Inhibitory Activity and Docking Analysis of Antimalarial Agents from Stemona sp. toward Ferredoxin-NADP+ Reductase from Malaria Parasites

Abstract

Ferredoxin-NADP+ reductases (FNRs, EC 1.18.1.2) were found in the plastids of Plasmodium and have been considered as a target for the development of new antimalarial agents. Croomine, epi-croomine, tuberostemonine, javastemonine A, and isoprotostemonine are isolated alkaloids from the roots of Stemona sp. and their inhibitory effect on FNRs from Plasmodium falciparum (PfFNR) was investigated. Croomine showed the highest level of inhibition (33.9%) of electron transfer from PfFNR to PfFd, while tuberstemonine displayed the highest level of inhibition (55.4%) of diaphorase activity of PfFNR. Docking analysis represented that croomine is located at the middle position of PfFNR and PfFd. Croomine from S. tuberosa appeared to have potential as an antimalarial agent.

Reactions of Plasmodium falciparum Ferredoxin:NADP+ Oxidoreductase with Redox Cycling Xenobiotics: A Mechanistic Study

“…Thus, based on the available data, Pf FNR and possibly Pf Fd may play a central role in the reductive activation of pro-oxidant xenobiotics relevant for malaria chemotherapy. This also points to a versatility of the properties of Pf FNR, which may be relevant for the design of new antiplasmodial agents, because another intriguing approach to this task is the development of compounds that may bind at the Pf FNR-Pf Fd interface and inhibit the physiological reduction of Pf Fd [43,44]. Thus, an attractive possibility could be the derivatization of these ligands, chalcones or alkaloids [43,44] by redox-active quinone, ArNO 2 or ArN→O moieties.…”

“…This also points to a versatility of the properties of Pf FNR, which may be relevant for the design of new antiplasmodial agents, because another intriguing approach to this task is the development of compounds that may bind at the Pf FNR-Pf Fd interface and inhibit the physiological reduction of Pf Fd [43,44]. Thus, an attractive possibility could be the derivatization of these ligands, chalcones or alkaloids [43,44] by redox-active quinone, ArNO 2 or ArN→O moieties. These hybrid molecules may combine two mechanisms of antiplasmodial action: the inhibition of the electron supply to the apicoplast redox system and redox cycling.…”

Roles of Ferredoxin-Dependent Proteins in the Apicoplast of Plasmodium falciparum Parasites

“…5 ) ( 8 , 14 , 17 ). This system is an attractive drug target because it appears to play a central role in apicoplast metabolism and is not found in the human host ( 9 , 10 ).…”

“…The Fd/FNR system provides reducing equivalents to multiple enzymes within the apicoplast ( 7 , 8 ) and is presumed to be essential for parasite survival. Due to the absence of orthologs in the human host, the Fd/FNR system is an attractive drug target, and several attempts have been made to discover inhibitors ( 9 , 10 ).…”