Design and development of an isatin-1,2,3-triazole hybrid analogue as a potent anti-inflammatory agent with enhanced efficacy and gene expression modulation†

IF 3.9 3区 化学 Q2 CHEMISTRY, MULTIDISCIPLINARY
RSC Advances Pub Date : 2025-01-22 DOI:10.1039/D4RA07294D
A. Niranjana Kumar, Smruti Ranjan Das, J. Kotesh Kumar, K. V. N. S. Srinivas and Sarada D. Tetali
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引用次数: 0

Abstract

Isatin (1H-indole-2,3-dione) and its derivatives have been found to exhibit various biological activities, including anticancer and antidiabetic properties. In this study, a series of nine isatin-1,2,3-triazole conjugates were synthesized and evaluated for their anti-inflammatory potential via in vitro experiments. Their synthesis involved the propargylation of isatin 1 with propargyl bromide to obtain N-propargyl isatin 2, which was subjected to click reactions with different aromatic azides to yield isatin-N-1,2,3-triazoles (3a–i). The structures of all the compounds were confirmed via NMR and HR-MS. The final isatin analogues were tested for their ability to attenuate the production of proinflammatory cytokines in the lipopolysaccharide (LPS)-induced human leukemia monocytic THP-1 cells. Importantly, none of the compounds had any negative effect on THP-1 cell viability at the tested concentrations of 4 mM and 8 mM. LPS induced the production of the cytokines: Tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) by 351.4, 7.9 and 14.3 fold, respectively, in THP-1 cells. However, treatment with compound 3e markedly attenuated the levels of TNF-α (by 6.6 fold and 1.5 fold), IL-6 (by 1.03 fold and 1.41 fold) and MCP-1 (by 3.3 fold and 1.7 fold) by several fold at concentrations of 4 mM and 8 mM, respectively. Furthermore, in the gene expression modulation studies, 3e was found to downregulate the genes responsible for the production of TNF-α (24 and 25 fold), IL-6 (148 and 502 fold) and MCP-1 (50 and 25 fold) at the two tested concentrations compared with their expression in the LPS-induced THP-1 cells (135 fold, 6612 fold, and 68.8 fold, respectively). Thus, 3e markedly attenuated the secretion of TNF-α, IL-6 and MCP-1 from LPS-treated THP-1 cells, and also the expression of the concerned genes. At the lowest dose tested, i.e., 4 mM, 3e had the greatest effect on both gene expression and marker secretion.

Abstract Image

isatin-1,2,3-三唑杂交类似物的设计和开发,作为一种有效的抗炎药,具有增强的疗效和基因表达调节†
Isatin (1h -吲哚-2,3-二酮)及其衍生物已被发现具有多种生物活性,包括抗癌和抗糖尿病特性。本研究合成了一系列9种isatin-1,2,3-三唑缀合物,并通过体外实验评价了它们的抗炎作用。它们的合成涉及isatin- 1与丙炔溴的丙炔基化,得到n-丙炔基isatin 2,该n-丙炔基isatin 2与不同的芳香叠氮化合物发生点击反应,得到isatin- n- 1,2,3-三唑(3a-i)。所有化合物的结构均经核磁共振和质谱证实。对最终的isatin类似物进行了测试,以证明它们能够减弱脂多糖(LPS)诱导的人白血病单核THP-1细胞中促炎细胞因子的产生。重要的是,在4毫米和8毫米的浓度下,这些化合物都没有对THP-1细胞活力产生任何负面影响。LPS诱导THP-1细胞中细胞因子:肿瘤坏死因子-α (TNF-α)、白细胞介素-6 (IL-6)和单核细胞化学引诱蛋白-1 (MCP-1)的产生分别为351.4倍、7.9倍和14.3倍。然而,在4 mM和8 mM浓度下,化合物3e显著降低TNF-α(分别降低6.6倍和1.5倍)、IL-6(分别降低1.03倍和1.41倍)和MCP-1(分别降低3.3倍和1.7倍)的水平。此外,在基因表达调节研究中,3e被发现在两种测试浓度下下调负责产生TNF-α(24和25倍),IL-6(148和502倍)和MCP-1(50和25倍)的基因,而在lps诱导的THP-1细胞中表达(分别为135倍,6612倍和68.8倍)。因此,3e显著降低lps处理的THP-1细胞的TNF-α、IL-6和MCP-1的分泌,以及相关基因的表达。在最低剂量下,即4 mM, 3e对基因表达和标记物分泌的影响最大。
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来源期刊
RSC Advances
RSC Advances chemical sciences-
CiteScore
7.50
自引率
2.60%
发文量
3116
审稿时长
1.6 months
期刊介绍: An international, peer-reviewed journal covering all of the chemical sciences, including multidisciplinary and emerging areas. RSC Advances is a gold open access journal allowing researchers free access to research articles, and offering an affordable open access publishing option for authors around the world.
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