Macromolecular 4-aminoquinoline compounds as potential antimalarial drugs

Aderibigbe, Atim Blessing
Journal Title
Journal ISSN
Volume Title
4-Aminoquinolines have a long and successful history as antimalarials as they have provided a number of useful antimalarials. P. falciparum, a causative organism of the most deadly form of human malaria, is generally slow to develop resistance to these drugs. 4-Aminoquinoline derivatives appear to bind to nucleoproteins and interfere with protein synthesis in susceptible organisms; the drugs intercalate readily into double-stranded DNA and inhibit both DNA and RNA polymerase. In addition, 4-aminoquinolines are found to concentrate in parasites’ digestive vacuoles, thereby increasing the pH of the vacuoles, and thus interfere with the parasites’ ability to metabolize. 4-Aminoquinolines on the other hand have raised considerable interest because of their anti-carcinogenic properties and their ability to inhibit tumor development and presently are being used in combination therapy with anti-cancer drugs to inhibit development of drug resistance in cancer cells caused by anti-cancer drugs. 8-Aminoquinoline mechanism is quite different from that of 4-aminoquinoline in that the 8-aminoquinolines are converted in the liver to an active quinone metabolite creating oxygen free radicals that interfere with the plasmodial electron chain transport chain during respiration. Anti-cancer drugs are often toxic when delivered straight, but the bioreversible drug conjugation of anticancer drugs to water-soluble macromolecular carriers has proved to enhance the therapeutic effectiveness of anticancer drugs. Following facilitated pharmacokinetics pathways, the conjugates, acting as prodrugs, will release the active drug species in the transformed target cells and their designs are geared towards reducing pharmacological barriers of toxicity, drug resistance and poor bioavailability encountered with currently used anti-cancer drugs. In order to demonstrate the multidrug binding capacity of polyaspartamide, the co-conjugation of 4- and 8-aminoquinoline derivatives with anti-cancer agents was achieved, and the co-conjugates are expected to serve as resistance-reducing agents. This present project aimed at the anchoring of 4-aminoquinoline to various amine functionalized polymeric carriers, and selected macromolecular 4-aminoquinoline compounds were screened for in vitro antiplasmodial activity.