Marine Drugs and Natural Products

Biography

Biography: Rajendra S Bhakuni

Abstract

A series of new artemisinin derivatives have been prepared and assessed in vitro against chloroquine sensitive NF-54 strain of Plasmodium falciparum. In general the incorporation of nitro functionality enhances the activity relative to artemisinin. Three most potent derivatives 12α-dihydroartemisinyl-4’-nitrobenzoate, 12α-dihydroartemisinyl-5’-nitrobenzoate and 12α-artepiperonyloylester possessed several folds more activity than artemisinin against Pf. Molecular docking and ADMET studies were performed to explore the possible mode of action of active compounds into the binding site of target enzyme plasmepsin-II and evaluated compliance with oral bioavailability and pharmacokinetics parameters. Expressing high metabolism activity (66.5%) by fungi Rhizopus stolonifer, artemisinin afforded two novel sesquiterpenoids, 1α-hydroxyartemisinin and 10β-hydroxyartemisinin. The major compound 10β-hydroxyartemisinin was chemically converted to five new derivatives. Under in vitro anti-malarial testing 10β-hydroxy-12β-arteether, IC50, 18.29 nM was found to be 10 times better active than the precursor (184.56 nM) and equipotent antimalarial with artemisinin. Therefore, the major biotransformation product can be exploited for further modification into new clinically potent molecules. The results show the versatility of microbial-catalyzed biotransformations leading to the introduction of a hydroxyl group at tertiary position in artemisinin (1α-hydroxyartemisinin). Artemisinin, artemethers and precursor artemisinic acid were also transformed by cell suspension cultures of Catharanthus roseus (L.) / Lavandula officinalis( L) /.Glycyrrhiza glabra (Linn.)/ Panax quinquefolium and fungus Trichothecium roseumCIMAPN1 into novel derivatives. The detailed results of the studies will be discussed in the conference.