title: Synthesis and antimalarial activity of novel side chain modified antimalarial agents derived from 4-aminoquinoline.
abstract: Malaria is one of the foremost public health problems in developing countries affecting nearly 40% of the global population. Apart from this, the past two decade's emergence of drug resistance has severely limited the choice of available antimalarial drugs. Furthermore, the general trend emerging from the SAR-studies is that chloroquine resistance does not involve any change to the target of this class of drugs but involves compound specific efflux mechanism. Based on this premise a number of groups have developed short chain analogues of 4-aminoquinoline, which are active against CQ-resistant strains of P. falciparum in in vitro studies. However, these derivatives undergo biotransformation (de-alklyation) significantly affecting lipid solubility of the drug. In view of this background information, we thought that it would be interesting to study the effect of additional lipophilicity and cationic charge at the lateral side chain of 4-aminoquinoline. This prompted us to explore the cationic amino acid conjugates namely, lysine and ornithine of 4-aminoquinoline with a view to achieve improved antimalarial activity and to the best of our knowledge such amino acid conjugates have not been hitherto reported in the literature in the case of 4-aminoquinolines. In the present study, a new series of side-chain modified 4-aminoquinolines have been synthesized and found active against both susceptible and multidrug resistant strains of P. falciparum in vitro and P. yoelli in vivo. The seminal finding of the present study is that a new series of compounds having significantly more activity against CQ resistant parasites has been identified.
authors.affiliation: Division of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow 226 001, India.
authors.forename: V Raja
authors.initials: VR
authors.lastname: Solomon
authors.forename: W
authors.initials: W
authors.lastname: Haq
authors.forename: M
authors.initials: M
authors.lastname: Smilkstein
authors.forename: Kumkum
authors.initials: K
authors.lastname: Srivastava
authors.forename: S
authors.initials: S
authors.lastname: Rajakumar
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Puri
authors.forename: S B
authors.initials: SB
authors.lastname: Katti
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D020128:Inhibitory Concentration 50; D008239:Lysine / Q000737:chemistry / Q000494:pharmacology; D009952:Ornithine / Q000737:chemistry / Q000494:pharmacology; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D000634:Aminoquinolines; D000962:Antimalarials; D002738:Chloroquine; D009952:Ornithine; C001920:4-aminoquinoline; D008239:Lysine