title: A new library of C-16 modified artemisinin analogs and evaluation of their anti-parasitic activities.
abstract: A library of C-16 modified artemisinin analogs was prepared and their antimalarial as well as antileishmanial activities were evaluated. Synthesis of these compounds involved the conversion of artemisinin to its phenol derivatives 7 and 12, and subsequent parallel derivatization by introducing new chemical groups through ester, carbamate, sulfate, phosphate and isourea linkages. Comparison of in vitro antimalarial activities showed that C9-beta artemisinin analogs (8a-f) are more potent than the corresponding C9-alpha diastereomers (9a-f); however, their antileishmanial activities were in the same range. Many of the 10-deoxoartemisinin analogs studied here showed promising antiparasitic activities. For example, compounds 13a-e are approximately three times more active against drug resistant W2 strain of P. falciparum, compared to artemisinin (IC(50), approximately 0.2 - 0.6 nM; cf. artemisinin = 1.6 nM). Further, a number of compounds in this series were notably leishmanicidal, with activities comparable to or better than pentamidine (e.g., 13g and 13j). Detailed in vivo studies involving these active compounds are underway to identify lead candidates for further development.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, University, MS 38677-1848, USA.
authors.forename: Rani B
authors.initials: RB
authors.lastname: Menon
authors.forename: Muraleedharan M
authors.initials: MM
authors.lastname: Kannoth
authors.forename: Babu L
authors.initials: BL
authors.lastname: Tekwani
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Rosenthal
authors.forename: Mitchell A
authors.initials: MA
authors.lastname: Avery
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D037621:Artemisinins / Q000737:chemistry* / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D020128:Inhibitory Concentration 50; D007893:Leishmania donovani / Q000187:drug effects*; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D012717:Sesquiterpenes / Q000737:chemistry* / Q000494:pharmacology*; D014709:Vero Cells
chemical_list: D000981:Antiprotozoal Agents; D037621:Artemisinins; D012717:Sesquiterpenes; C031327:artemisinin