Discovery and development of 2-aminobenzimidazoles as potent antimalarials

Shane M. Devine, Matthew P. Challis, Jomo K. Kigotho, Ghizal Siddiqui, Amanda De Paoli, Christopher A. MacRaild, Vicky M. Avery, Darren J. Creek, Raymond S. Norton, Peter J. Scammells

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9 Citations (Scopus)


The emergence of Plasmodium falciparum resistance to frontline antimalarials, including artemisinin combination therapies, highlights the need for new molecules that act via novel mechanisms of action. Herein, we report the design, synthesis and antimalarial activity of a series of 2-aminobenzimidazoles, featuring a phenol moiety that is crucial to the pharmacophore. Two potent molecules exhibited IC50 values against P. falciparum 3D7 strain of 42 ± 4 (3c) and 43 ± 2 nM (3g), and high potency against strains resistant to chloroquine (Dd2), artemisinin (Cam3.IIC580Y) and PfATP4 inhibitors (SJ557733), while demonstrating no cytotoxicity against human cells (HEK293, IC50 > 50 μM). The most potent molecule, possessing a 4,5-dimethyl substituted phenol (3r) displayed an IC50 value of 6.4 ± 0.5 nM against P. falciparum 3D7, representing a 12-fold increase in activity from the parent molecule. The 2-aminobenzimidazoles containing a N1-substituted phenol represent a new class of molecules that have high potency in vitro against P. falciparum malaria and low cytotoxicity. They possessed attractive pharmaceutical properties, including low molecular weight, high ligand efficiency, high solubility, synthetic tractability and low in vitro clearance in human liver microsomes.

Original languageEnglish
Article number113518
Number of pages17
JournalEuropean Journal of Medicinal Chemistry
Publication statusPublished - 5 Oct 2021


  • 2-Aminobenzimidazole
  • Malaria
  • Plasmodium falciparum
  • Structure-activity relationships

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