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Exploration of 2, 4-diaminopyrimidine and 2, 4-diamino-s-triazine derivatives as potential antifilarial agents

Published online by Cambridge University Press:  03 April 2013

R. D. SHARMA ,
S. BAG ,
N. R. TAWARI ,
M. S. DEGANI ,
K. GOSWAMI  and
M. V. R. REDDY
R. D. SHARMA
Affiliation:
JB Tropical Disease Research Centre and Department of Biochemistry, Mahatma Gandhi Institute of Medical Sciences, Sevagram 442102, India
S. BAG
Affiliation:
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga (E), Mumbai 400019, India
N. R. TAWARI
Affiliation:
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga (E), Mumbai 400019, India
M. S. DEGANI
Affiliation:
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga (E), Mumbai 400019, India
K. GOSWAMI*
Affiliation:
JB Tropical Disease Research Centre and Department of Biochemistry, Mahatma Gandhi Institute of Medical Sciences, Sevagram 442102, India
M. V. R. REDDY
Affiliation:
JB Tropical Disease Research Centre and Department of Biochemistry, Mahatma Gandhi Institute of Medical Sciences, Sevagram 442102, India
*
*Corresponding author. JB Tropical Disease Research Centre and Department of Biochemistry, Mahatma Gandhi Institute of Medical Sciences, Sevagram 442102, India. Tel: 07152 284341. Fax: 07152 284038. E-mail: [email protected]
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Summary

In view of the mandate from the World Health Organization (WHO) for developing novel drug candidates against human lymphatic filariasis, dihydrofolate reductase (DHFR) inhibitors are explored as potential antifilarial agents. The in vitro biological evaluation of an in-house library of 12 diverse antifolate compounds with 2,4-diaminopyrimidine and 2,4-diamino-s-triazine structural features against Brugia malayi is reported. To confirm the DHFR inhibitory potential of these compounds, reversal studies using folic acid and folinic acid were undertaken. Inhibition of DHFR can induce apoptosis; in this light, preliminary evidence of apoptosis by test compounds was detected using ethidium bromide–acridine orange staining and the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition assay. Among the evaluated compounds, 3 showed significant activity against both microfilariae and adult worms. The effects of 2 of these compounds were mostly reversed by folic acid, validating DHFR inhibitory activity. Partial reversal of the effect of 2 compounds by folinic acid and non-reversal of the effect of the third compound both by folic and folinic acids are discussed. This study opens new avenues for the discovery of lead molecules by exploiting the folate pathway against one of the major neglected tropical diseases, filariasis.

Keywords

DHFR2,4-diaminopyrimidine2,4-diamino-s-triazineantifilarialBrugia malayifilariasis
Type
Research Article
Information
Parasitology , Volume 140 , Issue 8 , July 2013 , pp. 959 - 965
Copyright
Copyright © Cambridge University Press 2013 

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References

REFERENCES

Ash, L. R. and Riley, J. M. (1970). Development of subperiodic Brugia malayi in the jird, Meriones unguiculatus, with notes on infections in other rodents. Journal of Parasitology 56, 969–973.CrossRefGoogle ScholarPubMed
Bag, S., Tawari, N. R., Degani, M. S. and Queener, S. F. (2010 a). Design, synthesis, biological evaluation and computational investigation of novel inhibitors of dihydrofolate reductase of opportunistic pathogens. Bioorganic and Medicinal Chemistry 18, 3187–3197. doi: 10.1016/j.bmc.2010.03.031.CrossRefGoogle ScholarPubMed
Bag, S., Tawari, N. R., Queener, S. F. and Degani, M. S. (2010 b). Synthesis and biological evaluation of biguanide and dihydrotriazine derivatives as potential inhibitors of dihydrofolate reductase of opportunistic microorganisms. Journal of Enzyme Inhibition and Medicinal Chemistry 25, 331–339. doi: 10.3109/14756360903179443.CrossRefGoogle ScholarPubMed
Bag, S., Tawari, N. R., Sharma, R., Goswami, K., Reddy, M. V. and Degani, M. S. (2010 c). In vitro biological evaluation of biguanides and dihydrotriazines against Brugia malayi and folate reversal studies. Acta Tropica 113, 48–51. doi: 10.1016/j.actatropica.2009.09.004.CrossRefGoogle ScholarPubMed
Bohm, I. (2006). The apoptosis marker enzyme poly-(ADP-ribose) polymerase (PARP) in systemic lupus erythematosus. Zeitschrift für Rheumatologie 65, 541–544. doi: 10.1007/s00393-006-0045-4.CrossRefGoogle Scholar
Chandrashekar, R., Rao, U. R., Rajasekariah, G. R. and Subrahmanyam, D. (1984). Isolation of microfilariae from blood on iso-osmotic percoll gradients. Indian Journal of Medical Research 79, 497–501.Google ScholarPubMed
Gangjee, A., Kurup, S. and Namjoshi, O. (2007). Dihydrofolate reductase as a target for chemotherapy in parasites. Current Pharmaceutical Design 13, 609–639.CrossRefGoogle ScholarPubMed
Gupta, S. and Srivastava, A. K. (2005). Biochemical targets in filarial worms for selective antifilarial drug design. Acta Parasitologica 50, 1–18.Google Scholar
Huang, R. F., Ho, Y. H., Lin, H. L., Wei, J. S. and Liu, T. Z. (1999). Folate deficiency induces a cell cycle-specific apoptosis in HepG2 cells. Journal of Nutrition 129, 25–31.CrossRefGoogle ScholarPubMed
Mullen, P. (2004). PARP cleavage as a means of assessing apoptosis. Methods in Molecular Medicine 88, 171–181.Google ScholarPubMed
Navarro-Peran, E., Cabezas-Herrera, J., Garcia-Canovas, F., Durrant, M. C., Thorneley, R. N. and Rodriguez-Lopez, J. N. (2005). The antifolate activity of tea catechins. Cancer Research 65, 2059–2064. doi: 10.1158/0008-5472.CAN-04-3469.CrossRefGoogle ScholarPubMed
Norões, J., Dreyer, G., Santos, A., Mendes, V. G., Medeiros, Z. and Addiss, D. (1997). Assessment of the efficacy of diethylcarbamazine on adult Wuchereria bancrofti in vivo. Transactions of the Royal Society of Tropical Medicine and Hygiene 91, 78–81.CrossRefGoogle ScholarPubMed
Ribble, D., Goldstein, N. B., Norris, D. A. and Shellman, Y. G. (2005). A simple technique for quantifying apoptosis in 96-well plates. BMC Biotechnology 5, 12. doi: 10.1186/1472-6750-5-12.CrossRefGoogle ScholarPubMed
Sahare, K. N., Anandharaman, V., Meshram, V. G., Meshram, S. U., Gajalakshmi, D., Goswami, K. and Reddy, M. V. (2008 a). In vitro effect of four herbal plants on the motility of Brugia malayi microfilariae. Indian Journal of Medical Research 127, 467–471.Google ScholarPubMed
Sahare, K. N., Anandhraman, V., Meshram, V. G., Meshram, S. U., Reddy, M. V., Tumane, P. M. and Goswami, K. (2008 b). Anti-microfilarial activity of methanolic extract of Vitex negundo and Aegle marmelos and their phytochemical analysis. Indian Journal of Experimental Biology 46, 128–131.Google ScholarPubMed
Sanger, I., Lammler, G. and Kimmig, P. (1981). Filarial infections of Mastomys natalensis and their relevance for experimental chemotherapy. Acta Tropica 38, 277–288.Google ScholarPubMed
Sharma, R. D., Janardhanan, A. S., Gajalakshmi, D., Reddy, M. V. R. and Goswami, K. (2008). Direct microscopy: an alternative tool for assessment of viability of microfilariae. Internet Journal of Parasitic Diseases 3 (1).Google Scholar
Singh, S. K., Goswami, K., Sharma, R. D., Reddy, M. V. R. and Dash, D. (2012). Novel microfilaricidal activity of nanosilver. International Journal of Nanomedicine 7, 1023–1030.Google ScholarPubMed
World Health Organization (2012). http://www.who.int/mediacentre/factsheets/fs102/en/.Google Scholar