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喹啉酮酸类HIV-1整合酶抑制剂的研究进展 被引量：2

Research Progress of Quinolone Acid Derivatives as HIV-1 Integrase Inhibitors
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摘要 整合酶是人类免疫缺陷病毒(HIV)进入宿主细胞复制过程中必不可少的一种酶,而人体组织中无此酶,因此,此酶成为高效、低毒的抗HIV药物研发的理想靶标。简介HIV-1整合酶及其抑制剂的作用机制,分类综述具有二酮酸药效团类似结构的喹啉酮酸类HIV-1整合酶抑制剂的研究进展。 Integrase is an essential enzyme for HIV-1 retroviral replication in host cells but it hasn＇t been found in human tissue. Therefore it is a rational target for the development of new anti-HIV drugs with high efficiency and low toxicity. The functional mechanisms of HIV-1 integrase and its inhibitors were briefly introduced. The recent researches on the quinolone acid derivatives with similar pharmacophore of diketo acids as HIV-1 integrase inhibitors were classifiedly reviewed.
作者 罗再刚 徐雪梅 胡利明
机构地区 安徽理工大学化学工程学院 北京工业大学生命科学与生物工程学院
出处 《药学进展》 CAS 2013年第3期97-104,共8页 Progress in Pharmaceutical Sciences
基金 国家自然科学基金青年科学基金(No.21102003) 安徽理工大学人才引进启动基金 安徽理工大学青年教师科学研究基金
关键词 HIV-1 整合酶抑制剂 二酮酸 喹啉酮酸类衍生物 构效关系 HIV-1 integrase inhibitor diketo acid quinolone acid derivative structure-activity relationship
分类号 R978.7 [医药卫生—药品] R914.2 [医药卫生—药物化学]
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  • 8General procedure for the preparation of 3: 4-nitrobenzene sulfonamide 2 were dissolved in EtOAc (50-100 mL) and SnCl2-2H2O (1.125 g per mmol nitro compound) was added. The mixture was heated under reflux for 4 h. Then, NaHCO3 solution was added until pH 7-8 was reached and the organic layer was separated. The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. Then, the solvent was removed in vacuo to obtain the crude products. General procedure for the preparation of 4: a mixture of diethyl ethoxymethylenemalonate (46 mmol) and 4-aminobenzene sulfonamide 3 (46 mmol) in 1,4-dioxane solution (25 mL) was refluxed for 3.5 h until the reaction was finished (monitor by thin lay chromatography). Then the solvent was removed under reduced pressure and the residue was recrystallized from Petroleum ether to obtain the pure products. General procedure for the preparation of 5: phenyl ether (40 mL) was heated under stirring at 250 ℃ containing catalytic p-chlorobenzoic acid. The aminomethylenemalonate 4 (10 mmol) was slowly added, and the resulting mixture was remained the temperature at 250 ℃ for 0.5 h. After the mixture was cooled at room temperature, the resulting precipitate was collected by filtration, washed with petroleum ether, and re.crystallized from DMF to provide quinolone 5. General procedure for the preparation of 6: quinolone 5 (1 mmol) was dissolved in the mixed solution of EtOH/H2O (25 mL) and NaOH ( 1.1 mmol) was added. The mixture was refluxed for 1 h. Removal of the solvents under reduced pressure and acidification with 10% H2SO4 gave a solid, which was washed with water, dichloromethane and dried. The resulting quinoline-3-carboxylic acid 6 was recrystallized from the appropriate solvent.
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  • 10Selected data of title compounds: 6a: Yellow powder, yield 71%, mp: 284-286 ℃, ^1H NMR (DMSO-de, 400 MHz, δ ppm): 1.40-1.66 (m, 12H, -CH2-adamantane), 1.91 (s, 3H, CH-adamantane), 2.40 (d, 2H, J = 6.8 Hz, CH2- Adamantane), 7.74 (t, 1H, J = 3.4 Hz, NHSO2), 8.00 (d, IH, J = 8.8 Hz, HT), 8.21 (dd, 1 H, J = 2.0 and 8.8 Hz, H8), 8.67 (d, 1 H, J = 2.0 Hz, H5), 8.98 (s, 1H, H2), 13.66 (s, 1 H, COOH). 13C NMR (DMSO- de, 100 MHz, δ ppm): 178.62, 166.27, 147.03, 141.74, 138.68, 131.36, 124.59, 121.73, 109.13, 54.78, 36.86, 33.32, 28.06. MS (ESI)m/z: 417 [M + H]^+, 439 [M + Na]^+. 6b: white powder, yield 72%, mp> 290 ℃, ^1H NMR (DMSO-de, 400 MHz, δ ppm): 1.45-1.70 (m, 12H, CH2- adamantane), 1.92 (s, 3H, CH-adamantane), 7.83 (t, 1H, NHSO2), 7.99 (d, 1H, J = 8.8 Hz, H7), 8.25 (dd, 1H, J = 2.0 and 8.8 Hz, H8), 8.73 (d,1H, J -- 2.0 Hz, H5), 8.97 (s, 1H, H2), 13.65 (s, 1H, Nil), 14.87 (s, 1H, COOH). ^13C NMR (DMSO-d6, 100 MHz, δ ppm): 178.62, 166.29, 146.94, 142.79, 141.48, 131.20, 124.56, 124.04, 121.51, 109.11, 54.55, 42.93, 35.89, 29.29. 6e: White powder, yield 76%, mp>290 ℃, ^1H NMR (DMSO-d6, 400 MHz, δ ppm): 1.56 (m, 2H, CH2), 1.90 (m, 2H, CH2), 2.25 (m, 1H, CH), 2.46 (m, 2H, CH2), 3.54 (m, 2H, CH2), 8.03 (d, 1H, J =8.8 Hz, H7), 8.17 (dd, 1H, J = 2.4 and 8.8 Hz, H8), 8.54 (d, 1H, J = 2.0 Hz, H5), 9.03 (s, 1H, H2), 12.30 (s, 1H, COOH), 13.71 (s, 1H, NH), 14.77 (s, 1H, COOH). MS (ESI) m/z: 379 [M-H]^-, 759 [2M-H]^-. 6 h: White powder, yield 83%, mp: 265-268 ~C, 1H NMR (DMSO-d6, 400 MHz, δ ppm): 3.08 (m, 4H, CH2), 3.23 (In, 41-1, CH2), 6.80 (m, 1H, H-Ar), 6.89 (m, 2H, H-Ar), 7.18 (m, 2H, H-At), 8.05 (d, 1H, J = 8.4 Hz, H7), 8.20 (dd, 1H, J = 2.0 and 8.8 Hz, H8), 8.58 (d, 1H, J = 2.0 Hz, H5), 9.03 (s, 1H, H2), 13.71 (s, 1H, NH), 14.75 (s, 1H, COOH). MS (ESI) m/ z: 412 [M-H]^-, 825 [2M-H]^-.

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