Synthesis and antimalarial activity of new 4-amino-7-chloroquinolyl amides, sulfonamides, ureas and thioureas

We report the synthesis and in vitro antimalarial activities of more than 50 7-chloro-4-aminoquinolyl-derived sulfonamides 3–8 and 11–26, ureas 19–22, thioureas 23–26, and amides 27–54. Many of the CQ analogues prepared for this study showed submicromolar antimalarial activity versus HB3 (chloroquine sensitive) and Dd2 (chloroquine resistant strains of Plasmodium falciparum) and low resistance indices were obtained in most cases. Systematic variation of the side chain length and introduction of fluorinated aliphatic and aromatic termini revealed promising leads that overcome CQ resistance. In particular, sulfonamide 3 exhibiting a short side chain with a terminal dansyl moiety combined high antiplasmodial potency with a low resistance index and showed IC50s of 17.5 and 22.7 nM against HB3 and Dd2 parasites.

More than 50 new chloroquine analogues exhibiting systematically varied side chains have been synthesized and tested against sensitive and resistant strains of Plasmodium falciparum. Important SAR principles and new lead compounds are presented.Figure optionsDownload as PowerPoint slide