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Pyrrolidine-Acridine hybrid in Artemisinin-based combination: a pharmacodynamic study

  • SWAROOP KUMAR PANDEY (a1), SUBHASISH BISWAS (a2), SARIKA GUNJAN (a1), BHAVANA SINGH CHAUHAN (a1), SUNIL KUMAR SINGH (a1), KUMKUM SRIVASTAVA (a1) (a3), SARIKA SINGH (a4), SANJAY BATRA (a2) (a3) and RENU TRIPATHI (a1) (a3)...

Summary

Aiming to develop new artemisinin-based combination therapy (ACT) for malaria, antimalarial effect of a new series of pyrrolidine-acridine hybrid in combination with artemisinin derivatives was investigated. Synthesis, antimalarial and cytotoxic evaluation of a series of hybrid of 2-(3-(substitutedbenzyl)pyrrolidin-1-yl)alkanamines and acridine were performed and mode of action of the lead compound was investigated. In vivo pharmacodynamic properties (parasite clearance time, parasite reduction ratio, dose and regimen determination) against multidrug resistant (MDR) rodent malaria parasite and toxicological parameters (median lethal dose, liver function test, kidney function test) were also investigated. 6-Chloro-N-(4-(3-(3,4-dimethoxybenzyl)pyrrolidin-1-yl)butyl)-2-methoxyacridin-9-amine (15c) has shown a dose dependent haem bio-mineralization inhibition and was found to be the most effective and safe compound against MDR malaria parasite in Swiss mice model. It displayed best antimalarial potential with artemether (AM) in vitro as well as in vivo. The combination also showed favourable pharmacodynamic properties and therapeutic response in mice with established MDR malaria infection and all mice were cured at the determined doses. The combination did not show toxicity at the doses administered to the Swiss mice. Taken together, our findings suggest that compound 15c is a potential partner with AM for the ACT and could be explored for further development.

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Corresponding author

*Corresponding authors: Division of Parasitology, CSIR-CDRI, Lucknow (India) 220031, India. E-mail: renu1113@rediffmail.com and Medicinal and Process Chemistry Division, CSIR-CDRI, Lucknow 220031, India. E-mail: batra_san@yahoo.co.uk, s_batra@cdri.res.in

References

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Agrawal, R., Tripathi, R., Tekwani, B. L., Jain, S. K., Dutta, G. P. and Shukla, O. P. (2002). Haem polymerase as novel target of antimalarial action of cyproheptadine. Biochemical Pharmacology 64, 13991406.
Baguley, B. C., Denny, W. A., Atwell, G. J. and Cain, B. F. (1981). Potential antitumor agents. 34. Quantitative relationships between DNA binding and molecular structure for 9-anilinoacridines substituted in the anilino ring. Journal of Medicinal Chemistry 24, 170177.
Batra, S. and Bhaduri, A. P. (1997). Reversal of Chloroquine resistance in malaria: a new concept of chemotherapy. Advances in Drug Research 30, 202252.
Batra, S., Srivastava, P., Roy, K., Pandey, V. C. and Bhaduri, A. P. (2000). A new class of potential chloroquine-resistance reversal agents for plasmodia: syntheses and biological evaluation of 1-(3′-N,N-Diethylaminopropyl)-3-(substituted phenyl-methylene)-pyrrolidine. Journal of Medicinal Chemistry 43, 34283433.
Bell, A. (2005). Antimalarial drug synergism and antagonism: mechanistic and clinical significance. FEMS Microbiology Letters 253, 171184.
Bloland, P. B. (2001). Drug resistance in malaria. World Health 41, 4553.
Chang, C., Lin-Hua, T. and Jantanavivat, C. (1992). Studies on a new antimalarial compound: Pyronaridine. Transactions of the Royal Society of Tropical Medicine and Hygiene 86, 710.
Chavalitshewinkoon-Petmitr, P., Pongvilairat, G., Ralph, R. K., Denny, W. a. and Wilairat, P. (2001). Inhibitory effects of 9-anilinoacridines on Plasmodium falciparum gametocytes. Tropical Medicine and International Health 6, 4245.
Chen, T. K., Fico, R. and Canellakis, E. S. (1978). Diacridines,-bifunctional-intercalators.-Chemistry-and-antitumor-activity_1978 _Journal-of-Medicinal-Chemistry.pdf. 21, 868874.
Croft, S. L., Duparc, S., Arbe-Barnes, S. J., Craft, J., Shin, C.-S., Fleckenstein, L., Borghini-Fuhrer, I. and Rim, H.-J. (2012). Review of pyronaridine anti-malarial properties and product characteristics. Malaria Journal 11, 270. doi: 10.1186/1475-2875-11-270.
De, D., Bhaduri, A. P. and Milhous, W. K. (1993). A novel pyrrolidonoalkaneamine (WR 268954) that modulates chloroquine resistance of P. falciparum in vitro. American Journal of Tropical Medicine and Hygiene 49, 113120.
Dorn, A., Vippagunta, S. R., Matile, H., Jaquet, C., Vennerstrom, J. L. and Ridley, R. G. (1998). An assessment of drug-haematin binding as a mechanism for inhibition of haematin polymerisation by quinoline antimalarials. Biochemical Pharmacology 55, 727736.
Duparc, S., Borghini-Fuhrer, I., Craft, C. J., Arbe-Barnes, S., Miller, R. M., Shin, C.-S. and Fleckenstein, L. (2013). Safety and efficacy of pyronaridine-artesunate in uncomplicated acute malaria: an integrated analysis of individual patient data from six randomized clinical trials. Malaria Journal 12, 70.
Dutta, G. P., Puri, S. K., Awasthi, A., Mishra, M. and Tripathi, R. (2000). Pyronaridine: an effective antimalarial against multidrug-resistant malaria. Life Sciences 67, 759763.
Fang, L., Appenroth, D., Decker, M., Kiehntopf, M., Roegler, C., Deufel, T., Fleck, C., Peng, S., Zhang, Y. and Lehmann, J. (2008). Synthesis and biological evaluation of NO-donor-tacrine hybrids as hepatoprotective anti-Alzheimer drug candidates. Journal of Medicinal Chemistry 51, 713716.
Fattorusso, C., Campiani, G., Kukreja, G., Persico, M., Butini, S., Romano, M. P., Altarelli, M., Ros, S., Brindisi, M., Savini, L., Novellino, E., Nacci, V., Fattorusso, E., Parapini, S., Basilico, N., Taramelli, D., Yardley, V., Croft, S., Borriello, M. and Gemma, S. (2008). Design, synthesis, and structure-activity relationship studies of 4-quinolinyl- and 9-acrydinylhydrazones as potent antimalarial agents. Journal of Medicinal Chemistry 51, 13331343.
Fong, K. Y., Sandlin, R. D. and Wright, D. W. (2015). Identification of β-hematin inhibitors in the MMV Malaria Box. International Journal for Parasitology: Drugs and Drug Resistance 5, 8491.
Gamage, S. a., Tepsiri, N., Wilairat, P., Wojcik, S. J., Figgitt, D. P., Ralph, R. K. and Denny, W. a. (1994). Synthesis and in vitro evaluation of 9-anilino-3,6-diaminoacridines active against a multidrug-resistant strain of the malaria parasite Plasmodium falciparum . Journal of Medicinal Chemistry 37, 14861494.
Gemma, S., Campiani, G., Butini, S., Joshi, B. P., Kukreja, G., Coccone, S. S., Bernetti, M., Persico, M., Nacci, V., Fiorini, I., Novellino, E., Taramelli, D., Basilico, N., Parapini, S., Yardley, V., Croft, S., Keller-Maerki, S., Rottmann, M., Brun, R., Coletta, M., Marini, S., Guiso, G., Caccia, S. and Fattorusso, C. (2009). Combining 4-aminoquinoline- and clotrimazole-based pharmacophores toward innovative and potent hybrid antimalarials. Journal of Medicinal Chemistry 52, 502513.
Jones, M. (2009). Antitumour and antimalarial activity of artemisinin – acridine hybrids. Bioorganic and Medicinal Chemistry Letters 19, 20332037.
Kelly, J. X., Smilkstein, M. J., Brun, R., Wittlin, S., Cooper, R. A., Lane, K. D., Janowsky, A., Johnson, R. A., Dodean, R. A., Winter, R., Hinrichs, D. J. and Riscoe, M. K. (2009). Discovery of dual function acridones as a new antimalarial chemotype. Nature 459, 270273.
Kumar, A., Srivastava, K., Raja Kumar, S., Puri, S. K. and Chauhan, P. M. S. (2010). Synthesis of new 4-aminoquinolines and quinoline-acridine hybrids as antimalarial agents. Bioorganic and Medicinal Chemistry Letters 20, 70597063.
Loiseau, P. M. and Nguyen, D. X. (1996). Plasmodium berghei mouse model: antimalarial activity of new alkaloid salts and of thiosemicarbazone and acridine derivatives. Tropical Medicine and International Health 1, 379384.
Looareesuwan, S., Kyle, D. E., Viravan, C., Vanijanonta, S., Wilairatana, P. and Wernsdorfer, W. H. (1996). Clinical study of pyronaridine for the treatment of acute uncomplicated falciparum malaria in Thailand. American Journal of Tropical Medicine and Hygiene 54, 205209.
May, B. C. H., Witkop, J., Sherrill, J., Anderson, M. O., Madrid, P. B., Zorn, J. a., Prusiner, S. B., Cohen, F. E. and Guy, R. K. (2006). Structure-activity relationship study of 9-aminoacridine compounds in scrapie-infected neuroblastoma cells. Bioorganic and Medicinal Chemistry Letters 16, 49134916.
Noedl, H., Se, Y., Schaecher, K., Smith, B. L., Socheat, D. and Fukuda, M. M. (2008). Evidence of artemisinin-resistant malaria in western Cambodia. The New England Journal of Medicine 359, 26192620.
Okombo, J., Kamau, A. W., Marsh, K., Sutherland, C. J. and Ochola-Oyier, L. I. (2014). Temporal trends in prevalence of Plasmodium falciparum drug resistance alleles over two decades of changing antimalarial policy in coastal Kenya. International Journal for Parasitology. Drugs and Drug Resistance 4, 152163.
Padmanaban, G., Arun Nagaraj, V. and Rangarajan, P. N. (2012). Artemisinin-based combination with curcumin adds a new dimension to malaria therapy. Current Science 102, 704711.
Pandey, S. K., Dwivedi, H., Singh, S., Siddiqui, W. A. and Tripathi, R. (2013). Antimalarial interaction of quinine and quinidine with clarithromycin. Parasitology 140, 406413.
Ramharter, M., Kurth, F., Schreier, A. C., Nemeth, J., Von Glasenapp, I., Bélard, S., Schlie, M., Kammer, J., Koumba, P. K., Cisse, B., Mordmüller, B., Lell, B., Issifou, S., Oeuvray, C., Fleckenstein, L. and Kremsner, P. G. (2008). Fixed-dose pyronaridine-artesunate combination for treatment of uncomplicated falciparum malaria in pediatric patients in Gabon. The Journal of Infectious Diseases 198, 911919.
Ringwald, P., Bickii, J. and Basco, L. (1996). Randomised trial of pyronaridine versus chloroquine for acute uncomplicated falciparum malaria in Africa. Lancet 34, 2428.
Schlitzer, M. (2007). Malaria chemotherapeutics part I: history of antimalarial drug development, currently used therapeutics, and drugs in clinical development. ChemMedChem 2, 944986.
Sharma, M., Chauhan, K., Srivastava, R. K., Singh, S. V., Srivastava, K., Saxena, J. K. III, Puri, S. K. and Chauhan, P. M. S. (2014). Design and synthesis of a new class of 4-Aminoquinolinyl- and 9-Anilinoacridinyl Schiff Base Hydrazones as potent antimalarial agents. Chemical Biology and Drug Design 84, 175181.
Singh, S., Srivastava, R. K., Srivastava, M., Puri, S. K. and Srivastava, K. (2011). In-vitro culture of Plasmodium falciparum: utility of modified (RPNI) medium for drug-sensitivity studies using SYBR Green I assay. Experimental Parasitology 127, 318321.
Srivastava, K. D., Kattan, J. D., Zou, S. M., Li, J. H., Zhang, L., Wallenstein, S., Goldfarb, J., Sampson, H. A. and Li, X. M. (2005). The Chinese herbal medicine formula FAHF-2 completely blocks anaphylactic reactions in a murine model of peanut allergy. The Journal of Allergy and Clinical Immunology 11, 171178.
Tripathi, R., Umesh, a., Mishra, M., Puri, S. K. and Dutta, G. P. (2000). Plasmodium yoelii nigeriensis (MDR)-efficacy of oral pyronaridine against multidrug-resistant malaria in Swiss mice. Experimental Parasitology 94, 190193.
Tripathi, R., Pandey, S. K. and Rizvi, A. (2011). Clarithromycin, a cytochrome P450 inhibitor, can reverse mefloquine resistance in Plasmodium yoelii nigeriensis- infected Swiss mice. Parasitology 138, 10691076.
Valdés, A. F.-C. (2011). Acridine and acridinones: old and new structures with antimalarial activity. The Open Medicinal Chemistry Journal 5, 1120.
Walter, R. D., Seth, M. and Bhaduri, A. P. (1993). Reversal of chloroquine resistance in P. falciparum by CDRI 87/209 and analogues. Tropical Medicine and Parasitology 44, 58.
Wells, T. N., Hooft van, H. R. and Van Voorhis, W. C. (2015). Malaria medicines: a glass half full? Nature Reviews Drug Discovery 14, 424442.
White, N. J. (1997). Assessment of the pharmacodynamic properties of antimalarial drugs in vivo . Antimicrobial Agents and Chemotherapy 41, 14131422.
White, N. J. (2008 a). Qinghaosu (artemisinin): the price of success. Science (New York, N.Y.) 320, 330334.
White, N. J. (2008 b). The role of anti-malarial drugs in eliminating malaria. Malaria Journal 7(Suppl 1), S8.
World Health Organization (WHO) (2014). WORLD MALARIA REPORT 2014 SUMMARY. http://www.who.int/malaria/publications/world_malaria_report_2014/report/en/.

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Pyrrolidine-Acridine hybrid in Artemisinin-based combination: a pharmacodynamic study

  • SWAROOP KUMAR PANDEY (a1), SUBHASISH BISWAS (a2), SARIKA GUNJAN (a1), BHAVANA SINGH CHAUHAN (a1), SUNIL KUMAR SINGH (a1), KUMKUM SRIVASTAVA (a1) (a3), SARIKA SINGH (a4), SANJAY BATRA (a2) (a3) and RENU TRIPATHI (a1) (a3)...

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