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.
Laboratory of Microbiology, Parasitology and Hygiene, University of Antwerp, 2610 Wilrijk, Belgium.
Molecules. 2023 Jun 23;28(13):4939. doi: 10.3390/molecules28134939.
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 5.9). Through systematic modification of pyrazolopyrimidinone analogs, we discovered the promising analog (NPD-3547), which exhibited approximately one log unit higher in vitro potency (pIC 6.8) against . Furthermore, we identified several other BIPPO analogs (, , and ) with potent antimalarial activity (pIC > 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.
疟疾仍然构成重大健康威胁，每年导致数千人死亡。疫苗和药物的供应有限，再加上耐药性的出现，使对抗这种疾病的斗争更加复杂。在这项研究中，我们旨在提高之前报道的命中化合物 BIPPO（pIC5.9）的抗疟效力。通过对吡唑并嘧啶酮类似物的系统修饰，我们发现了有前途的类似物（NPD-3547），其对的体外效力（pIC6.8）提高了约一个对数单位。此外，我们还鉴定了几种其他 BIPPO 类似物（、、和），它们具有强大的抗疟活性（pIC>6.0）和在小鼠肝微粒体中的良好代谢稳定性。这些化合物可以作为进一步优化的新工具，以开发用于抗疟研究的潜在候选药物。
