CN104497083B - 具有抗寄生虫活性的核苷‑苯基丙烯酮杂化体及其制备方法和应用 - Google Patents
具有抗寄生虫活性的核苷‑苯基丙烯酮杂化体及其制备方法和应用 Download PDFInfo
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- -1 Nucleosides phenylpropen ketone Chemical class 0.000 title claims abstract description 24
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- 230000002514 anti-leishmanial effect Effects 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 238000006467 substitution reaction Methods 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
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- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
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- 239000003096 antiparasitic agent Substances 0.000 abstract description 7
- 239000002585 base Substances 0.000 description 18
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- 241000222727 Leishmania donovani Species 0.000 description 2
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- 150000008062 acetophenones Chemical class 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
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- 229930182470 glycoside Natural products 0.000 description 2
- PQLXHQMOHUQAKB-UHFFFAOYSA-N miltefosine Chemical compound CCCCCCCCCCCCCCCCOP([O-])(=O)OCC[N+](C)(C)C PQLXHQMOHUQAKB-UHFFFAOYSA-N 0.000 description 2
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- YOMBUJAFGMOIGS-UHFFFAOYSA-N 2-fluoro-1-phenylethanone Chemical compound FCC(=O)C1=CC=CC=C1 YOMBUJAFGMOIGS-UHFFFAOYSA-N 0.000 description 1
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- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种具有抗寄生虫活性的核苷‑苯基丙烯酮杂化体及其制备方法和应用。本发明的技术方案要点为：具有抗寄生虫活性的核苷‑苯基丙烯酮杂化体，具有以下结构：
Description
技术领域
本发明属于具有抗寄生虫活性的化合物技术领域，具体涉及一种具有抗寄生虫活性的核苷-苯基丙烯酮杂化体及其制备方法和应用。
背景技术
苯基丙烯酮（如查尔酮）类化合物在天然产物中广泛存在，多见于甘草、红花等药用植物中。研究表明，苯基丙烯酮结构单元能与生物体内不同的受体结合，从而显示出多样的生物活性，如抗肿瘤、抗病毒、抗菌、抗溃疡、抗寄生虫、抑制和清除氧自由基等。Boeck等（Boeck, P.; Falcão C. A. B.; Leal, P. C. et a1. Synthesis of chalcone analogues with increased antileishmanial activity. Bioorg. Med. Chem., 2006, 14(5), 1538-1545.）的研究发现，苯基丙烯酮衍生物（其结构式如下所示）有良好的抗寄生虫活性，而且对宿主细胞没有毒性。Liu等（Liu M.; Wilairat, P.; Croft, S. L. et al. Structure-activity relationships of antileishmanial and antimalarial chalcones. Bioorg. Med. Chem., 2003. 11(13), 2729-2738.）的研究发现，苯基丙烯酮衍生物可以通过抑制在寄生虫呼吸链中起重要作用的FRD酶而显示出抗无鞭毛型利什曼原虫生长活性。
另一方面，许多核苷衍生物也表现出良好的抗利什曼原虫活性。其中，Shin等（Shin, S.; Tanifuji, H.; Arata, Y. et al. 3'-Deoxy-3'-fluoroinosine as a potent antileishmanial agent. Parasitol Res., 1995, 81, 622-626.）的研究发现3'-脱氧-3'-氟代肌苷在体内及体外实验中均表现出很好的抗热带利什曼原虫和杜氏利什曼原虫活性，且细胞毒性较低。Silva等（Da Silva, A. D.; Coimbra, E. S.; Fourrey, J. L. et al. Expeditious enantioselective synthesis of carbocyclic nucleosides with antileishmanial activity. Tetrahedron Lett., 1993, 34(42), 6745-6748.）的研究表明，天然碳环核苷neplanocin A 的衍生物也具有较强的抗利什曼原虫活性。
基于以上研究背景，我们设计经由5-甲酰基嘧啶核苷与（取代）苯乙酮的缩合反应，制备核苷-苯基丙烯酮杂化体，从而将核苷结构单元与苯基丙烯酮结构单元结合起来，通过将两种药效基团的组合，以获得具有更好抗利什曼原虫活性的新型杂化体类药物。目前，关于这类杂化体抑制剂的结构、合成方法及抗利什曼原虫活性，均未见报道。
发明内容
本发明解决的技术问题是提供了一种具有抗寄生虫活性的核苷-苯基丙烯酮杂化体及其制备方法，此类化合物具有潜在的药用价值，含有此类化合物的药物组合物可用于制备抗寄生虫药物，尤其是抗利什曼原虫药物。
本发明的技术方案为：具有抗寄生虫活性的核苷-苯基丙烯酮杂化体，其特征在于：所述的核苷-苯基丙烯酮杂化体A具有以下结构：
A
其中：R1为下列基团中的一种： (2R,4S,5S)-4-叠氮基-2,3,4,5-四氢-5-羟甲基呋喃-2-基、 (2R,5S)-2,5-二氢-5-羟甲基呋喃-2-基、(2R,5S)-2,3,4,5-四氢-5-羟甲基呋喃-2-基、(2R,4S,5R)-4-羟基-2,3,4,5-四氢-5-羟甲基呋喃-2-基、(2R,4S,5R)-4-氟代-2,3,4,5-四氢-5-羟甲基呋喃-2-基或(2R,3R,4S,5R)-3,4-二羟基-2,3,4,5-四氢-5-羟甲基呋喃-2-基，对应的结构式分别为： 、、、、或，R2为下列基团中的一种：苯基或取代苯基，其中取代苯基是单取代苯基或多取代苯基，取代苯基苯环上的取代基为烷基、烷氧基、氰基、硝基、羟基、氟、氯或溴，烷基为10个碳以内的直链烷基或支链烷基，烷氧基中的烷基为10个碳以内的直链烷基或支链烷基，取代基的位置为苯环上的邻位、间位或对位。
本发明所述的具有抗寄生虫活性的核苷-苯基丙烯酮杂化体的制备方法，其特征在于合成步骤如下：将R1为不同取代基的5-甲酰基嘧啶核苷化合物（1）和苯乙酮或取代苯乙酮（2）混合，置于溶剂中，在碱的存在下，于0-50℃搅拌反应，TLC跟踪监测至反应结束，得到目标产物A，其具体反应方程式如下：
，
其中R1、R2是如结构式A所定义的。
本发明所述的反应物（1）为下列化合物中的一种：5-甲酰基-3'-叠氮基-2', 3'-双脱氧尿嘧啶核苷、5-甲酰基-2', 3'-双脱氧-2', 3'-双脱氢尿嘧啶核苷、5-甲酰基-2',3'-双脱氧尿嘧啶核苷、5-甲酰基-2'-脱氧尿嘧啶核苷、5-甲酰基-3'-氟代-2', 3'-双脱氧尿嘧啶核苷或5-甲酰基尿嘧啶核苷。
本发明所述的反应物（2）为下列化合物中的一种：苯乙酮或取代苯乙酮，其中取代苯乙酮中的取代基为烷基、烷氧基、氰基、硝基、羟基、氟、氯或溴中的一种或多种，烷基为10个碳以内的直链烷基或支链烷基，烷氧基中的烷基为10个碳以内的直链烷基或支链烷基，取代基的位置为苯环上的邻位、间位或对位。
本发明所述的碱为氢氧化钠、氢氧化钾、叔丁醇钾、甲醇钠或乙醇钠。
本发明所述的溶剂为水、甲醇、乙醇、N,N-二甲基甲酰胺、乙腈、四氢呋喃和丙酮中的一种或两种以上的混合溶剂。
本发明还涉及具有抗寄生虫活性的药物组合物，所述的具有抗寄生虫活性的药物组合物是由核苷-苯基丙烯酮杂化体A和可药用辅料组成的。
本发明所述的具有抗寄生虫活性的药物组合物可用于制备抗寄生虫药物，特别是用于制备抗利什曼原虫药物。
本发明利用5-甲酰基嘧啶核苷化合物（1）和苯乙酮或取代苯乙酮（2）的缩合反应，高效合成了核苷-苯基丙烯酮杂化体，该制备方法合成路线短，制备过程简单。另外，本发明所提供的核苷-苯基丙烯酮杂化体具有显著的抗寄生虫活性，含有核苷-苯基丙烯酮杂化体A的药物组合物可用于抗寄生虫的治疗，特别是抗利什曼原虫的治疗。
具体实施方式
以下通过实施例对本发明的上述内容做进一步详细说明，但不应该将此理解为本发明上述主题的范围仅限于以下的实施例，凡基于本发明上述内容实现的技术均属于本发明的范围。
实施例1
5-((E)-3-(3-氯苯基)-3-氧代丙烯-1-基)-3'-叠氮基-2', 3'-双脱氧尿嘧啶核苷（产物a）的合成
将5-甲酰基-3'-叠氮基-2', 3'-双脱氧尿嘧啶核苷（0.281 g, 1 mmol）和间氯苯乙酮（0.155 g, 1 mmol）依次加入到乙醇（5 mL）中，然后加入氢氧化钠（0.060 g,1.5mmol），于0℃搅拌反应，TLC跟踪监测至反应结束。减压除去溶剂后，残留物经柱色谱分离得到白色固体产物a（0.293 g），收率70%。
产物a的结构式及结构表征数据如下：
mp 150-152ºC; 1H NMR (DMSO-d 6, 400 MHz) δ: 2.35-2.41 (m, 1H, CH2-1),2.48-2.55 (m, 1H, CH2-2), 3.60-3.65 (m, 1H, CH2-1), 3.71-3.76 (m, 1H, CH2-2),3.85-3.87 (m, 1H, CH), 4.42 (q, J = 6.4 Hz,, 1H, CH), 6.07 (t, J = 5.2 Hz,1H, CH), 7.52 (d, J = 15.2 Hz, 1H, CH), 7.58 (t, J = 8.0 Hz, 1H, ArH), 7.70(d, J = 8.0 Hz, 1H, ArH), 7.87-7.89 (m, 2H, 2ArH), 8.01 (d, J = 15.2 Hz, 1H,CH), 8.57 (s, 1H, CH); 13C NMR (DMSO-d 6, 100 MHz) δ: 37.40, 59.24, 60.36,85.04, 85.13, 109.04, 120.04, 127.07, 127.95, 131.30, 133.00, 134.26, 139.13,140.13, 145.37, 149.52, 162.15, 188.48. MS: m/z 418 [M+H]+.
产物a的抗利什曼原虫活性：IC50 = 7.45 ± 0.23 µM。
实施例2
5-((E)-3-(4-氯苯基)-3-氧代丙烯-1-基)-3'-叠氮基-2', 3'-双脱氧尿嘧啶核苷（产物b）的合成
将5-甲酰基-3'-叠氮基-2', 3'-双脱氧尿嘧啶核苷（0.281 g, 1 mmol）和对氯苯乙酮（0.155 g, 1 mmol）依次加入到体积比为1:1的乙醇/水溶液（5 mL）中，然后加入氢氧化钠（0.060 g, 1.5 mmol），于室温搅拌反应，TLC跟踪监测至反应结束。减压除去溶剂后，残留物经柱色谱分离得到白色固体产物b（0.251 g），收率60%。
产物b的结构式及结构表征数据如下：
mp 198-199ºC; 1H NMR (DMSO-d 6, 400 MHz) δ: 2.34-2.41 (m, 1H, CH2-1),2.48-2.54 (m, 1H, CH2-2), 3.60-3.65 (m, 1H, CH2-1), 3.72-3.76 (m, 1H, CH2-2),3.85-3.87 (m, 1H, CH), 4.43 (q, J = 6.4Hz, 1H, CH), 5.39 (t, J = 5.2 Hz, 1H,OH), 6.07 (t, J = 5.2 Hz, 1H, CH), 7.51 (d, J = 15.2 Hz, 1H, CH), 7.62 (d, J= 8.4 Hz, 2H, 2ArH), 7.94 (d, J = 8.4 Hz, 2H, 2ArH), 8.02 (d, J = 15.2 Hz,1H, CH), 8.54 (s, 1H, CH), 11.71 (s, 1H, NH); 13C NMR (DMSO-d 6, 100 MHz) δ:37.41, 59.36, 60.57, 85.07, 109.14, 120.25, 129.40, 130.33, 136.94, 138.23,138.79, 145.20, 149.60, 162.21, 188.65. MS: m/z 418 [M+H]+.
产物b的抗利什曼原虫活性：IC50 = 6.00 ± 0.26 µM。
实施例3
5-((E)-3-(4-甲基苯基)-3-氧代丙烯-1-基)-3'-叠氮基-2', 3'-双脱氧尿嘧啶核苷（产物c）的合成
将5-甲酰基-3'-叠氮基-2', 3'-双脱氧尿嘧啶核苷（0.281 g, 1 mmol）和对甲基苯乙酮（0.134 g, 1 mmol）依次加入到乙醇（5 mL）中，然后加入乙醇钠（0.102 g,1.5mmol），于室温搅拌反应，TLC跟踪监测至反应结束。减压除去溶剂后，残留物经柱色谱分离得到白色固体产物c（0.231 g），收率58%。
产物c的结构式及结构表征数据如下：
mp 199-201ºC; 1H NMR (DMSO-d 6, 400 MHz) δ: 2.34-2.40(m, 4H, CH3, CH2-1), 2.48-2.56 (m, 1H, CH2-2), 3.60-3.64 (m, 1H, CH2-1), 3.72-3.75 (m, 1H, CH2-2), 3.84-3.86 (m, 1H, CH), 4.40-4.46 (m, 1H, CH), 5.42 (t, J = 4.8 Hz, 1H,OH), 6.08(t, J = 5.2 Hz, 1H, CH), 7.35 (d, J =7.6 Hz, 2H, 2ArH), 7.48 (d, J =15.2 Hz, 1H, CH), 7.85 (d, J =7.6 Hz, 2H, 2ArH), 8.05 (d, J = 15.2 Hz, 1H,CH), 8.53 (s, 1H, CH), 11.72 (s, 1H, NH); 13C NMR (DMSO-d 6, 100 MHz) δ: 21.56,37.39, 59.31, 60.53, 85.02, 109.25, 120.66, 128.59, 129.84, 135.72, 137.83,143.74, 144.76, 149.64, 162.28, 189.15. MS: m/z 398 [M+H]+.
产物c的抗利什曼原虫活性：IC50 = 9.83 ± 0.81 µM。
实施例4
5-((E)-3-(4-氟苯基)-3-氧代丙烯-1-基)-2'-脱氧尿嘧啶核苷（产物d）的合成
将5-甲酰基-2'-脱氧尿嘧啶核苷（0.256 g, 1 mmol）和对氟苯乙酮（0.138 g, 1mmol）依次加入到体积比为1:1的乙醇/水溶液（5 mL）中，然后加入氢氧化钠（0.060 g,1.5mmol），于0℃搅拌反应，TLC跟踪监测至反应结束。减压除去溶剂后，残留物经柱色谱分离得到黄色固体产物d（0.188 g），收率50%。
产物d的结构式及结构表征数据如下：
mp 150-152ºC; 1H NMR (DMSO-d 6, 400 MHz) δ: 2.17-2.24 (m, 2H, CH2),3.58-3.69 (m, 2H, CH2), 3.80-3.82 (m, 1H, CH), 4.25-4.28 (m, 1H, CH), 5.18-5.25 (m, 2H, 2×OH), 6.13 (t, J = 6.4 Hz, 1H, CH), 7.36 (t, J = 8.4 Hz, 2H,2ArH), 7.49 (d, J = 15.2 Hz, 1H, CH), 8.01-8.04 (m, 3H, 2ArH, CH), 8.56 (s,1H, CH), 11.67 (s, 1H, NH); 13C NMR (DMSO-d 6, 100 MHz) δ: 61.16, 70.01, 85.43,88.12, 109.14, 116.22, 116.44, 120.19, 131.33, 131.43, 134.94, 138.51,145.15, 149.67, 162.27, 162.44, 188.26. MS: m/z 377 [M+H]+.
产物d的抗利什曼原虫活性数据是IC50= 15.02 ± 1.26 µM。
实施例5
5-((E)-3-(4-甲氧基苯基)-3-氧代丙烯-1-基)-2'-脱氧尿嘧啶核苷（产物e）的合成
将5-甲酰基-2'-脱氧尿嘧啶核苷（0.256 g, 1 mmol）和对甲氧基苯乙酮（0.150g, 1 mmol）依次加入到甲醇（5 mL）中，然后加入甲醇钠（0.081 g, 1.5mmol），于0℃搅拌反应，TLC跟踪监测至反应结束。减压除去溶剂后，残留物经柱色谱分离得到黄色固体产物e（0.314 g），收率81%。
产物e的结构式及结构表征数据如下：
mp 184-186ºC; 1H NMR (DMSO-d 6, 400 MHz) δ: 2.17-2.22 (m, 2H, CH2),3.60-3.67 (m, 2H, CH2), 3.80-3.82 (m, 1H, CH), 3.84 (s, 3H, CH3), 4.25-4.28(m,1H, CH), 5.20 (t, J = 5.6Hz, 1H, OH), 5.23 (d, J = 4.0 Hz, 1H, OH), 6.14 (t,J = 6.4 Hz, 1H, CH), 7.07 (d, J = 8.8 Hz, 2H, 2ArH), 7.45 (d, J = 15.2 Hz,1H, CH), 7.93 (d, J = 8.8 Hz, 2H, 2ArH), 8.04 (d, J = 15.2 Hz, 1H, ArH), 8.53(s, 1H, CH), 11.64 (s, 1H, NH); 13C NMR (DMSO-d 6, 100 MHz) δ: 55.93, 61.24,62.11, 70.11, 85.43, 87.40, 88.15, 90.23, 109.36, 114.51, 120.60, 130.78,131.09, 137.24, 144.48, 149.71, 162.30, 163.46, 187.95. MS: m/z 389 [M+H]+.
实施例6
5-((E)-3-苯基-3-氧代丙烯-1-基)-尿嘧啶核苷（产物f）的合成
将5-甲酰基尿嘧啶核苷（0.272 g, 1 mmol）和苯乙酮（0.120 g, 1 mmol）依次加入到甲醇（5 mL）中，然后加入氢氧化钠（0.060 g, 1.5mmol），于室温搅拌反应，TLC跟踪监测至反应结束。减压除去溶剂后，残留物经柱色谱分离得到白色固体产物f（0.232 g），收率62%。
产物f的结构式及结构表征数据如下：
mp 156-157 ºC; 1H NMR (DMSO-d 6, 400 MHz) δ: 3.60-3.63 (m, 1H, CH2-1),3.73-3.77 (m, 1H, CH2-2), 3.87-3.89 (m, 1H, CH), 4.01-4.04 (m, 1H, CH), 4.08-4.10 (m, 1H, CH), 5.08 (d, J = 5.6 Hz, 1H, OH), 5.38 (t, J = 5.2Hz, 1H, OH),5.48 (d, J = 5.2 Hz, 1H, OH), 5.76 (d, J = 4.0 Hz, 1H, CH), 7.47 (d, J = 15.2Hz, 1H, CH), 7.55 (t, J = 7.6 Hz, 2H, 2ArH), 7.64 (t, J = 7.2 Hz, 1H, ArH),7.93 (d, J = 7.2 Hz, 2H, 2ArH),8.03 (d, J = 15.2 Hz, 1H, CH), 8.66 (s, 1H,CH), 11.73 (s, 1H, NH); 13C NMR (DMSO-d 6, 100 MHz) δ: 60.51, 69.31, 74.39,85.02, 89.31, 109.21, 120.61, 128.46, 129.33, 133.40, 138.02, 138.21, 144.87,149.87, 162.27, 189.78. MS: m/z 375 [M+H]+.
实施例7
体外抗利什曼原虫活性测定实验
实验中用到杜氏利什曼原虫（L. donovani LV9）前鞭毛体和两种对照药物十六烷胆碱磷酸（Hexadecylphosphocholine，HePC）和两性霉素B（amphotericin B）。
在96孔微量滴定板的每一孔中加入含有40 mM HEPES缓冲液、100 µM 腺苷、0.5mg/mL 血晶素、10%热灭活胎牛血清(hi-FCS)和50 µg/ml 庆大霉素的M-199 培养基。将药物溶液梯度稀释，然后将不同浓度的溶液加入到滴定板的孔中。接着，在每孔中加入利什曼原虫前鞭毛体100 µL（2×105个细胞/ml）。标本置27℃（5% CO2气氛中）培养72小时。每个浓度重复实验3次。用MTT比色法检查前鞭毛体的活动度。MTT试剂和细胞一起培养以后，加入DMSO溶解有色的结晶体。用ELISA 酶联免疫检测仪在570 nm波长处测定光吸收值（光度值和成活细胞数成正比例关系）。实验结果用3天培养期后抑制寄生虫生长50%的浓度IC50来表示。在这些条件下，药物对照物十六烷胆碱磷酸的IC50是6.72 ± 0.48 µM，两性霉素B的IC50是0.38 ± 0.08 µM。
以上实施例描述了本发明的基本原理、主要特征及优点，本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。
Claims (1)
1.具有抗寄生虫活性的药物组合物在制备抗利什曼原虫药物中的应用，其特征在于：所述的具有抗寄生虫活性的药物组合物是由核苷-苯基丙烯酮杂化体A和可药用辅料组成的，该核苷-苯基丙烯酮杂化体A具有以下结构：
A
其中：R1为 (2R,4S,5S)-4-叠氮基-2,3,4,5-四氢-5-羟甲基呋喃-2-基或(2R,4S,5R)-4-羟基-2,3,4,5-四氢-5-羟甲基呋喃-2-基，对应的结构式分别为： 或，R2为取代苯基，取代苯基中的取代基为氟、氯或甲基，取代基的位置为苯环上的间位或对位。
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