A Broad Spectrum Antiparasitic Activity of Organotin (IV) Derivatives and Its Untargeted Proteomic Profiling Using Leishmania donovani.
A Broad Spectrum Antiparasitic Activity of Organotin (IV) Derivatives and Its Untargeted Proteomic Profiling Using Leishmania donovani.
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DOI：
10.3390/pathogens11121424
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发表时间：
2022-11-26
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影响因子：
--
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中科院分区：
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自古以来，金属就被用于医学中，用于治疗各种疾病，如铁，金和砷。金属配合物也被报道显示出抗生素和抗寄生虫活性。在这种情况下，我们测试了10个有机锡（IV）衍生物4-（4-甲氧基苯基氨基）-4-氧代丁酸（MS 26）对7个真核病原体的医学重要性：杜氏利什曼原虫，克氏锥虫，布氏锥虫，溶组织内阿米巴，贾第鞭毛虫，福氏耐格里原虫和曼氏血吸虫的抗寄生虫潜力。在具有和不具有抗寄生虫活性的化合物中，化合物MS 26 Et 3以0.21和0.19 μM的50%有效浓度（EC 50）对L. donovani，0.24 μM对T. cruzi，0.09 µM对T.布氏杆菌1.4 μM; fowleri和受损成年S. 1.25 µM下的mansoni活力。在宿主/病原体选择性方面，MS 26 Et 3对宿主细胞表现出相对轻度的细胞毒性，对B10 R细胞（小鼠单核细胞系）的50%活力浓度为4.87 µM，对C2 C12细胞（小鼠成肌细胞系）为2.79 µM，对HEK 923细胞（人胚肾细胞系）为1.24 µM。选择性指数支持该分子作为广谱抗寄生虫替代品的治疗起点。L.感染宿主细胞的蛋白质组学分析donovani细胞在MS 26 Et 3作用下Rab 7表达减少，可能影响了内体与溶酶体的融合，从而影响了L. donovani到无鞭毛体的形式。未来研究MS 26 Et 3的分子靶标和作用机制将支持其化学优化。
Metals have been used in medicine since ancient times for the treatment of different ailments with various elements such as iron, gold and arsenic. Metal complexes have also been reported to show antibiotic and antiparasitic activity. In this context, we tested the antiparasitic potential of 10 organotin (IV) derivatives from 4-(4-methoxyphenylamino)-4 oxobutanoic acid (MS26) against seven eukaryotic pathogens of medical importance: Leishmania donovani, Trypanosoma cruzi, Trypanosoma brucei, Entamoeba histolytica, Giardia lamblia, Naegleria fowleri and Schistosoma mansoni. Among the compounds with and without antiparasitic activity, compound MS26Et3 stood out with a 50% effective concentration (EC50) of 0.21 and 0.19 µM against promastigotes and intracellular amastigotes of L. donovani, respectively, 0.24 µM against intracellular amastigotes of T. cruzi, 0.09 µM against T. brucei, 1.4 µM against N. fowleri and impaired adult S. mansoni viability at 1.25 µM. In terms of host/pathogen selectivity, MS26Et3 demonstrated relatively mild cytotoxicity toward host cells with a 50% viability concentration of 4.87 µM against B10R cells (mouse monocyte cell line), 2.79 µM against C2C12 cells (mouse myoblast cell line) and 1.24 µM against HEK923 cells (human embryonic kidney cell line). The selectivity index supports this molecule as a therapeutic starting point for a broad spectrum antiparasitic alternative. Proteomic analysis of host cells infected with L. donovani after exposure to MS26Et3 showed a reduced expression of Rab7, which may affect the fusion of the endosome with the lysosome, and, consequently, impairing the differentiation of L. donovani to the amastigote form. Future studies to investigate the molecular target(s) and mechanism of action of MS26Et3 will support its chemical optimization.
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影响因子：
15.8
作者：
Abdulla MH;Lim KC;Sajid M;McKerrow JH;Caffrey CR
通讯作者：
Caffrey CR
影响因子：
3.8
作者：
Gunatilleke, Shamila S.;Calvet, Claudia M.;Podust, Larissa M.
通讯作者：
Podust, Larissa M.
影响因子：
3.8
作者：
Bashyal, Bharat;Li, Linfeng;LaBarbera, Daniel V.
通讯作者：
LaBarbera, Daniel V.
影响因子：
2.6
作者：
Boechat, Nubia;Kover, Warner B.;de Frugulhetti, Izabel Christina P. P.
通讯作者：
de Frugulhetti, Izabel Christina P. P.
影响因子：
4.9
作者：
de Moraes, Josue;Dario, Bruno S.;da Costa Ferreira, Ana M.
通讯作者：
da Costa Ferreira, Ana M.