title: Antiplasmodial activity of new 4-aminoquinoline derivatives against chloroquine resistant strain.
abstract: Emergence and spread of multidrug resistant strains of Plasmodium falciparum has severely limited the antimalarial chemotherapeutic options. In order to overcome the obstacle, a set of new side-chain modified 4-aminoquinolines were synthesized and screened against chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of P. falciparum. The key feature of the designed molecules is the use of methylpiperazine linked α, β(3)- and γ-amino acids to generate novel side chain modified 4-aminoquinoline analogues. Among the evaluated compounds, 20c and 30 were found more potent than CQ against K1 and displayed a four-fold and a three-fold higher activity respectively, with a good selectivity index (SI=5846 and 11,350). All synthesized compounds had resistance index between 1.06 and >14.13 as against 47.2 for chloroquine. Biophysical studies suggested that this series of compounds act on heme polymerization target.
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Manish
authors.initials: M
authors.lastname: Sinha
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Vasanth R
authors.initials: VR
authors.lastname: Dola
authors.affiliation: Parasitology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Pooja
authors.initials: P
authors.lastname: Agarwal
authors.affiliation: Parasitology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Kumkum
authors.initials: K
authors.lastname: Srivastava
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Wahajul
authors.initials: W
authors.lastname: Haq
authors.affiliation: Parasitology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Puri
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India. Electronic address: setu_katti@yahoo.com.
authors.forename: Seturam B
authors.initials: SB
authors.lastname: Katti
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D002738:Chloroquine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000187:drug effects; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000166:cytology / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014709:Vero Cells
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D002738:Chloroquine; C001920:4-aminoquinoline
keywords: 4-Aminoquinoline; Chloroquine; Malaria; Resistant strains