Cell-based optimization of novel benzamides as potential antimalarial leads

Area of Science:

• Medicinal Chemistry
• Parasitology
• Drug Discovery

Background:

• Malaria remains a significant global health burden, necessitating the development of new antimalarial drugs.
• Existing treatments face challenges due to drug resistance.
• Targeting Plasmodium falciparum proliferation is a key strategy in malaria drug development.

Purpose of the Study:

• To discover novel compounds with antiplasmodial activity.
• To optimize initial hits into potent drug candidates.
• To evaluate the safety and efficacy of optimized compounds.

Main Methods:

• Screening of an in-house compound library using a cell-based Plasmodium falciparum proliferation assay.
• Lead optimization of identified hit scaffolds.
• In vitro cellular potency assays against multiple Plasmodium falciparum strains.
• In vivo efficacy studies in relevant models.

Main Results:

• A known pan-kinase inhibitor scaffold was identified as an initial hit.
• Optimization yielded a novel benzamide scaffold with potent antiplasmodial activity.
• The optimized benzamide series demonstrated selectivity, lacking human kinase activity.
• Candidates exhibited good cellular potency and a decent in vivo profile.

Conclusions:

• The novel benzamide scaffold represents a promising new chemical class for antimalarial drug development.
• These compounds offer a potential alternative to existing therapies, addressing drug resistance.
• Further development of these candidates could lead to effective treatments for malaria.