Mehta Naimee, Ferrins Lori, Leed Susan E, Sciotti Richard J, Pollastri Michael P
Department of Chemistry and Chemical Biology , Northeastern University , 360 Huntington Avenue , Boston , Massachusetts 02115 , United States.
Experimental Therapeutics , Walter Reed Army Institute for Research , 2460 Linden Lane , Silver Spring , Maryland 20910 , United States.
ACS Infect Dis. 2018 Apr 13;4(4):577-591. doi: 10.1021/acsinfecdis.7b00212. Epub 2018 Jan 17.
We recently reported the medicinal chemistry reoptimization of a known human tyrosine kinase inhibitor, lapatinib, against a variety of parasites responsible for numerous tropical diseases, including human African trypanosomiasis ( Trypanosoma brucei), Chagas disease ( T. cruzi), Leishmaniasis ( Leishmania spp.), and malaria ( Plasmodium falciparum). Herein, we report our continuing efforts to optimize this series against P. falciparum. Through the design of a library of compounds focused on reducing the lipophilicity and molecular weight, followed by an SAR exploration, we have identified NEU-1953 (40). This compound is a potent inhibitor of P. falciparum with an improved ADME profile over the previously reported compound, NEU-961 (3).
我们最近报道了对一种已知的人类酪氨酸激酶抑制剂拉帕替尼进行药物化学再优化，以对抗多种导致众多热带疾病的寄生虫，包括人类非洲锥虫病（布氏锥虫）、恰加斯病（克氏锥虫）、利什曼病（利什曼原虫属）和疟疾（恶性疟原虫）。在此，我们报告我们针对恶性疟原虫优化该系列化合物的持续努力。通过设计一个专注于降低亲脂性和分子量的化合物库，随后进行构效关系探索，我们鉴定出了NEU-1953（40）。该化合物是一种强效的恶性疟原虫抑制剂，与先前报道的化合物NEU-961（3）相比，其药代动力学性质有所改善。
