2,4-Diaminothienopyrimidines as orally active antimalarial agents

Area of Science:

• Medicinal Chemistry
• Parasitology
• Pharmacology

Background:

• Malaria remains a significant global health challenge, necessitating the development of novel antimalarial agents.
• Existing antimalarials face challenges including drug resistance and toxicity.
• High-throughput screening (HTS) is a valuable tool for identifying novel chemical scaffolds with therapeutic potential.

Purpose of the Study:

• To identify novel antimalarial compounds through whole-cell HTS.
• To synthesize and characterize 2,4-diaminothienopyrimidine analogues.
• To evaluate the antiplasmodial activity, cytotoxicity, and in vivo efficacy of the identified compounds.

Main Methods:

• Whole-cell HTS of a SoftFocus ion channel library against malaria parasites.
• Chemical synthesis of 2,4-diaminothienopyrimidine derivatives.
• Structure-activity relationship (SAR) studies to optimize antiplasmodial potency.
• In vitro cytotoxicity assays against mammalian cell lines.
• In vivo efficacy studies using the Plasmodium berghei mouse model.

Main Results:

• Identification of a novel series of 2,4-diaminothienopyrimidines with potent antiplasmodial activity.
• Optimized analogues demonstrated low in vitro cytotoxicity.
• Several compounds exhibited significant in vivo antimalarial activity upon oral administration in a mouse model.
• A key liability identified was the inhibition of the hERG potassium channel.

Conclusions:

• 2,4-diaminothienopyrimidines represent a promising scaffold for the development of new antimalarial drugs.
• Further medicinal chemistry efforts are warranted to mitigate hERG channel inhibition while retaining antiplasmodial efficacy.
• These compounds show potential for oral administration in malaria treatment.