Novel 3-Aminothieno[2,3-b]pyridine-2-carboxamides with Activity against Mycobacterium tuberculosis.

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-01-03 eCollection Date: 2025-02-13 DOI:10.1021/acsmedchemlett.4c00472

Brock E Lynde, Danielle M Chemaly, Vanessa Pietrowski Baldin, Eric Greve, Christopher L Harding, Jasmin M Graner, Mason Hardy, Sultan Chowdhury, Tanya Parish

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Abstract

We conducted an exploration of the 3-aminothieno[2,3-b]pyridine-2-carboxamide (TPA) series for its potential as a drug scaffold against Mycobacterium tuberculosis. Existing analogs were active against a recombinant strain of M. tuberculosis with reduced expression of the sole signal peptidase LepB, but with poor activity against the wild-type strain. Our aim was to improve potency and explore the structure-activity relationship of the series. We identified two subsets of TPA. The first subset of compounds had equipotent activity against wild-type and LepB hypomorph strains and may represent a series with a different target. The second subset of compounds had increased activity against the LepB hypomorph strain and thus appears to be pathway-specific. Among this latter set we identified 17af as a potent inhibitor (IC₉₀ = 1.2 μM) with some cytotoxicity (IC₅₀ = 19 μM) and which retained increased activity against the LepB hypomorph (IC₉₀ = 0.41 μM).

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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.