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5-chloro-3-(2-(2,4-dinitrophenyl) hydrazono)indolin-2-one: synthesis, characterization, biochemical and computational screening against SARS-CoV-2
Chemical Papers ( IF 2.1 ) Pub Date : 2024-03-14 , DOI: 10.1007/s11696-023-03274-5
Felicite Majoumo-Mbe 1 , Neba Abongwa Sangbong 1 , Alain Tadjong Tcho 1 , Cyril T Namba-Nzanguim 1, 2 , Conrad V Simoben 2 , Donatus B Eni 1, 2 , Mustafa Alhaji Isa 3 , Adi Narayana Reddy Poli 4 , Joel Cassel 4 , Joseph M Salvino 4 , Luis J Montaner 4 , Ian Tietjen 4 , Fidele Ntie-Kang 1, 2, 5
Affiliation  

Abstract

Chemical prototypes with broad-spectrum antiviral activity are important toward developing new therapies that can act on both existing and emerging viruses. Binding of the SARS-CoV-2 spike protein to the host angiotensin-converting enzyme 2 (ACE2) receptor is required for cellular entry of SARS-CoV-2. Toward identifying new chemical leads that can disrupt this interaction, including in the presence of SARS-CoV-2 adaptive mutations found in variants like omicron that can circumvent vaccine, immune, and therapeutic antibody responses, we synthesized 5-chloro-3-(2-(2,4-dinitrophenyl)hydrazono)indolin-2-one (H2L) from the condensation reaction of 5-chloroisatin and 2,4-dinitrophenylhydrazine in good yield. H2L was characterised by elemental and spectral (IR, electronic, Mass) analyses. The NMR spectrum of H2L indicated a keto–enol tautomerism, with the keto form being more abundant in solution. H2L was found to selectively interfere with binding of the SARS-CoV-2 spike receptor-binding domain (RBD) to the host angiotensin-converting enzyme 2 receptor with a 50% inhibitory concentration (IC50) of 0.26 μM, compared to an unrelated PD-1/PD-L1 ligand–receptor-binding pair with an IC50 of 2.06 μM in vitro (Selectivity index = 7.9). Molecular docking studies revealed that the synthesized ligand preferentially binds within the ACE2 receptor-binding site in a region distinct from where spike mutations in SARS-CoV-2 variants occur. Consistent with these models, H2L was able to disrupt ACE2 interactions with the RBDs from beta, delta, lambda, and omicron variants with similar activities. These studies indicate that H2L-derived compounds are potential inhibitors of multiple SARS-CoV-2 variants, including those capable of circumventing vaccine and immune responses.



中文翻译:


5-氯-3-(2-(2,4-二硝基苯基)亚肼基)吲哚啉-2-酮:针对 SARS-CoV-2 的合成、表征、生化和计算筛选


 抽象的


具有广谱抗病毒活性的化学原型对于开发可作用于现有和新兴病毒的新疗法非常重要。 SARS-CoV-2 刺突蛋白与宿主血管紧张素转换酶 2 (ACE2) 受体结合是 SARS-CoV-2 进入细胞所必需的。为了识别可以破坏这种相互作用的新化学先导物,包括在 omicron 等变体中发现的 SARS-CoV-2 适应性突变存在的情况下,这些突变可以规避疫苗、免疫和治疗性抗体反应,我们合成了 5-氯-3-(2 -(2,4-二硝基苯基)亚肼基)二氢吲哚-2-酮(H 2 L)由5-氯靛红和2,4-二硝基苯肼的缩合反应得到,收率良好。 H 2 L 通过元素和光谱(红外、电子、质谱)分析进行表征。 H 2 L 的核磁共振谱表明酮-烯醇互变异构,酮形式在溶液中更丰富。发现 H 2 L 选择性干扰 SARS-CoV-2 刺突受体结合域 (RBD) 与宿主血管紧张素转换酶 2 受体的结合,其 50% 抑制浓度 (IC 50 ) 为 0.26 μM。不相关的 PD-1/PD-L1 配体-受体结合对,体外 IC 50为 2.06 μM(选择性指数 = 7.9)。分子对接研究表明,合成的配体优先结合在 ACE2 受体结合位点内,该位点的区域与 SARS-CoV-2 变体中发生尖峰突变的区域不同。与这些模型一致,H 2 L 能够破坏 ACE2 与具有类似活性的 beta、delta、lambda 和 omicron 变体的 RBD 的相互作用。 这些研究表明,H 2 L 衍生化合物是多种 SARS-CoV-2 变体的潜在抑制剂,包括那些能够规避疫苗和免疫反应的变体。

更新日期:2024-03-14
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