Structural Optimization of BIPPO Analogs as Potent Antimalarials
Yang Zheng,
An Matheeussen,
Louis Maes,
Guy Caljon,
Geert Jan Sterk,
Rob Leurs
Affiliations
Yang Zheng
Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands
An Matheeussen
Laboratory of Microbiology, Parasitology and Hygiene, University of Antwerp, 2610 Wilrijk, Belgium
Louis Maes
Laboratory of Microbiology, Parasitology and Hygiene, University of Antwerp, 2610 Wilrijk, Belgium
Guy Caljon
Laboratory of Microbiology, Parasitology and Hygiene, University of Antwerp, 2610 Wilrijk, Belgium
Geert Jan Sterk
Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands
Rob Leurs
Division of Medicinal Chemistry, Amsterdam Institute for Molecules, Medicines and Systems, Faculty of Science, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands
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 (pIC50 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 (pIC50 6.8) against Plasmodium falciparum. Furthermore, we identified several other BIPPO analogs (23, 28, 29 and 47a) with potent antimalarial activity (pIC50 > 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.
