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

doi:10.1016/j.ejmech.2021.113518

Discovery and development of 2-aminobenzimidazoles as potent antimalarials

Eur J Med Chem. 2021 Oct 5:221:113518. doi: 10.1016/j.ejmech.2021.113518. Epub 2021 May 13.

Affiliations

¹ Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia. Electronic address: shane.devine@monash.edu.
² Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia.
³ Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia.
⁴ Discovery Biology, Griffith University, Nathan, Queensland, 4111, Australia; School of Environment & Science, Griffith University, Nathan, Queensland, 4111, Australia.
⁵ Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia; ARC Centre for Fragment-Based Design, Monash University, Parkville, Victoria, 3052, Australia.
⁶ Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 3052, Australia. Electronic address: peter.scammells@monash.edu.

PMID: 34058708
DOI: 10.1016/j.ejmech.2021.113518

Abstract

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.II^C580Y) 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.

Keywords: 2-Aminobenzimidazole; Malaria; Plasmodium falciparum; Structure-activity relationships.

MeSH terms

Antimalarials / chemical synthesis
Antimalarials / chemistry
Antimalarials / pharmacology*
Benzimidazoles / chemical synthesis
Benzimidazoles / chemistry
Benzimidazoles / pharmacology*
Dose-Response Relationship, Drug
Drug Discovery*
HEK293 Cells
Humans
Malaria, Falciparum / drug therapy*
Molecular Structure
Parasitic Sensitivity Tests
Plasmodium falciparum / drug effects*
Structure-Activity Relationship

Substances

Antimalarials
Benzimidazoles
2-aminobenzimidazole