Third-generation analogues of Guttiferone A

IF 2.2 4区医学 Q3 CHEMISTRY, MEDICINAL Bioorganic & Medicinal Chemistry Letters Pub Date : 2025-07-01 Epub Date: 2025-03-12 DOI:10.1016/j.bmcl.2025.130186

David Hozain , Kevin Cottet , Yann Fromentin , Annabelle Dugay , Florence Souquet , Elisabeth Mouray , Philippe Grellier , Didier Buisson , Raimundo Gonçalves de Oliveira Junior , Marie-Christine Lallemand

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Abstract

This study introduces third-generation derivatives of guttiferone A, designed to enhance both bioactivity and selectivity against Plasmodium falciparum and Trypanosoma brucei. Following an optimized synthetic route, two dioxolane derivatives of 3,16-oxyguttiferone A were prepared: 14-monodioxolane-3,16-oxyguttiferone A (3) and 13,14-bisdioxolane-3,16-oxyguttiferone A (4). Biological evaluation revealed compound 3 to be the most effective, with a selectivity index (SI) of 457.1 against Trypanosoma brucei brucei strain and 57.1 against P. falciparum, significantly outperforming its precursors. Compound 4 also demonstrated substantial activity with an SI of 143.8 against T. brucei. These results highlight the potential of targeted structural modifications, particularly monodioxolane substitution, to improve the pharmacological profile of guttiferone A derivatives.

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古替弗龙A的第三代类似物

本研究介绍了第三代木糠铁酮A衍生物，旨在提高对恶性疟原虫和布鲁氏锥虫的生物活性和选择性。根据优化的合成路径，制备了3,16-氧化木牙铁酮A的两种二恶烷衍生物：14-单二恶烷-3,16-氧化木牙铁酮A(3)和13,14-双恶烷-3,16-氧化木牙铁酮A(4)。生物学评价表明，化合物3对布鲁氏锥虫的选择性指数（SI）为457.1，对恶性疟原虫的选择性指数（SI）为57.1，显著优于其前体。化合物4对布氏体的SI值为143.8。这些结果突出了靶向结构修饰的潜力，特别是单二恶烷取代，以改善木替铁酮A衍生物的药理学特征。

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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.