Lerisetron Analogues with Antimalarial Properties: Synthesis, Structure-Activity Relationship Studies, and Biological...

Area of Science:

• Medicinal Chemistry
• Parasitology
• Drug Discovery

Background:

• Malaria remains a significant global health burden, necessitating novel therapeutic strategies.
• Antimalarial drug resistance poses a continuous challenge, driving the search for new drug classes.

Purpose of the Study:

• To identify novel antimalarial compounds through phenotypic screening.
• To optimize lead compounds for improved potency and reduced toxicity.

Main Methods:

• High-throughput screening of a benzimidazole chemical series against Plasmodium falciparum asexual blood and liver stages.
• Medicinal chemistry optimization, including analogue synthesis and biological assessment.
• In vivo efficacy studies in mouse models of malaria and cardiotoxicity evaluation (hERG channel inhibition).

Main Results:

• A benzimidazole series, including the antiemetic drug Lerisetron, showed potent activity against malaria parasites.
• Chloro-substituted analogue 3 exhibited high potency against drug-sensitive and multidrug-resistant Plasmodium falciparum strains.
• Compounds 2 and 3 demonstrated in vivo efficacy in malaria mouse models, but hERG channel inhibition indicated cardiotoxicity risk.

Conclusions:

• Benzimidazole derivatives represent a promising chemical scaffold for antimalarial drug development.
• Further optimization is required to mitigate cardiotoxicity and enhance antiplasmodial potency.
• Medicinal chemistry efforts yielded analogues with improved potency compared to the lead compound.