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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: goswamikln@gmail.com
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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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