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 language | English |
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Article number | 4939 |
Pages (from-to) | 1-16 |
Number of pages | 16 |
Journal | Molecules (Basel, Switzerland) |
Volume | 28 |
Issue number | 13 |
Early online date | 23 Jun 2023 |
DOIs | |
Publication status | Published - 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.
Funders | Funder number |
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European Commission 7th Framework Program FP7-HEALTH-2013-INNOVATION-1 | PDE4NPD, 602666 |
European Cooperation in Science and Technology | CA21111 |
China Scholarship Council | 201506220185 |
Keywords
- antimalarial
- BIPPO analogs
- structural optimization