A Clerodane Diterpene from Aquarius scaber (Rataj) Christenh. & Byng Leaves as Inhibitor of Leishmania mexicana Trypanosomatid Enzymes

IF 0.9 Q4 CHEMISTRY, MEDICINAL

Journal of Biologically Active Products from Nature Pub Date : 2023-07-04 DOI:10.1080/22311866.2023.2256311

Kheytiany H.S. Lopes, Virgínia C.P. Silva, Marcos J. Jacinto, Aline A. de Souza, Camila G.D. Padovani, M. F. Machado, W. A. Judice, Paulo T. Sousa

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引用次数: 0

Abstract

Abstract The clerodane diterpenoid 2-oxo-5α,8α-cleroda-3,13-dien-16,15-olide (1) isolated from the leaves of A. scaber was identified by IR, 1H and 13C NMR (1D and 2D) and HRESIMS spectrometric analysis. This is the first report of this diterpene in the Aquarius genus. The inhibitory potential of 1 has been determined against cysteine proteases from Leishmania mexicana rCPB2.8, rCPB3.0 and rH84Y. The inhibitory constants (Ki and αKi) as well as the mechanism of action were also investigated. Compound 1 was 7- and 18-fold more potent in the inhibition of rCPB3.0 (IC50 = 4.2 µM) than rCPB2.8 (IC50 = 20 µM) and rH84Y (IC50 = 75 µM). From the kinetic mechanisms of inhibitor binding, we found that compound 1 has a higher affinity to rCPB3.0 (K i = 7.5 µM and αK i = 7.4 µM) than rCPB2.8 (K i = 15.4 µM, αK i = 14.7 µM) and rH84Y (K i = 81.4, and αK i = 27.9 μM and βKi = 41.5 µM). Compound 1 also presented a non-competitive linear simple inhibition mechanism at both enzymes rCPB3.0 and rCPB2.8. On the other hand, 1 presented a positive cooperativity mechanism of inhibition at rH84Y. GRAPHICAL ABSTRACT

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水瓶座疮痂（Rataj）Christenh. & Byng 叶中的一种 Clerodane 二萜作为墨西哥利什曼原虫锥虫酶的抑制剂

摘要通过红外光谱、1H 和 13C NMR（1D 和 2D）以及 HRESIMS 光谱分析，鉴定了从葶苈叶中分离出的 2-氧代-5α,8α-cleroda-3,13-二烯-16,15-内酯（1）。这是水瓶座属植物中首次报道这种二萜。测定了 1 对来自墨西哥利什曼病 rCPB2.8、rCPB3.0 和 rH84Y 的半胱氨酸蛋白酶的抑制潜力。此外，还研究了抑制常数（Ki 和 αKi）以及作用机制。化合物 1 对 rCPB3.0（IC50 = 4.2 µM）的抑制作用比 rCPB2.8（IC50 = 20 µM）和 rH84Y（IC50 = 75 µM）分别强 7 倍和 18 倍。从抑制剂结合的动力学机制来看，我们发现化合物 1 与 rCPB3.0（K i = 7.5 µM，αK i = 7.4 µM）的亲和力高于 rCPB2.8（K i = 15.4 µM，αK i = 14.7 µM）和 rH84Y（K i = 81.4，αK i = 27.9 μM，βKi = 41.5 µM）。化合物 1 对 rCPB3.0 和 rCPB2.8 两种酶也呈现出非竞争性的线性简单抑制机制。另一方面，化合物 1 对 rH84Y 的抑制机制呈正合作性。图表摘要

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来源期刊

Journal of Biologically Active Products from Nature Agricultural and Biological Sciences-Agricultural and Biological Sciences (miscellaneous)

CiteScore

2.10

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0.00%

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