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Current Topics in Medicinal Chemistry

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ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

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Research Article

In Vitro and In Silico Studies of Glycyrrhetinic Acid Derivatives as Anti- Filarial Agents

Author(s): Rekha Tyagi, Surjeet Verma, Shikha Mishra, Mrigank Srivastava, Sarfaraz Alam, Feroz Khan and Santosh Kumar Srivastava*

Volume 19, Issue 14, 2019

Page: [1191 - 1200] Pages: 10

DOI: 10.2174/1568026619666190618141450

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Abstract

Background: Lymphatic filariasis is one of the chronic diseases in many parts of the tropics and sub-tropics of the world despite the use of standard drugs diethylcarbamazine and ivermectin because they kill microfilaries and not the adult parasites. Therefore, new leads with activity on adult parasites are highly desirable.

Objective: Anti-filarial lead optimization by semi-synthetic modification of glycyrrhetinic acid (GA).

Methods: The GA was first converted into 3-O-acyl derivative, which was further converted into 12 amide derivatives. All these derivatives were assessed for their antifilarial potential by parasite motility assay. The binding affinity of active GA derivatives on trehalose-6-phosphate phosphatase (Bm-TPP) was assessed by molecular docking studies.

Results: Among 15 GA derivatives, GAD-2, GAD-3, and GAD-4 were found more potent than the GA and standard drug DEC. These derivatives reduced the motility of Brugia malayi adult worms by up to 74% while the GA and DEC reduced only up to 49%. Further, GA and most of its derivatives exhibited two times more reduction in MTT assay when compared to the standard drug DEC. These derivatives also showed 100% reduction of microfilariae and good interactions with Bm-TPP protein.

Conclusion: The present study suggests that 3-O-acyl and linear chain amide derivatives of glycyrrhetinic acid may be potent leads against B. malayi microfilariae and adult worms. These results might be helpful in developing QSAR model for optimizing a new class of antifilarial lead from a very common, inexpensive, and non toxic natural product.

Keywords: Glycyrrhetinic acid, Semi-synthetic derivatives, Anti-filarial activity, Brugia malayi, Trehalose-6-phosphate phosphatase, In-silico studies.

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[1]
Rana, G. Inhibition efficiency of a newly isolated flavonoid compound from Vitex negundo L. leaves against cattle-endosymbiont Setaria cervi: Phytomedicine for lymphatic filariasis. Parasite Epidemiol. Control, 2018, 3(2), 88-95.
[http://dx.doi.org/10.1016/j.parepi.2018.03.002] [PMID: 29988277]
[2]
Stillwaggon, E.; Sawers, L.; Rout, J.; Addiss, D.; Fox, L. Economic costs and benefits of a community-based lymphadema management program for lymphatic filariasis in Odisha state, India. Am. J. Trop. Med. Hyg., 2016, 95(4), 877-884.
[http://dx.doi.org/10.4269/ajtmh.16-0286] [PMID: 27573626]
[3]
Turner, H.C.; Bettis, A.A.; Chu, B.K.; McFarland, D.A.; Hooper, P.J.; Mante, S.D.; Fitzpatrick, C.; Bradley, M.H. Investment success in public health; An analysis of the cost-effectiveness and cost-benefit of the global programme to eliminate filariasis. Clin. Infect. Dis., 2017, 64(6), 728-735.
[PMID: 27956460]
[4]
World Health Organization. Validation of elimination of lymphatic filariasis as a public health problem 2017.(Available at:, http://www.who.int/lymphaticfilariasis/resources/978924151957/en/
[5]
Fischer, P.U.; King, C.L.; Jacobson, J.A.; Weil, G.J. Potential value of triple drug therapy with Ivermectin, Diethylcarbamazine, and Albendazole (IDA) to accelerate elimination of lymphatic filariasis and onchocerciasis in Africa. PLoS Negl. Trop. Dis., 2017, 11(1)e0005163
[http://dx.doi.org/10.1371/journal.pntd.0005163] [PMID: 28056015]
[6]
WHO. Global programme to eliminate lymphatic filariasis: Progress report, 2017 Weekly epidemiological record, No 44,. 2018, (93), 589-604.(Accessed on 13 December 2018 at, https://www.who.int/lymphatic_filariasis/resources/who_wer9344/en/
[7]
Dadzie, Y.; Neira, M.; Hopkins, D. Final report of the Conference on the eradicability of Onchocerciasis. Filaria J., 2003, 2(1), 2.
[http://dx.doi.org/10.1186/1475-2883-2-2] [PMID: 12605722]
[8]
Burkot, T.R.; Durrheim, D.N.; Melrose, W.D.; Speare, R.; Ichimori, K. The argument for integrating vector control with multiple drug administration campaigns to ensure elimination of lymphatic filariasis. Filaria J., 2006, 5, 10.
[http://dx.doi.org/10.1186/1475-2883-5-10] [PMID: 16914040]
[9]
Kalani, K.; Kushwaha, V.; Verma, R.; Murthy, P.K.; Srivastava, S.K. Glycyrrhetinic acid and its analogs: A new class of antifilarial agents. Bioorg. Med. Chem. Lett., 2013, 23(9), 2566-2570.
[http://dx.doi.org/10.1016/j.bmcl.2013.02.115] [PMID: 23541646]
[10]
Lustigman, S.; McCarter, J.P. Ivermectin resistance in Onchocerca volvulus: toward a genetic basis. PLoS Negl. Trop. Dis., 2007, 1(1)e76
[http://dx.doi.org/10.1371/journal.pntd.0000076] [PMID: 17989789]
[11]
Schwab, A.E.; Boakye, D.A.; Kyelem, D.; Prichard, R.K. Detection of benzimidazole resistance-associated mutations in the filarial nematode Wuchereria bancrofti and evidence for selection by albendazole and ivermectin combination treatment. Am. J. Trop. Med. Hyg., 2005, 73(2), 234-238.
[http://dx.doi.org/10.4269/ajtmh.2005.73.234] [PMID: 16103581]
[12]
Murthy, P.K.; Joseph, S.K.; Murthy, P.S. Plant products in the treatment and control of filariasis and other helminth infections and assay systems for antifilarial/anthelmintic activity. Planta Med., 2011, 77(6), 647-661.
[http://dx.doi.org/10.1055/s-0030-1250452] [PMID: 20957596]
[13]
Kushwaha, V.; Saxena, K.; Verma, S.K.; Lakshmi, V.; Sharma, R.K.; Murthy, P.K. Antifilarial activity of gum from Moringa oleifera Lam. on human lymphatic filaria Brugia malayi. Chron. Young Sci., 2011, 2(4), 202-206.
[http://dx.doi.org/10.4103/2229-5186.93025]
[14]
Priyanka; S. Misra; S. Misra-Bhattacharya; R. J. Butcher; D. Katiyar, Resolution, absolute configuration and antifilarial activity of coumarinyl amino alcohols. Tetrahedron Asymmetry, 2017, 28, 734-743.
[http://dx.doi.org/10.1016/j.tetasy.2017.04.005]
[15]
Roy, P.; Saha, S.K.; Gayen, P.; Chowdhury, P.; Sinha Babu, S.P. Exploration of antifilarial activity of gold nanoparticle against human and bovine filarial parasites: A nanomedicinal mechanistic approach. Colloids Surf. B Biointerfaces, 2018, 161, 236-243.
[http://dx.doi.org/10.1016/j.colsurfb.2017.10.057] [PMID: 29080508]
[16]
Saha, S.K.; Roy, P.; Mondal, M.K.; Roy, D.; Gayen, P.; Chowdhury, P.; Babu, S.P.S. Development of chitosan based gold nanomaterial as an efficient antifilarial agent: A mechanistic approach. Carbohydr. Polym., 2017, 157, 1666-1676.
[http://dx.doi.org/10.1016/j.carbpol.2016.11.047] [PMID: 27987881]
[17]
Kalani, K.; Kushwaha, V.; Sharma, P.; Verma, R.; Srivastava, M.; Khan, F.; Murthy, P.K.; Srivastava, S.K. In vitro, in silico and in vivo studies of ursolic acid as an anti-filarial agent. PLoS One, 2014, 9(11)e111244
[http://dx.doi.org/10.1371/journal.pone.0111244] [PMID: 25375886]
[18]
Kumar, S.; Chaudhary, K.; Foster, J.M.; Novelli, J.F.; Zhang, Y.; Wang, S.; Spiro, D.; Ghedin, E.; Carlow, C.K.S. Mining predicted essential genes of Brugia malayi for nematode drug targets. PLoS One, 2007, 2(11)e1189
[http://dx.doi.org/10.1371/journal.pone.0001189] [PMID: 18000556]
[19]
Ghedin, E.; Wang, S.; Spiro, D.; Caler, E.; Zhao, Q.; Crabtree, J.; Allen, J.E.; Delcher, A.L.; Guiliano, D.B.; Miranda-Saavedra, D.; Angiuoli, S.V.; Creasy, T.; Amedeo, P.; Haas, B.; El-Sayed, N.M.; Wortman, J.R.; Feldblyum, T.; Tallon, L.; Schatz, M.; Shumway, M.; Koo, H.; Salzberg, S.L.; Schobel, S.; Pertea, M.; Pop, M.; White, O.; Barton, G.J.; Carlow, C.K.; Crawford, M.J.; Daub, J.; Dimmic, M.W.; Estes, C.F.; Foster, J.M.; Ganatra, M.; Gregory, W.F.; Johnson, N.M.; Jin, J.; Komuniecki, R.; Korf, I.; Kumar, S.; Laney, S.; Li, B.W.; Li, W.; Lindblom, T.H.; Lustigman, S.; Ma, D.; Maina, C.V.; Martin, D.M.; McCarter, J.P.; McReynolds, L.; Mitreva, M.; Nutman, T.B.; Parkinson, J.; Peregrín-Alvarez, J.M.; Poole, C.; Ren, Q.; Saunders, L.; Sluder, A.E.; Smith, K.; Stanke, M.; Unnasch, T.R.; Ware, J.; Wei, A.D.; Weil, G.; Williams, D.J.; Zhang, Y.; Williams, S.A.; Fraser-Liggett, C.; Slatko, B.; Blaxter, M.L.; Scott, A.L. Draft genome of the filarial nematode parasite Brugia malayi. Science, 2007, 317(5845), 1756-1760.
[http://dx.doi.org/10.1126/science.1145406] [PMID: 17885136]
[20]
Kumar, S.; Chaudhary, K.; Foster, J.M.; Novelli, J.F.; Zhang, Y.; Wang, S.; Spiro, D.; Ghedin, E.; Carlow, C.K. Mining predicted essential genes of Brugia malayi for nematode drug targets. PLoS One, 2007, 2(11)e1189
[http://dx.doi.org/10.1371/journal.pone.0001189] [PMID: 18000556]
[21]
Pellerone, F.I.; Archer, S.K.; Behm, C.A.; Grant, W.N.; Lacey, M.J.; Somerville, A.C. Trehalose metabolism genes in Caenorhabditis elegans and filarial nematodes. Int. J. Parasitol., 2003, 33(11), 1195-1206.
[http://dx.doi.org/10.1016/S0020-7519(03)00173-5] [PMID: 13678635]
[22]
Behm, C.A. The role of trehalose in the physiology of nematodes. Int. J. Parasitol., 1997, 27(2), 215-229.
[http://dx.doi.org/10.1016/S0020-7519(96)00151-8] [PMID: 9088992]
[23]
Elbein, A.D.; Pan, Y.T.; Pastuszak, I.; Carroll, D. New insights on trehalose: a multifunctional molecule. Glycobiology, 2003, 13(4), 17R-27R.
[http://dx.doi.org/10.1093/glycob/cwg047] [PMID: 12626396]
[24]
Kormish, J.D.; McGhee, J.D. The C. elegans lethal gut-obstructed gob-1 gene is trehalose-6-phosphate phosphatase. Dev. Biol., 2005, 287(1), 35-47.
[http://dx.doi.org/10.1016/j.ydbio.2005.08.027] [PMID: 16197937]
[25]
Rao, K.N.; Kumaran, D.; Seetharaman, J.; Bonanno, J.B.; Burley, S.K.; Swaminathan, S. Crystal structure of trehalose-6-phosphate phosphatase-related protein: biochemical and biological implications. Protein Sci., 2006, 15(7), 1735-1744.
[http://dx.doi.org/10.1110/ps.062096606] [PMID: 16815921]
[26]
Shukla, A.; Tyagi, R.; Meena, S.; Datta, D.; Srivastava, S.K.; Khan, F. 2D- and 3D-QSAR modelling, molecular docking and in vitro evaluation studies on 18b-glycyrrhetinic acid derivatives against triple-negative breast cancer cell line. J. Biomol. Struct and Dynam., 2019. in press
[http://dx.doi.org/10.1080/07391102.2019.1570868]
[27]
Murthy, P.K.; Chatterjee, R.K. Evaluation of two in vitro test systems employing Brugia malayi parasite for screening of potential antifilarials. Curr. Sci., 1999, 77, 1084-1089.
[28]
Lakshmi, V.; Joseph, S.K.; Srivastava, S.; Verma, S.K.; Sahoo, M.K.; Dube, V.; Mishra, S.K.; Murthy, P.K. Antifilarial activity in vitro and in vivo of some flavonoids tested against Brugia malayi. Acta Trop., 2010, 116(2), 127-133.
[http://dx.doi.org/10.1016/j.actatropica.2010.06.006] [PMID: 20609356]
[29]
Sashidhara, K.V.; Rao, K.B.; Kushwaha, V.; Modukuri, R.K.; Verma, R.; Murthy, P.K. Synthesis and antifilarial activity of chalcone-thiazole derivatives against a human lymphatic filarial parasite, Brugia malayi. Eur. J. Med. Chem., 2014, 81, 473-480.
[http://dx.doi.org/10.1016/j.ejmech.2014.05.029] [PMID: 24863844]
[30]
Alam, S.; Khan, F. QSAR and docking studies on xanthone derivatives for anticancer activity targeting DNA topoisomerase IIα. Drug Des. Devel. Ther., 2014, 8, 183-195.
[PMID: 24516330]
[31]
Alam, S.; Khan, F. 3D-QSAR studies on Maslinic acid analogs for Anticancer activity against Breast Cancer cell line MCF-7. Sci. Rep., 2017, 7(1), 6019.
[http://dx.doi.org/10.1038/s41598-017-06131-0] [PMID: 28729623]
[32]
Alam, S.; Khan, F. QSAR, docking, ADMET, and system pharmacology studies on tormentic acid derivatives for anticancer activity. J. Biomol. Struct. Dyn., 2017, 36(9), 2373-2390.
[PMID: 28705120]
[33]
Alam, S.; Khan, F. Virtual screening, Docking, ADMET and System Pharmacology studies on Garcinia caged Xanthone derivatives for Anticancer activity. Sci. Rep., 2018, 8(1), 5524.
[http://dx.doi.org/10.1038/s41598-018-23768-7] [PMID: 29615704]
[34]
Farelli, J.D.; Galvin, B.D.; Li, Z.; Liu, C.; Aono, M.; Garland, M.; Hallett, O.E.; Causey, T.B.; Ali-Reynolds, A.; Saltzberg, D.J.; Carlow, C.K.S.; Dunaway-Mariano, D.; Allen, K.N. Structure of the trehalose-6-phosphate phosphatase from Brugia malayi reveals key design principles for anthelmintic drugs. PLoS Pathog., 2014, 10(7)e1004245
[http://dx.doi.org/10.1371/journal.ppat.1004245] [PMID: 24992307]
[35]
Kushwaha, S.; Singh, P.K.; Shahab, M.; Pathak, M.; Bhattacharya, S.M. In vitro silencing of Brugia malayi trehalose-6-phosphate phosphatase impairs embryogenesis and in vivo development of infective larvae in jirds. PLoS Negl. Trop. Dis., 2012, 6(8)e1770
[http://dx.doi.org/10.1371/journal.pntd.0001770] [PMID: 22905273]

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