Antileishmanial activity of hesperetin on Leishmania donovani, in vitro and in silico inhibition of acetylcholinesterase and investigation of the targets sterol C-24 reductase and N-myristoyltransferase

IF 1.4 4区 医学 Q3 PARASITOLOGY Experimental parasitology Pub Date : 2025-01-19 DOI:10.1016/j.exppara.2025.108903
Saiaka Ingrid Parente Rocha , Victor Borges Fernandes , Wildson Max Barbosa da Silva , Lucas Soares Frota , Andreza Raposo Garcia , Flora Fernanda Schulze Spíndola , Caio Henrique Alexandre Roberto , Vanessa Maria Rodrigues de Souza , Klinger Antonio da Franca Rodrigues , Igor de Almeida Rodrigues , Emmanuel Silva Marinho , Márcia Machado Marinho , Nadja Soares Vila-Nova , Selene Maia de Morais
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Abstract

The current treatment of leishmaniasis is confronted with significant challenges, including limited efficacy, adverse effects, and parasite resistance to drugs. The search for alternative therapeutic options, including the utilisation of natural products, has demonstrated considerable promise. In this study, the antileishmanial activity of the flavonoid hesperetin against Leishmania donovani, the causative agent of visceral leishmaniasis, was reported for the first time. Hesperetin was obtained through the hydrolysis of hesperidin and subsequently subjected to chemical characterisation via Infrared and NMR spectroscopy. The antileishmanial activity and cytotoxicity against RAW 264.7 macrophages were evaluated using the MTT colorimetric assay. In order to investigate the potential mechanisms of action, in vitro acetylcholinesterase inhibition assays and molecular docking analyses were conducted. Hesperetin showed an antipromastigote effect (IC50: 62.89 μM) with no evidence of cytotoxicity (CC50: 612.8 μM), with a selectivity index (SI) of 9.74, being 5.4 times more effective than trivalent antimony. In comparison, antimony showed an IC50 of 80.16 μM, a CC50 of 145.04 μM and a SI of 1.8, indicating a limited safety margin. The compound was observed to inhibit acetylcholinesterase (IC50 of 18.44 μg/mL), present in mitochondrial and plasma membrane of the parasite. Molecular docking and dynamic simulations indicated that hesperetin inhibit sterol C-24 reductase, essential for ergosterol biosynthesis and membrane integrity of L. donovani and shows activity against N-myristoyl transferase, responsible for parasite proliferation cycle. These findings open promising avenues for the development of effective antileishmanial therapies.

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橙皮素对多诺瓦利什曼原虫的体外和体内抗利什曼原虫活性、乙酰胆碱酯酶的抑制作用及靶点甾醇C-24还原酶和n -肉豆醇转移酶的研究。
目前利什曼病的治疗面临着重大挑战,包括疗效有限、不良反应和寄生虫对药物的耐药性。寻找替代治疗方案,包括利用天然产品,已经显示出相当大的希望。本研究首次报道了类黄酮橙皮素对内脏利什曼病病原多诺瓦利什曼原虫的抗利什曼活性。通过橙皮苷水解得到橙皮苷,随后通过红外和核磁共振光谱进行化学表征。采用MTT比色法评价其抗利什曼原虫活性和对RAW 264.7巨噬细胞的细胞毒性。为了探讨其潜在的作用机制,我们进行了体外乙酰胆碱酯酶抑制实验和分子对接分析。橙皮苷具有抗promastigote作用(IC50: 62.89 μM),无细胞毒性(CC50: 612.8 μM),选择性指数(SI)为9.74,是三价锑的5.4倍。相比之下,锑的IC50为80.16 μM, CC50为145.04 μM, SI为1.8,安全裕度有限。该化合物对疟原虫线粒体和质膜中存在的乙酰胆碱酯酶有抑制作用,IC50为18.44 μg/mL。分子对接和动态模拟结果表明,hesperetin抑制麦角甾醇生物合成和多诺vani膜完整性所必需的甾醇C-24还原酶,并显示出对寄生虫增殖周期负责的n -肉豆醇转移酶的活性。这些发现为开发有效的抗利什曼病疗法开辟了有希望的途径。
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来源期刊
Experimental parasitology
Experimental parasitology 医学-寄生虫学
CiteScore
3.10
自引率
4.80%
发文量
160
审稿时长
3 months
期刊介绍: Experimental Parasitology emphasizes modern approaches to parasitology, including molecular biology and immunology. The journal features original research papers on the physiological, metabolic, immunologic, biochemical, nutritional, and chemotherapeutic aspects of parasites and host-parasite relationships.
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Editorial Board Synthetic peptides derived from hypothetical proteins as potential antigens for the diagnosis of canine visceral leishmaniasis and tegumentary leishmaniasis Comparative larvicidal, pupicidal, adulticidal activity of Artemisia nilagirica (C.B. Cl) pamp extract in controlling Culex quinquefasciatus, Anopheles stephensi, Aedes aegypti and Aedes albopictus Editorial Board Bioactive-based spray and spot-on formulations: Development, characterization and in vitro efficacy against fleas and ticks
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