Structural Optimization of BIPPO Analogs as Potent Antimalarials

Malaria continues to pose a significant health threat, causing thousands of deaths each year. The limited availability of vaccines and medications, combined with the emergence of drug resistance, further complicates the fight against this disease. In this study, we aimed to enhance the antimalarial potency of the previously reported hit compound BIPPO (pIC(50) 5.9). Through systematic modification of pyrazolopyrimidinone analogs, we discovered the promising analog 30 (NPD-3547), which exhibited approximately one log unit higher in vitro potency (pIC(50) 6.8) against Plasmodium falciparum. Furthermore, we identified several other BIPPO analogs (23, 28, 29 and 47a) with potent antimalarial activity (pIC(50) > 6.0) and favorable metabolic stability in mouse liver microsomes. These compounds can serve as new tools for further optimization towards the development of potential candidates for antimalarial studies.

Automated summary

Malaria remains a significant health threat, causing thousands of deaths each year. This study aimed to enhance the antimalarial potency of a hit compound and discovered a promising analog with higher potency against Plasmodium falciparum. Several other analogs with potent antimalarial activity were also identified, which can be further optimized for potential antimalarial drug development.