Synthesis and biological evaluation of potential modulators of malarial glutathione-S-transferase(s).
Glutathione-S-transferase(s) (E.C.2.5.1.18, GSTs) have been investigated in parasitic protozoans with respect to their biochemistry and they have been identified as potential vaccine candidates in protozoan parasites and as a target in the synthesis of new antiparasitic agents. In a search towards the identification of novel biochemical targets for antimalarial drug design, the area of Plasmodium glutathione metabolism provides a number of promising chemotherapeutic targets. GST activity was determined in various subcellular fractions of malarial parasites Plasmodium yoelii and was found to be localized mainly in the cytosolic fraction (specific activity, c. 0.058 +/- 0.016 micromol/min/mg protein). Hemin, a known inhibitor of mammalian GST(s), maximally inhibited this enzyme from P. yoelii to nearly 86%. In a search towards synthetic modulators of malarial GST(s), 575 compounds belonging to various chemical classes were screened for their effect on crude GST from P. yoelii and 92 compounds belonging to various chemical classes were studied on recombinant GST from P. falciparum. Among all the compounds screened, 83 compounds inhibited/stimulated the enzyme from P. yoelii/P. falciparum to the extent of 40% or more.
Division of Biochemistry, Central Drug Research Institute, Lucknow, India.
Rumana
R
Ahmad
Arvind K
AK
Srivastava
Rama Pati
RP
Tripathi
Sanjay
S
Batra
Rolf D
RD
Walter
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors* / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D051379:Mice; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology*; D010967:Plasmodium yoelii / Q000187:drug effects* / Q000201:enzymology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
D000962:Antimalarials; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D005982:Glutathione Transferase