吲哚席夫碱类衍生物的合成及其抗HIV-1活性研究

Synthesis and anti-HIV-1 activities of indole schiff base derivatives

摘要:

设计、合成吲哚席夫碱类衍生物并研究其抗HIV-1活性。以3-吲哚甲醛衍生物为原料，在碱催化下与芳香胺发生缩合反应合成吲哚席夫碱类化合物，并采用通过 MTT 法测试了目标化合物在MT-4 细胞内的抗 HIV-1病毒株的活性。 合成了32个吲哚席夫碱类衍生物，其结构均通过1H NMR和MS加以确证。初步的生物活性结果测试表明，所合成的吲哚席夫碱类化合物对HIV-1均有优秀的抑制活性，并具有广谱的抗HIV-1活性。其中化合物31 (EC50 = 0.06 mol/L)展现出了最强的抗HIV-1活性，与阳性药物地拉韦啶 (DLV, EC50 = 0.57 mol/L)相当；同时，化合物31具有非常低的毒性，选择指数 (SI)高达2500，明显高于地拉韦啶 (DLV, SI = 1272.9)和依法韦仑 (EFV, SI = 321)。将吲哚和席夫碱两个药效团，能够得到高效、低毒的HIV-1逆转录酶抑制剂，为今后发展新型的HIV-1抑制剂提供了新思路。

Abstract:

To design and synthesis of indole schiff base derivatives and investigate their anti-HIV-1 activities. Indole Schiff base derivatives were synthesized from 3-indole-formaldehyde derivatives by aldehyde-amine condensation with aromatic amines under the catalysis of base. The anti-HIV activities was determined by MTT assays in MT-4 cells.Thirty-two indole schiff base derivatives were synthesized and the structures have been confirmed by 1H NMR and MS spectra. The preliminary biological results showed that all synthesized indole schiff base derivatives had good inhibitory effect on HIV-1 growth, and a broad spectrum of anti-HIV activities. Specifically, compound 31 (EC50 = 0.06 mol/L) exhibited the greatest anti-HIV potency, which was equipotent to reference drug delavirdine. Moreover, the toxicity of compound 31 was very low, and the selectivity index (SI) was as high as 2500, which was significantly higher than that of delavirdine (DLV, SI = 1272.9) and efavirapine (EFV, SI = 321g). Indole and schiff base unit are both important anti-HIV pharmacophore, HIV-1 non-nuclear nucleoside reverse transcriptase inhibitors (NNRTIs) with high efficiency and low toxicity can be obtained by coupling of indole and Schiff base, and this study provides a new idea for the development of new, structurally diverse NNRTIs.