Exploration of 2, 4-diaminopyrimidine and 2, 4-diamino-s-triazine derivatives as potential antifilarial agents.
Identifieur interne : 001C08 ( PubMed/Curation ); précédent : 001C07; suivant : 001C09Exploration of 2, 4-diaminopyrimidine and 2, 4-diamino-s-triazine derivatives as potential antifilarial agents.
Auteurs : R D Sharma [Inde] ; S. Bag ; N R Tawari ; M S Degani ; K. Goswami ; M V R. ReddySource :
- Parasitology [ 1469-8161 ] ; 2013.
Descripteurs français
- KwdFr :
- Aedes, Animaux, Antifoliques (), Antifoliques (isolement et purification), Antifoliques (pharmacologie), Brugia malayi (), Concentration inhibitrice 50, Dihydrofolate reductase (), Dihydrofolate reductase (métabolisme), Femelle, Filaricides (), Filaricides (isolement et purification), Filaricides (pharmacologie), Filariose lymphatique (parasitologie), Filariose lymphatique (traitement médicamenteux), Gerbillinae, Humains, Microfilaria, Murinae, Mâle, Protéines d'helminthes (), Protéines d'helminthes (métabolisme), Pyrimidines (), Pyrimidines (isolement et purification), Pyrimidines (pharmacologie), Tests de sensibilité parasitaire, Triazines (), Triazines (isolement et purification), Triazines (pharmacologie).
- MESH :
- isolement et purification : Antifoliques, Filaricides, Pyrimidines, Triazines.
- métabolisme : Dihydrofolate reductase, Protéines d'helminthes.
- parasitologie : Filariose lymphatique.
- pharmacologie : Antifoliques, Filaricides, Pyrimidines, Triazines.
- traitement médicamenteux : Filariose lymphatique.
- Aedes, Animaux, Antifoliques, Brugia malayi, Concentration inhibitrice 50, Dihydrofolate reductase, Femelle, Filaricides, Gerbillinae, Humains, Microfilaria, Murinae, Mâle, Protéines d'helminthes, Pyrimidines, Tests de sensibilité parasitaire, Triazines.
English descriptors
- KwdEn :
- Aedes, Animals, Brugia malayi (drug effects), Elephantiasis, Filarial (drug therapy), Elephantiasis, Filarial (parasitology), Female, Filaricides (chemistry), Filaricides (isolation & purification), Filaricides (pharmacology), Folic Acid Antagonists (chemistry), Folic Acid Antagonists (isolation & purification), Folic Acid Antagonists (pharmacology), Gerbillinae, Helminth Proteins (drug effects), Helminth Proteins (metabolism), Humans, Inhibitory Concentration 50, Male, Microfilariae, Murinae, Parasitic Sensitivity Tests, Pyrimidines (chemistry), Pyrimidines (isolation & purification), Pyrimidines (pharmacology), Tetrahydrofolate Dehydrogenase (drug effects), Tetrahydrofolate Dehydrogenase (metabolism), Triazines (chemistry), Triazines (isolation & purification), Triazines (pharmacology).
- MESH :
- chemical , chemistry : Filaricides, Folic Acid Antagonists, Pyrimidines, Triazines.
- drug effects : Brugia malayi, Helminth Proteins, Tetrahydrofolate Dehydrogenase.
- drug therapy : Elephantiasis, Filarial.
- chemical , isolation & purification : Filaricides, Folic Acid Antagonists, Pyrimidines, Triazines.
- chemical , metabolism : Helminth Proteins, Tetrahydrofolate Dehydrogenase.
- parasitology : Elephantiasis, Filarial.
- chemical , pharmacology : Filaricides, Folic Acid Antagonists, Pyrimidines, Triazines.
- Aedes, Animals, Female, Gerbillinae, Humans, Inhibitory Concentration 50, Male, Microfilariae, Murinae, Parasitic Sensitivity Tests.
Abstract
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.
DOI: 10.1017/S0031182013000309
PubMed: 23552564
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pubmed:23552564Le document en format XML
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<term>Animals</term>
<term>Brugia malayi (drug effects)</term>
<term>Elephantiasis, Filarial (drug therapy)</term>
<term>Elephantiasis, Filarial (parasitology)</term>
<term>Female</term>
<term>Filaricides (chemistry)</term>
<term>Filaricides (isolation & purification)</term>
<term>Filaricides (pharmacology)</term>
<term>Folic Acid Antagonists (chemistry)</term>
<term>Folic Acid Antagonists (isolation & purification)</term>
<term>Folic Acid Antagonists (pharmacology)</term>
<term>Gerbillinae</term>
<term>Helminth Proteins (drug effects)</term>
<term>Helminth Proteins (metabolism)</term>
<term>Humans</term>
<term>Inhibitory Concentration 50</term>
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<term>Microfilariae</term>
<term>Murinae</term>
<term>Parasitic Sensitivity Tests</term>
<term>Pyrimidines (chemistry)</term>
<term>Pyrimidines (isolation & purification)</term>
<term>Pyrimidines (pharmacology)</term>
<term>Tetrahydrofolate Dehydrogenase (drug effects)</term>
<term>Tetrahydrofolate Dehydrogenase (metabolism)</term>
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<term>Antifoliques (pharmacologie)</term>
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<term>Concentration inhibitrice 50</term>
<term>Dihydrofolate reductase ()</term>
<term>Dihydrofolate reductase (métabolisme)</term>
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<term>Filaricides (isolement et purification)</term>
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<term>Triazines (isolement et purification)</term>
<term>Triazines (pharmacologie)</term>
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<term>Triazines</term>
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<term>Triazines</term>
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<term>Pyrimidines</term>
<term>Triazines</term>
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<term>Triazines</term>
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<term>Animals</term>
<term>Female</term>
<term>Gerbillinae</term>
<term>Humans</term>
<term>Inhibitory Concentration 50</term>
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<term>Murinae</term>
<term>Parasitic Sensitivity Tests</term>
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<term>Animaux</term>
<term>Antifoliques</term>
<term>Brugia malayi</term>
<term>Concentration inhibitrice 50</term>
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<term>Murinae</term>
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<front><div type="abstract" xml:lang="en">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.</div>
</front>
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<Abstract><AbstractText>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.</AbstractText>
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