Structure-activity relationships of the antimalarial agent artemisinin. 2. Effect of heteroatom substitution at O-11: synthesis and bioassay of N-alkyl-11-aza-9-desmethylartemisinins.
A novel class of artemisinin analogs, N-alkyl-11-aza-9-desmethylartemisinins 17-29, were synthesized via ozonolysis and acid-catalyzed cyclization of precursor amides 5-16. These amides were prepared through condensation of an activated ester of the known intermediate acid 2 with the corresponding primary amine. The analogs were tested in vitro against W-2 and D-6 strains of Plasmodium falciparum and found in some cases to be more active than artemisinin. A comparison of the in vitro testing methods of Milhous and Makler was conducted and gave similar relative antimalarial activities for these artemisinin analogs. Log P values were determined for most of the compounds, but no apparent correlation between log P and in vitro activity was found.
Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, University 38677, USA.
M A
MA
Avery
J D
JD
Bonk
W K
WK
Chong
S
S
Mehrotra
R
R
Miller
W
W
Milhous
D K
DK
Goins
S
S
Venkatesan
C
C
Wyandt
I
I
Khan
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D037621:Artemisinins; D004353:Drug Evaluation, Preclinical; D004365:Drugs, Chinese Herbal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004912:Erythrocytes / Q000469:parasitology; D006801:Humans; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects*; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000962:Antimalarials; D037621:Artemisinins; D004365:Drugs, Chinese Herbal; D012717:Sesquiterpenes; C039060:artenimol; C055261:deoxyartemisinin; C031327:artemisinin