Design, synthesis and in vitro antimalarial evaluation of triazole-linked chalcone and dienone hybrid compounds Eric M. Guantai a , Kanyile Ncokazi a , Timothy J. Egan a , Jiri Gut b , Philip J. Rosenthal b , Peter J. Smith c , Kelly Chibale a,d,⇑ a Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa b Department of Medicine, San Francisco General Hospital, University of California, San Francisco, CA 94143, USA c Division of Pharmacology, University of Cape Town, Observatory 7925, South Africa d Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa article info Article history: Received 7 August 2010 Revised 27 September 2010 Accepted 5 October 2010 Available online 31 October 2010 Keywords: Malaria Chalcones Dienones Triazole Hybrid compounds Plasmodium falciparum Aminoquinolines Nucleosides abstract A targeted series of chalcone and dienone hybrid compounds containing aminoquinoline and nucleoside templates was synthesized and evaluated for in vitro antimalarial activity. The Cu(I)-catalyzed cycloaddition of azides and terminal alkynes was applied as the hybridization strategy. Several chalcone-chloroquinoline hybrid compounds were found to be notably active, with compound 8b the most active, exhibiting submicromolar IC 50 values against the D10, Dd2 and W2 strains of Plasmodium falciparum. Ó 2010 Elsevier Ltd. All rights reserved. 1. Introduction Malaria remains one of the most widespread infectious diseases, and poses a great challenge to world health. This is under- lined by staggering annual infection and mortality statistics. Estimates range from 300 to 500 million clinical cases of malaria each year, 90% of them in sub-Saharan Africa. The majority of these cases are caused by P. falciparum, 1,2 and result in about 1 million deaths annually, mostly in children under 5 years of age. 2,3 Resistance of malaria parasites to available antimalarial drugs remains a main challenge to the effective control of the disease. Varying levels of resistance to available classes of antimalarials has been reported for P. falciparum, the predominant Plasmodium species in Africa and the most virulent of them. 1,4 This has led to the adoption of combination therapies for the routine treatment of uncomplicated malaria, with particular emphasis on artemisi- nin-based combination therapies (ACTs). 5–7 However, recent evidence of diminished activity of artemisinins in Southeast Asia threatens this strategy. 8,9 With increasing resistance to available agents, intensive drug discovery efforts aimed at developing new antimalarial drugs or modifying existing agents are ongoing. Ideally, highly efficacious, novel antimalarial compounds will be developed to supplement available drugs. Molecular hybridization as a drug discovery strategy involves the rational design of new chemical entities by the fusion (usually via a covalent linker) of two drugs, both active compounds and/or pharmacophoric units recognized and derived from known bioac- tive molecules. 10,11 The selection of the two principles in the dual drug is usually based on their observed (or anticipated) synergistic or additive pharmacological activities to enable the identification of highly active novel chemical entities. In the context of attempt- ing to circumvent antimalarial drug resistance, hybridization is quite an attractive strategy, particularly when the pharmaco- phores/active molecules being merged possess independent modes of antimalarial action. Another basis for hybridization is to exploit active transport mechanisms by linking bioactive units to moieties that are recog- nized and actively transported into mammalian cells, such as amino acids 12 and nucleosides. 13 One of the potential disadvantages of molecular hybridization as a drug discovery strategy is the obvious possibility of transferring 0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2010.10.009 ⇑ Corresponding author. Tel.: +27 21 650 2553; fax: +27 21 689 7499. E-mail address: Kelly.Chibale@uct.ac.za (K. Chibale). Bioorganic & Medicinal Chemistry 18 (2010) 8243–8256 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc