新型抗结核分枝杆菌的含异恶唑噻吩化合物。

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-01-23 DOI:10.1016/j.bmcl.2025.130108

Gabrielle Martinez, Kirsten Tolentino, Paridhi Sukheja, Jasmine Webb, Case W. McNamara, Arnab K. Chatterjee, Baiyuan Yang

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引用次数: 0

摘要

在胆固醇培养基中筛选抗结核分枝杆菌（Mtb） H37Rv菌株的ChemDiv分子文库，鉴定出一种新型异唑噻吩hit作为Rv1625c/Cya激活剂，具有良好的体外活性和药动学性质。合成29个类似物，评价其构效关系，进一步提高药效。最显著的类似物是P15，在小鼠药代动力学（PK）研究中，以20 mg/kg口服给药时，其巨噬细胞内EC50 = 1.96 µM，口服生物利用度为58.0% %。整个药物化学运动显示有限的SAR，不支持进一步调查该系列。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Novel isoxazole thiophene-containing compounds active against Mycobacterium tuberculosis

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Novel isoxazole thiophene-containing compounds active against Mycobacterium tuberculosis

Screening of the ChemDiv molecular library in cholesterol media against Mycobacterium tuberculosis (Mtb) H37Rv strain identified a novel isoxazole thiophene hit as a putative Rv1625c/Cya activator with a promising in vitro activity and good pharmacokinetic properties. Twenty-nine analogs were synthesized to assess the structure–activity relationships (SAR) to further improve potency. The most notable analog was P15, which showed an intramacrophage EC₅₀ = 1.96 µM and exhibited 58.0 % oral bioavailability when it was dosed orally at 20 mg/kg in a mouse pharmacokinetic (PK) study. The overall medicinal chemistry campaign revealed limited SAR that did not support further investigation into this series.

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.