A new class of potential chloroquine-resistance reversal agents for Plasmodia: syntheses and biological evaluation of 1-(3'-diethylaminopropyl)-3-(substituted phenylmethylene)pyrrolidines.
1-(3'-Diethylaminopropyl)-3-(substituted phenylmethylene)pyrrolidines were synthesized and evaluated for CQ-resistant reversal activity. In general the compounds of the series elicit better biological response than their phenylmethyl analogues. The most active compound 4b has been evaluated in vivo in detail, and the results are presented. The possible mode of action of the compounds of this series is by inhibition of the enzyme heme oxygenase, thereby increasing the levels of heme and hemozoin, which are lethal to the parasite.
Batra
S
S
Divisions of Medicinal Chemistry, Pharmacokinetics and Metabolism, and Biochemistry, Central Drug Research Institute, Lucknow 226 001, India. batra_san@yahoo.co.uk
Srivastava
P
P
Roy
K
K
Pandey
V C
VC
Bhaduri
A P
AP
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002738:Chloroquine / Q000494:pharmacology*; D004351:Drug Resistance; D018432:Drug Resistance, Multiple; D006418:Heme / Q000037:antagonists & inhibitors / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000378:metabolism; D006420:Hemeproteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D010961:Plasmodium / Q000187:drug effects* / Q000378:metabolism; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
C413889:3-((4-methoxyphenyl)methylene)-1-(3-N,N-diethylaminopropyl)pyrrolidine; D000962:Antimalarials; D006420:Hemeproteins; D011759:Pyrrolidines; C020753:hemozoin; D006418:Heme; D002738:Chloroquine; D006419:Heme Oxygenase (Decyclizing)