title: Synthesis and antimalarial testing of neocryptolepine analogues: addition of ester function in SAR study of 2,11-disubstituted indolo[2,3-b]quinolines.
abstract: This report describes the synthesis, and in vitro and in vivo antimalarial evaluations of certain ester-modified neocryptolepine (5-methyl-5H-indolo[2,3-b]quinoline) derivatives. The modifications were carried out by introducing ester groups at the C2 and/or C9 position on the neocryptolepine core and the terminal amino group of the 3-aminopropylamine substituents at the C11 position with a urea/thiourea unit. The antiplasmodial activities of our derivative agents against two different strains (CQS: NF54, and CQR: K1) and the cytotoxic activity against normal L6 cells were evaluated. The test results showed that the ester modified neocryptolepine derivatives have higher antiplasmodial activities against both strains and a low cytotoxic activity against normal cells. The best results were achieved by compounds 9c and 12b against the NF54 strain with the IC50/SI value as 2.27 nM/361 and 1.81 nM/321, respectively. While against K1 strain, all the tested compounds showed higher activity than the well-known antimalarial drug chloroquine. Furthermore, the compounds were tested for β-haematin inhibition and 12 were found to be more active than chloroquine (IC50 = 18 μM). Structure activity relationship studies exposed an interesting linear correlation between polar surface area of the molecule and β-haematin inhibition for this series. In vivo testing of compounds 7 and 8a against NF54 strain on Plasmodium berghei female mice showed that the introduction of the ester group increased the antiplasmodial activity of the neocryptolepine core substantially.
authors.affiliation: Division of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan.
authors.forename: Wen-Jie
authors.initials: WJ
authors.lastname: Lu
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Wicht
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Kento
authors.initials: K
authors.lastname: Imai
authors.forename: Zhen-Wu
authors.initials: ZW
authors.lastname: Mei
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.forename: Ibrahim El Tantawy
authors.initials: Iel T
authors.lastname: El Sayed
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Egan
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Inokuchi
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000737:chemistry*; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects*; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000470:Alkaloids; D000962:Antimalarials; D007211:Indoles; D011804:Quinolines; C414982:neocryptolepine