New aminoquinoline antimalarial cysteine protease inhibitors based on the isatin natural product scaffold

• Main Author: Ntuli, Nelson Axe
• Other Authors: Chibale, Kelly
• Format: Dissertation
• Language: English
• Published: University of Cape Town 2014
• Subjects: Chemistry
• Online Access: http://hdl.handle.net/11427/6352

Includes bibliographical references (leaves 120-125). === Many antimalarial drugs including chloroquine are no longer effective against the disease, as their efficacy has been decreased by the spread of drug resistant strains. This loss has been a major barrier to the effective treatment of malaria and has necessitated an urgent need to discover new antimalarial drugs. New 4-aminoquinoline isatin derivatives have been designed and synthesised. Isatin was used as a biologically validated starting point for the design of chemical libraries directed at the intended target due to its privileged nature. Included in the design of these isatin derivatives is the thiosemicarbazone moiety previously demonstrated to inhibit cysteine proteases from mUltiple protozoan parasites. Synthesized compounds were tested against the enzyme falcipain-2 (Rec-FP-2) as well as the parasite source of this protease, Plasmodium Jalciparum (P.f. W2). The results of structure activity relationship studies demonstrate the influence of substituents at position 5 of the isatin scaffold. With respect to the chain length, a two carbon methylene spacer between the aminoquinoline and isatin moieties, was found optimum. A 5-bromo isatin derivative with this spacer, compound 79b, was found to be the most active with an IC₅₀ value of 163.5 nM against the W2 parasite strain and second most active against the enzyme (lC₅₀ = 3.65 μM).