du1301 and quinoline

Discovery and development of antimalarial drugs have long been dominated by single-target therapy. Continuous effort has been made to explore and identify different targets in malaria parasite crucial for the malaria treatment. The single-target drug therapy was initially successful, but it was later supplanted by combination therapy with multiple drugs to overcome drug resistance. Emergence of resistant strains even against the combination therapy has warranted a review of current antimalarial pharmacotherapy. This has led to the development of the new concept of covalent biotherapy, in which two or more pharmacophores are chemically bound to produce hybrid antimalarial drugs with multi-target functionalities. Herein, the review initially details the current pharmacotherapy for malaria as well as the conventional and novel targets of importance identified in the malaria parasite. Then, the rationale of multi-targeted therapy for malaria, approaches taken to develop the multi-target antimalarial hybrids, and the examples of hybrid molecules are comprehensively enumerated and discussed.

Topics: Animals; Antimalarials; Artemisinins; Drug Discovery; Drug Resistance; Humans; Malaria; Molecular Structure; Paclitaxel; Quinolines

PfATP6, a calcium-dependent ATPase of Plasmodium falciparum, is considered the putative target of the antimalarial drug artemisinin and its derivatives. Herein, the 3D structure of PfATP6 was modeled on the basis of the crystal structure of SERCA 1a, the mammalian homologue. Model validation was achieved using protein structure checking tools. AutoDock4 was used to predict the binding affinities of artemisinin (and analogues) and various other antimalarial agents for PfATP6, for which in vitro activity is also reported. No correlation was found between the affinity of the compounds for PfATP6 predicted by AutoDock4 and their antimalarial activity.

Topics: Animals; Antimalarials; Artemisinins; Calcium-Transporting ATPases; Computer Simulation; Enzyme Inhibitors; Plasmodium falciparum; Protein Binding; Quinolines; Sesquiterpenes