Biological activity and structure-activity relationship of dehydrodieugenol B analogues against visceral leishmaniasis.
Biological activity and structure-activity relationship of dehydrodieugenol B analogues against visceral leishmaniasis.
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DOI：
10.1039/d3md00081h
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发表时间：
2023-07-20
影响因子：
4.1
通讯作者：
中科院分区：
文献类型：
--
作者：
内脏利什曼病是一种被忽视的高死亡率原生动物疾病。现有的治疗方法有一些局限性，对公共卫生构成重大挑战，特别是在疟疾流行的发展中国家。由于临床试验中潜在药物的渠道有限，天然产物可以提供有吸引力的新药物原型来源，尤其是由于它们具有高度的化学多样性。在本工作中，研究了反l。（L.）对39个以新木脂脱氢双酚b为核心支架的化合物进行了婴儿电位实验，其中14个化合物对细胞内无尾菌丝体具有抑制活性，其50%抑制浓度（IC50）在3.0 ~ 32.7 μM之间。结构-活性关系（SAR）分析表明，需要极性功能来提高活性。化合物24缺乏哺乳动物细胞毒性，对临床相关形式的寄生虫表现出最高的效力，成为最有希望的药物，符合被忽视疾病药物倡议（DNDi）定义的内脏利什曼病的命中标准。本研究强调了脱氢双丁香酚B类似物作为治疗内脏利什曼病的新候选物的潜力，并建议24是未来优化的合适化合物，包括作用机制和药代动力学研究。以新寡糖脱氢双丁香酚B为核心支架合成的39个化合物对利什曼原虫胞内无尾线虫具有抑制作用。
Visceral leishmaniasis is a neglected protozoan disease with high mortality. Existing treatments exhibit a number of limitations, resulting in a significant challenge for public health, especially in developing countries in which the disease is endemic. With a limited pipeline of potential drugs in clinical trials, natural products could offer an attractive source of new pharmaceutical prototypes, not least due to their high chemodiversity. In the present work, a study of anti-L. (L.) infantum potential was carried out for a series of 39 synthetic compounds based on the core scaffold of the neolignan dehydrodieugenol B. Of these, 14 compounds exhibited activity against intracellular amastigotes, with 50% inhibitory concentration (IC50) values between 3.0 and 32.7 μM. A structure–activity relationship (SAR) analysis demonstrated a requirement for polar functionalities to improve activity. Lacking mammalian cytotoxicity and presenting the highest potency against the clinically relevant form of the parasite, compound 24 emerged as the most promising, fulfilling the hit criteria for visceral leishmaniasis defined by the Drugs for Neglected Diseases initiative (DNDi). This study emphasizes the potential of dehydrodieugenol B analogues as new candidates for the treatment of visceral leishmaniasis and suggests 24 to be a suitable compound for future optimization, including mechanism of action and pharmacokinetic studies. 39 synthetic compounds based on the core scaffold of the neoligan dehydrodieugenol B presented activity against intracellular amastigotes of Leishmania.
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影响因子：
14.9
作者：
Xiong G;Wu Z;Yi J;Fu L;Yang Z;Hsieh C;Yin M;Zeng X;Wu C;Lu A;Chen X;Hou T;Cao D
通讯作者：
Cao D
影响因子：
120.1
作者：
Katsuno, Kei;Burrows, Jeremy N.;Slingsby, B. T.
通讯作者：
Slingsby, B. T.
影响因子：
2.4
作者：
Don, Rob;Ioset, Jean-Robert
通讯作者：
Ioset, Jean-Robert
影响因子：
5.1
作者：
Grecco, Simone S.;Costa-Silva, Thais A.;Lago, Joao Henrique G.
通讯作者：
Lago, Joao Henrique G.
影响因子：
2.2
作者：
TADA, H;SHIHO, O;TSUKAMOTO, K
通讯作者：
TSUKAMOTO, K