Scaffold Hopping Strategy toward New 4‑Aminoquinazolines Active Against Extracellular and Intracellular.

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-06-30 eCollection Date: 2025-07-10 DOI:10.1021/acsmedchemlett.5c00276

Guilherme Arraché Gonçalves, Alexia de Matos Czeczot, Marcia Alberton Perelló, Eric Greve, Renee Allen, Camili Zanella Zotti, Laura Calle González, Andresa Berger, Josiane Delgado Paz, Lídia Klatt Oliveira, Sidnei Moura E Silva, Cristiano Valim Bizarro, Luiz Augusto Basso, Tanya Parish, Pablo Machado

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引用次数: 0

Abstract

A series of 4-aminoquinazolines was designed through a scaffold hopping approach inspired by pharmacophoric features of known antimycobacterial agents. The compounds were synthesized via a one-pot silylation-amination reaction under solvent-free conditions, affording the desired molecules in 70%-99% yields. Antimycobacterial evaluation using multiple strains and assay platforms revealed potent activity, with MIC values as low as 0.28 μM. Structure-activity relationship analysis identified the N-(3-phenylpropyl)-quinazolin-4-amine scaffold as a promising chemotype. Mechanistic studies indicated that the compounds do not act via QcrB inhibition, membrane disruption, ROS induction, or MmpL3 targeting. The most active derivatives displayed favorable selectivity indices, lacked broad-spectrum antibacterial activity, and demonstrated intracellular efficacy in a macrophage infection model. Despite low metabolic stability, the scaffold's potency, selectivity, and intracellular activity support its potential as a lead series. These findings suggest a novel, yet unidentified mechanism of action and provide a promising starting point for anti-TB drug campaigns.

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抗细胞外和细胞内活性新4 -氨基喹唑啉的支架跳跃策略。

受已知抗真菌药物药效特性的启发，通过支架跳跃方法设计了一系列4-氨基喹唑啉类药物。该化合物在无溶剂条件下通过一锅硅烷胺化反应合成，产率为70%-99%。通过多种菌株和实验平台对其进行抑菌评价，其MIC值低至0.28 μM。构效关系分析表明N-（3-苯基丙基）-喹唑啉-4-胺支架是一种很有前途的化学型。机制研究表明，这些化合物不通过QcrB抑制、膜破坏、ROS诱导或MmpL3靶向作用。大多数活性衍生物显示出良好的选择性指数，缺乏广谱抗菌活性，并在巨噬细胞感染模型中显示出细胞内功效。尽管代谢稳定性较低，但支架的效力，选择性和细胞内活性支持其作为先导系列的潜力。这些发现提示了一种新的但尚未确定的作用机制，并为抗结核药物运动提供了一个有希望的起点。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.