Aminobenzosuberone derivatives as PfA-M1 inhibitors: Molecular recognition and antiplasmodial evaluation.,Bioorganic Chemistry

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Aminobenzosuberone derivatives as PfA-M1 inhibitors: Molecular recognition and antiplasmodial evaluation.
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2020-03-11 , DOI: 10.1016/j.bioorg.2020.103750
Emmanuel Salomon ₁ , Marjorie Schmitt ₁ , Elisabeth Mouray ₂ , Alastair G McEwen ₃ , Lotfi Bounaadja ₂ , Morgan Torchy ₃ , Pierre Poussin-Courmontagne ₃ , Sarah Alavi ₁ , Céline Tarnus ₁ , Jean Cavarelli ₃ , Isabelle Florent ₂ , Sébastien Albrecht ₁

Affiliation

Aminobenzosuberone-based PfA-M1 inhibitors were explored as novel antimalarial agents against two different Plasmodium falciparum strains. The 4-phenyl derivative 7c exhibited the most encouraging growth inhibitory activity with IC50 values of 6.5-11.2 µM. X-ray crystal structures and early assessment of DMPK/ADME-Tox parameters allowed us to initiate structure-based drug design approach and understand the liabilities (such as potential metabolic and aqueous solubility issues) as well as identify the opportunities for improvement of this aminobenzosuberone series. It also suggested that compound 7c should be regarded as an attractive chemical tool to investigate the different biological roles of this multifunctional PfA-M1 protein.

中文翻译：

氨基苯并亚砜衍生物作为PfA-M1抑制剂：分子识别和抗血浆评价。

研究了基于氨基苯并亚砜的PfA-M1抑制剂作为针对两种不同恶性疟原虫菌株的新型抗疟药。4-苯基衍生物7c表现出最令人鼓舞的生长抑制活性，IC50值为6.5-11.2 µM。X射线晶体结构和DMPK / ADME-Tox参数的早期评估使我们能够启动基于结构的药物设计方法，并了解其责任（例如潜在的代谢和水溶性问题），并确定改进这种氨基苯并亚砜的机会系列。还建议将化合物7c视为研究此多功能PfA-M1蛋白的不同生物学作用的有吸引力的化学工具。

更新日期：2020-03-12

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