Synthesis and biological evaluation of 4,7,9-trisubstituted benzoxazepines as antileishmanial agents

被引：2

作者：

Kadayat, Tara Man ^{[1
]}

Kwiatkowski, Stefan ^{[1
]}

Ortiz, Diana ^{[2
]}

Shoeran, Gaurav ^{[1
]}

Hammill, Jared T. ^{[1
]}

Kim, Ho Shin ^{[1
]}

Cholewo, Joanna ^{[1
]}

Landfear, Scott M. ^{[2
]}

Guy, R. Kiplin ^{[1
]}

机构：

[1] Univ Kentucky, Coll Pharm, Dept Pharmaceut Sci, Lexington, KY 40536 USA

[2] Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97239 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2024年 / 114卷

关键词：

Benzoxazepine; Leishmaniasis; Pharmacophore analysis; Antileishmanial agents; Neglected tropical disease; DRUG DISCOVERY; LEISHMANIASIS; OPTIMIZATION; CANDIDATE; LEADS;

D O I：

10.1016/j.bmcl.2024.130003

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Herein we report a series of antileishmanial analogues derived from 4-[(3,5-dimethyl-4-isoxazolyl)acetyl]-9-[(1methyl-3-piperidinyl)methoxy]-7-(5-methyl-2-thienyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (1), which was identified through a previously reported high-throughput phenotypic screen. The analogue series was designed, synthesized, and evaluated for antileishmanial activity to establish pharmacophore elements and preliminary structure-activity relationships as key steps in validating the series for further optimization. This study led to identification of the early lead compound 46 , which exhibited sub-micromolar proliferation inhibitory activity against intra-macrophage L. mexicana amastigotes, modest selectivity towards host macrophages (J774A.1 line), and good aqueous solubility.

引用

页数：6

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