Synthesis of isocryptolepine analogues and their structure-activity relationship studies as antiplasmodial and antiproliferative agents.
Novel isocryptolepine analogues have been conveniently synthesized and evaluated for antimalarial and antiproliferative activities. We have found 3-fluoro-8-bromo-isocryptolepine (1n) to have the highest activities against chloroquine-resistant K1, chloroquine-sensitive 3D7, and chloroquine- and mefloquine-resistant SKF58 and SRIV35 strains. Several fluorine-substituted analogues (1b, 1n, and 1q) also showed excellent selectivities while maintaining good to excellent activities against all four Plasmodium falciparum strains. Additionally, antiproliferative properties of isocryptolepine derivatives against HepG2, HuCCA-1, MOLT-3 and A549 cancer cell lines are reported for the first time in this study. 2-Chloroisocryptolepine (1c) and benzo-fused-2-chloroisocryptolepine (1i) showed significant bioactivities whereas several novel fluorinated compounds and 2-chloro-8-bromoisocryptolepine (1f) displayed excellent selectivities.
Program on Chemical Biology, Chulabhorn Graduate Institute, Center of Excellence on Environmental Health and Toxicology, CHE, Ministry of Education, 54 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand.
Pasuk
P
Aroonkit
Program on Chemical Biology, Chulabhorn Graduate Institute, Center of Excellence on Environmental Health and Toxicology, CHE, Ministry of Education, 54 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand; Chulabhorn Research Institute, 54 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand. Electronic address: charnsak@cri.or.th.
Charnsak
C
Thongsornkleeb
Program on Chemical Biology, Chulabhorn Graduate Institute, Center of Excellence on Environmental Health and Toxicology, CHE, Ministry of Education, 54 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand; Chulabhorn Research Institute, 54 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand. Electronic address: jumreang@cri.or.th.
Jumreang
J
Tummatorn
Chulabhorn Research Institute, 54 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand.
Suppachai
S
Krajangsri
Department of Parasitology, Phramongkutklao College of Medicine, Ratchawithi Road, Bangkok 10400, Thailand.
Mathirut
M
Mungthin
Program on Chemical Biology, Chulabhorn Graduate Institute, Center of Excellence on Environmental Health and Toxicology, CHE, Ministry of Education, 54 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand; Chulabhorn Research Institute, 54 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand.
Somsak
S
Ruchirawat
D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D002738:Chloroquine / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004351:Drug Resistance; D006801:Humans; D026121:Indole Alkaloids / Q000737:chemistry*; D010963:Plasmodium falciparum / Q000187:drug effects; D011804:Quinolines / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000962:Antimalarials; D000970:Antineoplastic Agents; D026121:Indole Alkaloids; D011804:Quinolines; C577868:isocryptolepine; D002738:Chloroquine
Antiplasmodial; Antiproliferative; Azide rearrangement; Cytotoxicity; Indoloquinoline alkaloid; Isocryptolepine