荧光马里诺喹啉衍生物作为恶性疟原虫抑制剂：SAR分析、作用方式和体内研究。

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-09-30 DOI:10.1021/acs.jmedchem.5c00138

Patricia Santos Barbosa,Guilherme Eduardo Souza,Sarah El Chamy Maluf,Vinícius Bonatto,Caio Silva Moura,Giovana Rossi Mendes,Talita Alvarenga Valdes,Yasmin Annunciato,Barbara Dos Santos Rossetto,Priscilla Dantas de Souza Ventura,Gilberto Gaspar Duarte Ortin,Wellington da Silva,Marcelo Yudi Icimoto,Amália Dos Santos Ferreira,Fabio C Cruz,Carolina B G Teles,Dhelio B Pereira,Gustavo Capatti Cassiano,Sofia Santana,Miguel Prudêncio,Camila S Barbosa,Igor M R Moura,Renan Marcel Giampauli,Irene Layane De Sousa,Silvana Aparecida Rocco,Marcos L Gazarini,Carlos Roque Duarte Correia,Anna Caroline Campos Aguiar,Rafael Victorio Carvalho Guido

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引用次数: 0

摘要

我们提出了marinoquinolines （MQ）的作用机制的见解，这是一类新的先导候选药物。使用发散合成方法，我们开发了一系列20个具有荧光性质的新类似物。结构活性关系的分析,科学家们发现了19个为一个有吸引力的化合物表现出良好的体外的组合(IC503D7 = 0.28μM; CC50HepG2 = 53μM),体外(EC50Pf = 1.2μM, EC50Pv = 0.53μM),体内(3×50毫克/公斤口服剂量导致寄生虫血症在疟原虫berghei-infected老鼠)减少96%,物理化学(Sol7.4 = 171μM; LogD7.4 = 3.9),和药代动力学(P_app = 9.4×10 - 6 cm / s,人类Clinthep麦克风= 0.61 - -0.68μL最低为1 mg-1)属性。化合物19选择性地在被感染的红细胞中积累，进入消化液泡并抑制恶性疟原虫的蛋白水解活性，表明MQs具有蛋白酶抑制剂的作用。这些发现加强了MQs是抗疟疾药物发现的有希望的主要候选者的证据。

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Fluorescent Marinoquinoline Derivative as Inhibitors of Plasmodium falciparum: SAR Analysis, Mode of Action and In Vivo Studies.

We present insights into the mechanism of action of marinoquinolines (MQ), a novel class of lead candidates. Using a divergent synthetic approach, we developed a series of 20 new analogues with fluorescence properties. Structure-activity relationships analysis identified 19 as an attractive compound showing a combination of favorable in vitro (IC503D7 = 0.28 μM; CC50HepG2 = 53 μM), ex vivo (EC50Pf = 1.2 μM; EC50Pv = 0.53 μM), in vivo (3 × 50 mg/kg oral dose resulted in a 96% reduction in parasitemia in Plasmodium berghei-infected mice), physicochemical (Sol7.4 = 171 μM; LogD7.4 = 3.9), and pharmacokinetic (P_app = 9.4 × 10-6 cm/s, human Clinthep,mic = 0.61-0.68 μL min-1 mg-1) properties. Compound 19 selectively accumulates in infected erythrocytes, enters the digest vacuole and inhibits Plasmodium falciparum proteolytic activity, suggesting that MQs act as protease inhibitors. These findings strengthen the evidence that MQs are promising lead candidates for antimalarial drug discovery.

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.