatives as an antifilarial, we took filarial GST as a drug target and conducted in vivo and in vitro studies on Setaria cervi, because this parasite is reported to contain significant GST activity. 20,21 To our knowledge, this is the first report where chalcone is shown as a potential antifilarial agent. All various substituted chalcones were synthesized by the Claisen-Schmidt condensation as reported in our earlier communication. 13

Adult, motile S. cervi worms were procured from the peritoneal fluid of freshly slaughtered Indian water buffaloes. Worms were washed with phosphate-buffered saline (PBS) and maintained in Krebs Ringer bicarbonate (KRB) buffer supplemented with streptomycin, penicillin, glutamine, and 1% glucose (maintenance medium). Homogenate was prepared from adult parasites as described earlier, 20 and protein content was estimated by the Bradford method. 22

For in vivo experiments, 1 mg/mL stock solution of each compound was prepared in 10% DMSO for further preparation of maintenance medium containing 3 μmol/L of chalcones. Equal numbers of adult female S. cervi (N = 16) were incubated in the maintenance medium containing 3 μmol/L of compounds for 4 hours at 37°C. Worms incubated in medium containing 0.01% DMSO alone served as a control. After the desired period of incubation, worms were recovered, washed with fresh PBS, homogenized, centrifuged, and assayed for enzyme activity.

Motility and viability of parasites was performed by visual inspection and MTT assay, respectively. Parasites incubated in KRB medium containing compound were assessed visually for 4 hours and scored as either positive or negative depending on their motility. After 4 hours, the recovery of motility was recorded by keeping the worms in fresh medium for 1 hour. Parasite viability was assessed quantitatively by MTT [3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide] reduction assay as described earlier. 23

GST activity in fresh worm extract was assessed spectro-photometrically according to the method of Habig and others 24 using GSH (2.4 mmol/L) and CDNB (1 mmol/L) as substrate. Assay was initiated with 50 μL enzyme in 0.5 mL phosphate buffer (0.1 mol/L), pH 6.5, at 25°C. One unit of enzyme activity is defined as the amount of enzyme catalyzing the oxidation of 1 μmol of substrate (CDNB)/mL/min at 25°C.

To estimate the GSH level, homogenate was prepared from adult female parasites and centrifuged at 9,615g for 30 minutes. An equal volume of 5% perchloric acid in supernatant of extract was mixed and centrifuged at 805g for 10 minutes at 4°C. The reaction mixture (2 mL) contained 100 μL supernatant, 1.88 mL 0.1 mol/L potassium phosphate buffer, pH 8.0, and 0.02 mL 4% DTNB. Incubation of the reaction mixture was carried out at room temperature for 3 minutes, and absorbance of the developed color was recorded at 412 nm. 25 Distilled water was used as a blank. A standard graph was prepared using GSH.

All experiments were set up in duplicate, and the results were expressed as the mean of two independent trials. Each treatment group consisted of 16 parasites, and the mean value of each data was compared with the mean value of a control group of equal size. The significant values were calculated using the Student t test.

Chalcone is an exceptional chemical template having multifarious biologic activities. To explore their effects on nematodes, two series of chalcones, chloro and methoxy functional groups, were synthesized ( Figure 2 ) and tested against the adult female S. cervi. In an initial experiment, we recorded the motility and viability of adult worms treated with chalcone derivatives.

A marked suppression in motility of treated worms was recorded after 4 hours of incubation, which did not recover in worms incubated with Compounds 3, 5, and 7. Motility gradually decreased in worms treated with Compound 5 starting from 2 to 4 hours, whereas it was totally diminished within 2 hours of exposure with Compounds 3 and 7. However, when transferred into fresh medium, motility was recovered in worms incubated with Compounds 1, 2, 4, and 6 (Table 1). Interestingly, Compounds 3-(4-chlorophenyl)-1-(4-piperidin-1-yl-phenyl)prop-2-en-1-one (3), 1-(4-benzotriazol-1-yl-phenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (5), and 3-(4-methoxyphenyl)-1-(4-pyrrolidin-1-yl-phenyl)prop-2-en-1-one (7) also showed an irreversible effect on parasite viability compared with control, with a very significant inhibition of 96%, which resulted in parasite death (Table 2). More or less, all compounds showed a paralyzing effect on the motility and viability of parasites, ranging from 25% to 97% inhibition, except Compound 2, where a slight increase (12%) in viability was recorded.

It has been reported that xenobiotics and free radicals are metabolized by cellular enzymes to generate superoxide and electrophiles. 26 Here we suggest that the accumulation of such free radicals might lead to oxidative stress in worms and in turn cause cell death, which is also in accordance with an earlier report. 20 We proposed that both lipophilic and hydrophobic small nitrogen-containing substituents in chalcones might be involved in motility and viability loss. However, the exact mechanism of action of these substituted chalcones on parasites is elusive.

A slight increase in the activity of GST was observed after 4 hours of exposure of worms with chalcones (3 μmol/L). Of seven compounds, Compounds 2 and 7 containing pyrazolechloro and pyrrolidine-methoxy substituents showed a 21–26% increase in GST activity, whereas in the chloro series, Compounds 1 and 3 containing pyrrole and piperidine substituents, and in methoxy series, Compounds 4 and 5 containing pyrazole and benzotriazole showed a > 40% increase. However, with Compound 6, containing morpholine and methoxy substituents, activity was increased by 63% compared with control, which is highest among all the compounds (Table 3). It is reported that chalcones attain their inhibitory effect by depleting the cellular level of GSH or electrophilic attack by an α,β-unsaturated carbonyl moiety on the thiol group of GSH by a Michael-type addition reaction in bovine aortic endothelial cells (BAECs). 27 Here, we predict the occurrence of the same reaction (Figure 1B), which might reduce the GSH level and further induce oxidative stress in parasites. Because GST activity is correlated with oxidative stress and metabolism of xenobiotics, 28 this could be one of the possible reasons for increased GST activity in worms treated with chalcone derivatives. However, GST does not always participate in enzymatic neutralization of xenobiotics. It is reported that detoxification can also lead to binding of GST with electrophiles. 29 In this context, we can speculate that the resulted death of worms treated with chalcones could also be associated with the high toxicity generated by GST–chalcone intermediate formation.

Furthermore, the level of glutathione was significantly reduced by both the chloro and methoxy series of compounds, ranging from 52% to 100% (Table 4). However, GSH depletion was more pronounced in worms treated with the methoxy series compound. This mechanism could be involved in drug resistance because depletion of free GSH may induce the expression of some antioxidant enzymes. 30 Nevertheless, increased GST expression is correlated to drug resistance, and in certain nematodes, such as Haemonchus contortus, it has already been reported. 31

It is noticeable that the decreased GSH level and GST activity observed in worms treated with Compound 7 provide a possibility that inclination toward the resistance could be less pronounced with Compound 7 compared with other derivatives, because only a very slight increase in GST activity was observed with exposure to Compound 7.

Significant inhibition in GST activity was observed with both chloro and methoxy series compounds in vitro. However, chloro compounds (1–3) showed 73–84% inhibition, whereas activity was totally diminished by the methoxy group (4–7) with 100% inhibition (Table 3). As mentioned before, chalcone forms a β-carbonyl–glutathione covalent complex. Here, in an in vitro enzyme assay, this complex might have reduced the free GSH for catalysis, which further inhibited the GST activity in the reaction mixture. The inhibitory role of GSH-chalcone on GST is also reported in Onchocerca volvulus.32 We also suspect the formation of a complex between GST and chalcone, which could block the substrate binding site and thus lead to inactivation of this enzyme. However, confirmation of this hypothesis requires further study. The difference in the effect of various compounds on parasite GST may be attributed to side chain substituents because inhibition obtained was highest with methoxy series compounds.

Our results are comparable to earlier published results. 3,33 Furthermore, the in silico structure modeling and docking studies on WbGST revealed that β-carbonyl are the ideal molecules which could be used as GST inhibitors.3 The biochemical and immunological significance of ScGST 20,34 reported by us also supports the evaluation of GST for drug targeting studies.

Here we report for the first time that chalcone exhibits antifilarial activity; however, this is a preliminary in vivo and in vitro study in which living worms were incubated with chalcones. The results of 4-chloro and 4-methoxy–substituted chalcones strongly support that small- and medium-sized highly lipophilic or hydrophobic groups containing single or multiple nitrogen or oxygen in an acetophenone ring of chalcone have potent inhibitory effects on motility, viability, and GST activity of the parasite, supporting the antifilarial efficacy of chalcone. The most significant effect on parasites was exerted by methoxy substituted chalcones, suggesting that these substituents can be used for further studies against filariasis. Moreover, to understand the mode of action of chalcones on filarial parasites, additional work is needed to generate a library of substituted chalcones to establish meaningful structure activity relationships (SARs). Meanwhile, these compounds are also being screened against other antioxidant enzymes.

Table 1

Effect of chalcone derivatives on motility of worms

Table 1
Table 2

Effect of chalcone derivatives on the viability of adult female S. cervi determined by MTT reduction assay

Table 2
Table 3

In vivo and in vitro effect of chalcone derivatives on S. cervi GST activity

Table 3
Table 4

GSH level in S. cervi treated with chalcone derivatives

Table 4
Figure 1.
Figure 1.

A, Structure of diethylcarbamazine (DEC). B, The proposed Michael-type addition of glutathione to chalcones mediated by glutathione-S-transferase.

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 80, 5; 10.4269/ajtmh.2009.80.764

Figure 2.
Figure 2.

Various substituted chalcones exploited in the study.

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 80, 5; 10.4269/ajtmh.2009.80.764

*

Address correspondence to Satish K. Awasthi, Chemical Biology Laboratory, Department of Chemistry, Delhi 110007, India. E-mails: skawasthi@chemistry.du.ac.in or awasthisatish@yahoo.com

Authors’ addresses: Satish K. Awasthi, Nidhi Mishra, and Sandeep Kumar Dixit, Chemical Biology Laboratory, Department Of Chemistry, University of Delhi, Delhi 110007, India. Alka Singh, Marshleen Yadav, Sudhanshu S. Yadav, and Sushma Rathaur, Department of Biochemistry, Faculty of Science, Banaras Hindu University, Varanasi 221005, India.

Acknowledgments: S.K.A. thanks Prof. Liam Good, Department of Pathology and Infectious Diseases, Royal Veterinary College, University of London, UK, for reviewing the manuscript.

Financial support: S.K.A. and S.R. are grateful to the Department of Science and Technology (DST; Scheme SR/S0/BB-65//2003), University of Delhi, Delhi, and University Grant Commission (UGC; Scheme F.30-214/2004), New Delhi, India, respectively, for financial assistance. The University of Delhi assisted with publication expenses.

REFERENCES

  • 1

    Reed DJ, 1995. Molecular and Cellular Mechanisms of Toxicity. Boca Raton, FL: CRC Press.

  • 2

    Ottesen EA, Vijayaseksran V, Kumaraswami V, Pillai SVP, Sadanandam A, Sheila F, Prabhakar R, Tripathy SP, 1990. A controlled trial of ivermectin and diethylcarbamazine in lymphatc filariasis. N Engl J Med 322 :1113–1117.

    • Search Google Scholar
    • Export Citation
  • 3

    Nathan ST, Methew N, Kalyanasundaram M, Balaraman K, 2005. Structure of glutathione S-transferase of the filarial parasite Wuchereria bancrofti: a target for drug development against adult worm. J Mol Model 11 :194–199.

    • Search Google Scholar
    • Export Citation
  • 4

    Bennett JL, Williams JF, Dave V, 1988. Pharmacology of ivermectin. Parasitol Today 4 :226–228.

  • 5

    Ginger CD, 1986. Advances in filarial chemotherapy and screening. Parasitol Today 2 :38–40.

  • 6

    Loiseau PM, 1993. In vitro antifilarial evaluation of phenoxycyclohexane derivatives. Ann Trop Med Parasitol 87 :469–476.

  • 7

    Singh SN, Bhatnagar S, Fatma N, Chauhan PMS, Chatterjee RK, 1997. Antifilarial activity of a synthetic marine alkaloid aplysinospin. Trop Med Int Health 2 :535–543.

    • Search Google Scholar
    • Export Citation
  • 8

    Townsend LB, Wise DS, 1990. The synthesis and chemistry of certain antihelmintic benzimidazole. Parasitol Today 6 :107–112.

  • 9

    Mannervik B, Danielson UH, 1988. Glutathione transferases, structure and catalytic activity. CRC Crit Rev Biochem 23 :283–337.

  • 10

    Gomez FJS, Gayarre J, Avellano MI, Sala DP, 2007. Direct evidence for the covalent modification of glutathione S-transferase Pf-1 by electrophilic prostaglandins: implications for enzyme inactivation and cell survival. Arch Biochem Biophys 457 :150–159.

    • Search Google Scholar
    • Export Citation
  • 11

    Ibarraa CMP, Grillob ML, Belloc M, Nucettellic TK, Atkinsa Bammlerd WM, 2003. Exploration of in vitro pro-drug activation and futile cycling by glutathione S-transferases: thiol ester hydrolysis and inhibitor maturation. Arch Biochem Biophys 414 :303–311.

    • Search Google Scholar
    • Export Citation
  • 12

    Nielsen SF, Larsen M, Bosen T, Schonning K, Kromann H, 2005. Cationic chalcone antibiotics. design, synthesis, and mechanism of action. J Med Chem 48 :2667–2677.

    • Search Google Scholar
    • Export Citation
  • 13

    Mishra N, Arora P, Kumar B, Mishra LC, Bhattacharya A, Awasthi SK, Bhasin VK, 2008. Synthesis of novel susbtituted 1,3-diaryl propenone derivatives and their antimalarial activity in vitro. Eur J Med Chem 43 :1530–1535.

    • Search Google Scholar
    • Export Citation
  • 14

    Awasthi SK, Mishra N, Kumar B, Sharma M, Mishra LC, Bhattacharya A, Bhasin VK, Potent antimalarial activity of newly synthesized substituted chalcone analogs in vitro. Med Chem Res. DOI: 10.1007/s00044-008-9137-9.

    • Search Google Scholar
    • Export Citation
  • 15

    Robinson PT, Hubbard RB IV, Ehlers TJ, Arbiser JL, Goldsmith DJ, Bowen PJ, 2005. Synthesis and biological evaluation of aromatic enones related to curcumin. Bioorg Med Chem 13 :4007–4013.

    • Search Google Scholar
    • Export Citation
  • 16

    Vaya J, Belinky PA, Aviram M, 1997. Antioxidant constituents from licorice roots: isolation, structure elucidation and antioxidative capacity toward LDL oxidation. Free Radic Biol Med 23 :302–313.

    • Search Google Scholar
    • Export Citation
  • 17

    Khatib S, Nerya O, Musa R, Shmuel M, Tamir S, Vaya J, 2005. Chalcones as potent tyrosinase inhibitors: the importance of a 2,4-substituted resorcinol moiety. Bioorg Med Chem 13 :433–441.

    • Search Google Scholar
    • Export Citation
  • 18

    Chen M, Theander TG, Christensen BS, Hviid L, Zhai L, Kharazmi A, 1994. Licochalcone A, a new antimalarial agent, inhibits in vitro growth of the human malaria parasite Plasmodium falciparum and protects mice from P. yoelii infection. Antimicrob Agents Chemother 38 :1470–1475.

    • Search Google Scholar
    • Export Citation
  • 19

    Li R, Kenyon GL, Cohen FE, Chen X, Gong B, Dominguez JN, Davidson E, Kurzban G, Miller RE, Nuzum EO, Rosenthal PJ, McKerrow JH, 1995. In vitro antimalarial activity of chalcones and their derivatives. J Med Chem 38 :5031–5037.

    • Search Google Scholar
    • Export Citation
  • 20

    Gupta S, Rathaur S, 2005. Filarial glutathione S-transferase: its induction by xenobiotics and potential as drug target. Acta Biochim Pol 52 :493–500.

    • Search Google Scholar
    • Export Citation
  • 21

    Gupta S, Singh A, Yadav M, Singh K, Rathaur S, 2007. MALDI mass sequencing and characterization of filarial glutathione-S-transferase. Biochem Biophys Res Commun 356 :381–385.

    • Search Google Scholar
    • Export Citation
  • 22

    Bradford MM, 1976. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72 :248–254.

    • Search Google Scholar
    • Export Citation
  • 23

    Mosmann TR, Coffman RL, 1989. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 7 :145–173.

    • Search Google Scholar
    • Export Citation
  • 24

    Habig WH, Pabst MJ, Jakoby WB, 1974. Glutathione-S-transferase: the first enzymatic step in mercapturic acid formation. J Biol Chem 249 :7130–7139.

    • Search Google Scholar
    • Export Citation
  • 25

    Ellman GL, 1959. Tissue sulfhydryl groups. Arch Biochem Biophys 82 :70–77.

  • 26

    Jaiswal AK, 2004. Nrf2 signalling in activation of gene expression, free radical coordinated. Biol Med (Paris) 36 :1199–1207.

  • 27

    Liu YC, Hsieh CW, Wu CC, Wung BS, 2007. Chalcone inhibits the activation of NF-γ B and STAT3 in endothelial cells via endogenous electrophile. Life Sci 80 :1420–1430.

    • Search Google Scholar
    • Export Citation
  • 28

    Huang J, Tan PH, Tan BK, Bay BH, 2004. GST-pi expression correlates with oxidative stress and apoptosis in breast cancer. Oncol Rep 12 :921–925.

    • Search Google Scholar
    • Export Citation
  • 29

    Forkert PG, Costa DD, Mestrah ME, 1999. Expression and inducibility of Alpha, Pi and Mu glutathione-S-transferase protein and mRNA in murine lung. Am J Respir Cell Mol Biol 20 :143–152.

    • Search Google Scholar
    • Export Citation
  • 30

    Nguyen T, Yang CS, Pickett CB, 2004. The pathways and molecular mechanisms regulating Nrf2 activation in response to chemical stress. Free Radic Biol Med 37 :433–441.

    • Search Google Scholar
    • Export Citation
  • 31

    Kawalek JC, Rew RS, Heavner J, 1984. Glutathione S-transferase a possible drug metabolizing enzyme in Haemouchus contoras: comparative activity of cambendazole resistant and susceptible strain. Int J Parasitol 14 :173–175.

    • Search Google Scholar
    • Export Citation
  • 32

    Brophy PM, Campbell AM, van Eldik AJ, Teesdale-Spittle PH, Liebau E, Wang MF, 2000. β-Carbonyl substituted glutathione conjugates as inhibitors of O. volvulus GST2. Bioorg Med Chem Lett 10 :979–981.

    • Search Google Scholar
    • Export Citation
  • 33

    Brophy PM, Barrett J, 1990. Glutathione transferase in helminths. Parasitol 100 :345–349.

  • 34

    Rathaur S, Yadav M, Gupta S, Anandharaman V, Reddy MVR, 2008. Filarial glutathione-S-transferase: a potential vaccine candidate against lymphatic filariasis. Vaccine 26 :4094–4100.

    • Search Google Scholar
    • Export Citation
Save