Synthesis and antimalarial evaluation of novel isocryptolepine derivatives

• Published in: Bioorganic & medicinal chemistry Vol. 19; no. 24; pp. 7519 - 7525
• Main Authors: Whittell, Louise R., Batty, Kevin T., Wong, Rina P.M., Bolitho, Erin M., Fox, Simon A., Davis, Timothy M.E., Murray, Paul E.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.12.2011; Elsevier
• Subjects: 3T3 Cells; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antimalarial; Antimalarials - chemical synthesis; Antimalarials - chemistry; Antimalarials - pharmacology; Antiparasitic agents; Biological and medical sciences; Chloroquine - pharmacology; Cryptolepis sanguinolenta; Humans; Indole Alkaloids - chemical synthesis; Indole Alkaloids - chemistry; Indole Alkaloids - pharmacology; Isocryptolepine; Malaria, Falciparum - drug therapy; Medical sciences; Mice; Pharmacology. Drug treatments; Plasmodium falciparum; Plasmodium falciparum - drug effects; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; Structure-Activity Relationship; PPA; Isocryptolepine; Antimalarial; CQS; CQR; NOE; Cryptolepis sanguinolenta; CQ; NBS; NCS; Protozoa; Apicomplexa; Nitrogen heterocycle; Tetracyclic compound; In vitro; Antiprotozoal agent; Plasmodium falciparum; Position isomer; Chlorine Organic compounds; Parasiticide; Bromine Organic compounds; Aromatic compound; Chemical synthesis
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2011.10.037

A novel series of mono- and di-substituted analogues of isocryptolepine have been synthesized and evaluated for in vitro antimalarial activity and cytotoxicity. A series of mono- and di-substituted analogues of isocryptolepine have been synthesized and evaluated for in vitro antimalarial activity against chloroquine sensitive (3D7) and resistant (W2mef) Plasmodium falciparum and for cytotoxicity (3T3 cells). Di-halogenated compounds were the most potent derivatives and 8-bromo-2-chloroisocryptolepine displayed the highest selectivity index (106; the ratio of cytotoxicity (IC50=9005nM) to antimalarial activity (IC50=85nM)). Our evaluation of novel isocryptolepine compounds has demonstrated that di-halogenated derivatives are promising antimalarial lead compounds.