Synthesis of Some Cryptolepine Analogues, Assessment of Their Antimalarial and Cytotoxic Activities, and Consideration of Their Antimalarial Mode of Action

• Published in: Journal of medicinal chemistry Vol. 48; no. 7; pp. 2701 - 2709
• Main Authors: Onyeibor, Onyeka, Croft, Simon L, Dodson, Hilary I, Feiz-Haddad, Mohammad, Kendrick, Howard, Millington, Nicola J, Parapini, Silvia, Phillips, Roger M, Seville, Scott, Shnyder, Steven D, Taramelli, Donatella, Wright, Colin W
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 07-04-2005
• Subjects: Algorithms; Alkaloids - chemical synthesis; Alkaloids - chemistry; Alkaloids - pharmacology; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiparasitic agents; Biological and medical sciences; Cell Line, Tumor; Female; Hemeproteins - antagonists & inhibitors; Hemeproteins - chemical synthesis; Indole Alkaloids; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Malaria - drug therapy; Medical sciences; Mice; Mice, Inbred BALB C; Miscellaneous; Pharmacology. Drug treatments; Plasmodium berghei; Plasmodium falciparum; Plasmodium falciparum - drug effects; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; Structure-Activity Relationship; Protozoa; Antimalarial; Nitro compound; Apicomplexa; Rodentia; Cytotoxicity; In vitro; Dose activity relation; Antiprotozoal agent; In vivo; Plasmodium falciparum; Vertebrata; Plasmodium berghei; Mammalia; Structure activity relation; Mouse; Animal; Parasiticide; Bromine Organic compounds; Mechanism of action; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm040893w

A series of analogues of cryptolepine (1) have been synthesized and evaluated for their in vitro antiplasmodial and cytotoxic properties. The IC50 values of several compounds (11a, 11k−m, 11o, 13) against Plasmodium falciparum (strain K1) were <0.1 μM, 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 (ED90 = 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 β-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.