title: Synthesis of some cryptolepine analogues, assessment of their antimalarial and cytotoxic activities, and consideration of their antimalarial mode of action.
abstract: A series of analogues of cryptolepine (1) have been synthesized and evaluated for their in vitro antiplasmodial and cytotoxic properties. The IC(50) values of several compounds (11a, 11k-m, 11o, 13) against Plasmodium falciparum (strain K1) were <0.1 muM, 5-10-fold lower than that of 1 but their cytotoxicities were only 2-4 times greater than that of 1. Compounds with a halogen in the quinoline ring and a halogen or a nitro group in the indole ring have enhanced antiplasmodial activity. In mice infected with P. berghei, the 7-bromo-2-chloro (11k) and 2-bromo-7-nitro (13) derivatives of 1 suppressed parasitemia by >90% at doses of 25 mg kg(-1) day(-1) with no apparent toxicity to the mice. 2,7-Dibromocryptolepine (15) was evaluated at several dose levels, and a dose-dependent suppression of parasitemia was seen (ED(90) = 21.6 mg kg(-1) day(-1)). The antimalarial mode of action of 1 appears to be similar to that of chloroquine and involves the inhibition of hemozoin formation. A number of analogues were assessed for their effects on the inhibition of beta-hematin (hemozoin) formation, and the results were compared with their antiplasmodial activities having taken account of their predicted accumulation into the acidic parasite food vacuole. No correlation was seen (r(2) = 0.0781) suggesting that the potent antimalarial activity of compounds such as 15 involves other mechanisms in addition to the inhibition of hemozoin formation.
authors.affiliation: The School of Pharmacy, Department of Biomedical Sciences and Tom Connors Cancer Research Centre, University of Bradford, West Yorkshire, BD7 1DP, UK.
authors.forename: Onyeka
authors.initials: O
authors.lastname: Onyeibor
authors.forename: Simon L
authors.initials: SL
authors.lastname: Croft
authors.forename: Hilary I
authors.initials: HI
authors.lastname: Dodson
authors.forename: Mohammad
authors.initials: M
authors.lastname: Feiz-Haddad
authors.forename: Howard
authors.initials: H
authors.lastname: Kendrick
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Millington
authors.forename: Silvia
authors.initials: S
authors.lastname: Parapini
authors.forename: Roger M
authors.initials: RM
authors.lastname: Phillips
authors.forename: Scott
authors.initials: S
authors.lastname: Seville
authors.forename: Steven D
authors.initials: SD
authors.lastname: Shnyder
authors.forename: Donatella
authors.initials: D
authors.lastname: Taramelli
authors.forename: Colin W
authors.initials: CW
authors.lastname: Wright
mesh_terms: D000465:Algorithms; D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D005260:Female; D006420:Hemeproteins / Q000037:antagonists & inhibitors / Q000138:chemical synthesis; D026121:Indole Alkaloids; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008288:Malaria / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000470:Alkaloids; D000962:Antimalarials; D000970:Antineoplastic Agents; D006420:Hemeproteins; D026121:Indole Alkaloids; D007211:Indoles; D011804:Quinolines; C020753:hemozoin; C024015:cryptolepine