Structural Optimization of BIPPO Analogs as Potent Antimalarials

Yang Zheng, An Matheeussen, Louis Maes, Guy Caljon, Geert Jan Sterk, Rob Leurs

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Article number4939
Pages (from-to)1-16
Number of pages16
JournalMolecules (Basel, Switzerland)
Volume28
Issue number13
Early online date23 Jun 2023
DOIs
Publication statusPublished - Jul 2023

Funding

This work was supported by the European Commission 7th Framework Program FP7-HEALTH-2013-INNOVATION-1 under project reference 602666 “Parasite-specific cyclic nucleotide phosphodiesterase inhibitors to target Neglected Parasitic Diseases” (PDE4NPD). YZ acknowledges the China Scholarship Council (CSC) for funding (Grant No. 201506220185). LMPH is a partner of the Excellence Centre ‘Infla-Med’ (www.uantwerpen.be/infla-med, accessed on 22 June 2023) and participates in COST Action CA21111.

FundersFunder number
European Commission 7th Framework Program FP7-HEALTH-2013-INNOVATION-1PDE4NPD, 602666
European Cooperation in Science and TechnologyCA21111
China Scholarship Council201506220185

    Keywords

    • antimalarial
    • BIPPO analogs
    • structural optimization

    Fingerprint

    Dive into the research topics of 'Structural Optimization of BIPPO Analogs as Potent Antimalarials'. Together they form a unique fingerprint.

    Cite this