Synthesis of isocryptolepine analogues and their structure-activity relationship studies as antiplasmodial and antiproliferative agents

Pasuk Aroonkit; Charnsak Thongsornkleeb; Jumreang Tummatorn; Suppachai Krajangsri; Mathirut Mungthin; Somsak Ruchirawat

doi:10.1016/j.ejmech.2015.02.047

Synthesis of isocryptolepine analogues and their structure-activity relationship studies as antiplasmodial and antiproliferative agents

Eur J Med Chem. 2015 Apr 13:94:56-62. doi: 10.1016/j.ejmech.2015.02.047. Epub 2015 Feb 26.

Authors

Pasuk Aroonkit¹, Charnsak Thongsornkleeb², Jumreang Tummatorn³, Suppachai Krajangsri⁴, Mathirut Mungthin⁵, Somsak Ruchirawat⁶

Affiliations

¹ 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.
² 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.
³ 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.
⁴ Chulabhorn Research Institute, 54 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand.
⁵ Department of Parasitology, Phramongkutklao College of Medicine, Ratchawithi Road, Bangkok 10400, Thailand.
⁶ 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.

PMID: 25747499
DOI: 10.1016/j.ejmech.2015.02.047

Abstract

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.

Keywords: Antiplasmodial; Antiproliferative; Azide rearrangement; Cytotoxicity; Indoloquinoline alkaloid; Isocryptolepine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antimalarials / chemical synthesis
Antimalarials / chemistry*
Antimalarials / pharmacology*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Cell Line / drug effects
Cell Line, Tumor / drug effects
Chemistry Techniques, Synthetic
Chloroquine / pharmacology
Drug Evaluation, Preclinical / methods
Drug Resistance
Humans
Indole Alkaloids / chemistry*
Plasmodium falciparum / drug effects
Quinolines / chemistry*
Structure-Activity Relationship

Substances

Antimalarials
Antineoplastic Agents
Indole Alkaloids
Quinolines
isocryptolepine
Chloroquine