title: 2-Aminopyrimidine based 4-aminoquinoline anti-plasmodial agents. Synthesis, biological activity, structure-activity relationship and mode of action studies.
abstract: 2-Aminopyrimidine based 4-aminoquinolines were synthesized using an efficacious protocol. Some of the compounds showed in vitro anti-plasmodial activity against drug-sensitive CQ(S) (3D7) and drug-resistant CQ(R) (K1) strains of Plasmodium falciparum in the nM range. In particular, 5-isopropyloxycarbonyl-6-methyl-4-(2-nitrophenyl)-2-[(7-chloroquinolin-4-ylamino)butylamino] pyrimidine depicted the lowest IC(50) (3.6 nM) value (56-fold less than CQ) against CQ(R) strain. Structure-activity profile and binding with heme, μ-oxo-heme have been studied. Binding assays with DNA revealed better binding with target parasite type AT rich pUC18 DNA. Most compounds were somewhat cytotoxic, but especially cytostatic. Molecular docking analysis with Pf DHFR allowed identification of stabilizing interactions.
authors.affiliation: Organic Synthesis Laboratory, Department of Applied Chemical Sciences and Technology, Guru Nanak Dev University, Amritsar 143005, India. kamaljit19in@yahoo.co.in
authors.forename: Kamaljit
authors.initials: K
authors.lastname: Singh
authors.forename: Hardeep
authors.initials: H
authors.lastname: Kaur
authors.forename: Kelly
authors.initials: K
authors.lastname: Chibale
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Susan
authors.initials: S
authors.lastname: Little
authors.forename: Prasad V
authors.initials: PV
authors.lastname: Bharatam
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004285:Dogs; D006418:Heme / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D010963:Plasmodium falciparum / Q000187:drug effects*; D011524:Protoporphyrins / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014780:Viruses / Q000187:drug effects
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D011524:Protoporphyrins; D011743:Pyrimidines; C012180:2-aminopyrimidine; D006418:Heme; D004247:DNA; C028025:protoporphyrin IX; C001920:4-aminoquinoline