新型HIV-1非核苷类逆转录酶抑制剂的设计、合成和活性研究
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摘要
艾滋病(AIDS)是当今世界严重威胁人类生命健康的传染性疾病,其病原体为人类免疫缺陷病毒(HIV),其中RNA逆转录病毒HIV-1是致病主要的病毒亚型。而HIV-1逆转录酶(reverse transcriptase, RT)在该病毒的复制周期中具有关键性的作用,使其成为抗HIV-1药物研发的重要靶点。作用于RT的抑制剂主要分为核苷类逆转录酶抑制剂(Nucleoside Reverse Transcriptase Inhibitors, NRTIs)和非核苷类逆转录酶抑制剂(NNRTIs)。其中,NNRTIs由于其活性高、选择性强、毒性低等诸多优点,是目前治疗艾滋病高效抗逆转录病毒疗法(HAART)重要组成部分。但是NNRTIs在临床治疗出现的耐药性、毒副作用以及药代动力学性质差的问题在一定程度上限制了其临床应用。因此,研发新型高效低毒、广谱抗耐药以及具有良好药代动力学性质的新型NNRTI是目前抗艾滋病药物研究的重要方向之一。
本论文第一部分研究将选取对HIV-1病毒具有高效抗耐药性NNRTIs—二芳基嘧啶类(Diarylpyridine, DAPY)上市药物TMC125(Etrivirine)和3-碘基-4-苯氧基吡啶酮类(3-iodo-4-phenoxy-2-pyridinones, IOPY)衍生物R221239为先导,基于两者结合模式和药效基团的类似性,根据它们与RT结合的晶体复合物分子叠合结果,运用分子杂合的药物设计策略,将两类抑制剂的优势结构片段进行合理组合,设计了一类新型DAPY-IOPY杂合体:NNRTIs:(1)以IOPY类衍生物的2-吡啶酮为母核,以保持其与K101和K103氨基酸残基骨架的氢键作用,同时在2-吡啶酮3位上引入卤素,以与V179和Y188形成静电作用；(2)将DAPY类化合物右翼的苯胺基团迁移到吡啶酮6位,并在芳环对位引入不同的取代基,考察其对活性的影响；(3)将DAPY类化合物的优势取代基—2,4,6-三取代苯氧基和IOPY类化合物的优势取代基—3,5-二甲基苯氧基分别迁移2-吡啶酮的4位。由此设计了一系列3-卤代-4-苯氧基-6-苯胺基-1H-2-吡啶酮衍生物(Series IA)。同时,对Series IA化合物右翼芳环与中心杂环之间的NH接基团以CH2取代,设计了第二系列DAPY-IOPY杂合体衍生物—3-碘-4-苯氧基-6-苄基-1H-2-吡啶酮衍生物(Series IB)。
经过定向合成我们得到了两个系列31个目标化合物,活性结果显示,大部分Series IA化合物对野生型HIV-1(ⅢB)毒株表现出亚微摩尔到微摩尔水平的活性,其中活性最好的化合物IA-7d对野生型HIV-1IIIB毒株的EC5o值为0.15μM,优于DLV(EC50=0.91μM)、ddC(EC50=1.39μM)和NVP(EC50=0.113DAPY-IOPY杂合衍生物Series IA的构效关系研究显示：(1)2-吡啶酮母环对保持活性非常重要,以2-氯吡啶或2-甲氧基吡啶取代吡啶酮环活性降低,在吡啶酮3位上引入卤素活性下降,3位取代基对活性的贡献顺序为H>I>Br/Cl;(2)两翼取代基的SAR特征同DAPY类化合物一致,与IOPY类化合物不同：右翼芳环上活性最高的取代基为CN,左翼芳环的最优取代基为TMC125的活性取代基—4-氰基-2,6-二甲基,但被R221239的优势取代基—3,5-二甲基取代时化合物活性完全丧失。与Series IA不同,Series IB化合物表现出与IOPY类衍生物类似的构效关系。尤其左翼芳环为3,5-二甲基取代的化合物IB-7a(EC50＝0.22μM),不仅其抗HIV-ⅢB活性高于2,4,6-三甲基取代的化合物IB-7b(EC50＝0.32μM),而且对RES056(K103N+Y181C)双突变严重耐药毒株也具有较好的活性(EC50=1.71μM)。我们对DAPY-IOPY杂合体衍生物Series IA和Series IB代表性化合物进行了分子对接研究,结果发现Series IA NNRTIs衍生物与RT的结合模式更加类似于TMC125,而Series IB杂合体NNRTIs与RT的结合模式基本与R221239相一致,与构效关系研究的结论相互印证。
我们对DAPY-IOPY杂合体NNRTIs体外抗HIV-1ⅢB活性最好的4个化合物,进行了进一步的活性研究。在脐带血单个核细胞系(cord blood mononuclear cells, CBMC)的抗HIV-1活性测试表明,IA-7d、IA-7c、IB-7a和IB-7b对病人体内分离的原始R5毒株和R4毒株的活性处于亚微摩尔级；ELISA双抗夹心法抗HIV-1逆转录酶活性测试显示,化合物IA-7d和IA-7c对RT的抑制活性分别为5.2μM和39μM；定量PCR分析MT-4细胞单轮感染HIV-1NL4-3毒株后细胞内病毒总DNA含量表明,化合物IA-7d、IA-7c、IB-7a或IB-7b浓度为10μM时,对病毒逆转录晚期DNA产物的抑制率达99.2%,88.6%,98.3%和97.5%,验证了本研究所设计DAPY-IOPY杂合化合物的通过抑制RT逆转录过程而发挥抗HIV-1活性。
本论文第二部分研究根据DAPY类化合物与NNIBP晶体结构的解析和分子对接模拟研究,在对NNIBP中可容纳区域Ⅰ和可容纳区域Ⅱ两个结构修饰有利位点的契合适配性分析基础上,通过在吡啶类DAPY衍生物的右翼芳环和中心毗啶环之间插入哌啶胺极性基团,并在右翼末端芳环上引入-SONH2等极性基团,以开发与NNIBP中可容纳区域Ⅰ周围氨基酸残基的氢键作用力,并改善药物溶解度,设计了一系列具有哌啶胺柔性侧链的吡啶类DAPY衍生物(Series IIA)。同时,本研究在嘧啶和吡啶类DAPY衍生物的中心杂环和右翼芳环上位于NNIBP可容纳区域Ⅰ和可容纳区域Ⅰ的位置,引入水溶性较高的吗啉或哌嗪基团,设计了第二系列吗啉和哌嗪基团修饰的吡啶和嘧啶类DAPY衍生物(Series IIB),并分别用分子对接研究验证了Series IIA和Series IIB化合物设计的合理性。
对定向合成得到的两个系列29个化合物的体外抗HIV-1病毒活性测试结构表明,化合物IIA-8c2, IIA-8c3, IIA-8c4和IIA-8b3抑制HIV-1NL4-3毒株的ECso值分别为0.1rM、0.05nM、0.8nM和0.3nM(SI=20349-242800);对HIV-ⅢB野生毒株的活性分别为9.1nM、7.4nM、9.3nM和7.8nM(SI=168-1283),远远好于上市药物NVP、3TC与DLV(EC50=0.29μM,3.1μM,0.61μM),并与上市药物ETV、AZT和EFV的活性(EC50=7.0nM,6.8nM,9.5nM)相当。此外,化合物IIA-8b2、ⅡA-8b3对具有严重耐药性的RES056(K103N+Y181C)毒株也表现出一定的活性(EC50=6.2μM,6.8μM)。Series IIA衍生物的构效关系研究表明,左翼苯环上取代基R1对活性的贡献顺序为4-CN-2,6-二甲基>2,4,6-三甲基；吡啶环6位取代基R3对活性的贡献顺序为C1>OCH3;右翼哌啶胺基团N1位取代基R2对活性的贡献顺序为4-S02NH2-苯基>4-SO2Me-苯基>吡啶-4-基>4-CONH2-苯基>苯基>环丙基或环丁基。Series ⅡB化合物的抗病毒活性结果表明,在NNIBP的可容纳区域Ⅰ和Ⅱ引入水溶性较好的吗啉或者哌嗪基团,基本上可以保持先导化合物原有的活性。该系列活性最好的化合物IIB-8b抑制HIV-1NL4-3毒株的EC5o值为9.1nM(SI=2596),同时有望具有改善的药代动力学性质。
本论文第三部分工作是在本课题组前期N2,N4-双取代-吡咯[1,2-b][1,2,4,6]噻三嗪-1,1,3-三酮衍生物(PTTDs)研究的基础上,进一步探讨该类化合物N2位上多样性取代基引入对构效关系的影响(Seires Ⅲ)。本研究尝试对PTTD类化合物合成采用了新的合成路线,阐明了其可能的反应机制。对所合成PTTD类目标化合物进行了体外抗HIV活性试验。结果表明化合物ⅢB-10a10具有抗野生型HIV-1毒株的活性,其N2位的3,5-二甲基丙烯基为已报道的多种活性NNRTI分子结构中的普遍存在的优势基团。分子对接研究显示,ⅢB-10a10N2位上的3,5-二甲基丙烯基与TIBO化合物的3,5-二甲基丙烯基在NNIBP中的位置基本叠合,都处于Y181和Y188形成疏水亚口袋中。该研究结果体现了NNRTIs优势结构片段的类似性和结合模式的类似性之间具有内在联系,为下一步继续基于NNRTIs的分子结构多样性以及结合模式和优势结构基团的类似性,进行PTTD类衍生物的结构优化提供了重要思路。
综上所述,本课题设计以先导化合物/RT复合物的三维结构解析和构效关系为研究起点,充分考虑先导化合物与结构多样的NNRTIs药效团上类似性,以优势结构片段为导向,变换中心杂环的骨架结构、修饰侧链取代基及边链,以开发与RT结合位点的附加作用力,并提高溶解度；药物设计综合运用生物电子等排体、分子杂合、片段迁移等经典药物设计手段,并与计算机辅助药物设计的应用相结合。最后经定向合成了三个系列75个化合物,经过活性测试发现了多个抗HIV-1活性达到纳摩尔甚至皮摩尔水平的抑制剂,并有3个化合物(IB-7a、 IIA-8b2、IIA-8b3)对多药耐药毒株RES056(K103N+Y181C)表现出良好的活性。同时,本课题在优化抗病毒活性和抗耐药性的同时,通过引入哌啶胺、吗啉、哌嗪等水溶性较好环杂烷基团以提高化合物的溶解度。因此所获得的化合物在具有高效抗HIV-1活性的同时,有望获得改善的药代动力学性质,具有进一步研究开发的价值。
In the life cycle of human immunodeficiency virus type1(HIV-1), reverse transcriptase (RT) is responsible for the conversion of single-stranded viral RNA into double-stranded proviral DNA, a prerequisite for integration into host DNA. Due to its important role in the HIV-1life-cycle, RT has been identified as a prime target for anti-HIV drug discovery. Among currently available RT inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs) represent an important component of drug combination therapy for the treatment of HIV-infected patients. Up to date, five NNRTIs have been approved for clinical application by FDA:nevirapine (NVP), delavirdine (DLV), efavirenz (EFV), etravirine (ETV) and rilpivirine (RPV). First generation of NNRTIs, NVP and EFV, are suffered from severe side-effects over long periods of therapy, as well as inevitable emergence of HIV-1resistant strains. Though the second generation of NNRTIs, DLV, ETV, and RPV perform well against a variety of variants bearing clinically prevalent mutations, the development of novel NNRTIs families are still demanded to address issues of side effects, poor solubility, cross-resistance, and virologic failure
The NNRTI is a class of specific HIV-1RT inhibitors with diverse structures but share some inherent similarities in their pharmacophoric elements and binding mode with the NNRTI binding pocket (NNIBP), which provides valuable information for the lead discovery and drug optimization. More importantly, the extensive crystallgraphic investigations on the NNRTI/RT complexes help to interpret the ligand-enzyme interactions and reveal some important structure features to maintain the antiviral activity against mutant HIV-1strains. In this thesis, we focus our research interest on developing of novel NNRTIs using the structure-based approaches using a combination of traditional medicinal chemistry, structural biology, and computational chemistry. My research work could be divided into three sections, which are summarized as follows:
Section One:The Design, Synthesis and Biological Evaluation of DAPY-IOPY Hybrid Derivatives
Based on the pharmacophoric similarity and crystallographic overlaps of TMC125and R221239, we designed a novel series of DAPY-IOPY hybrid derivatives through combining their privileged structural features using molecular hybridization strategy:i)2-pyridone ring of IOPY was kept as the central scaffold to develop hydrogen-bondings with K103and K101. Meanwhile, halogen atoms were introduced to the3-position of the2-pyridone ring, respectively, to evaluate their impacts on antiviral activity; ii) Fragment switching of the2-aniline group of DAPY into the6-position of2-pyridione template and modified the substituents at this phenyl ring; iii) Introduction of the favorable substitutions of4-phenoxy moiety of DAPY and IOPY into the4-position of novel2-pyridone template, respectively, to probe the substitution SAR patterns of these novel DAPY-IOPY hybrid derivatives.
In total, we synthesized31target compounds which could be classified into two series (Series IA and Series IB). The biological testing results showed that most compounds possessed submicromolar to micromolar level of inhibition activities against HIV-1Ⅲb strains in MT-4cell cultures. The most potent compound IA-7d showed anti-HIV-1IIIB activity with an EC50value of0.15μM, comparable to that of nevirapine, but superior to those of delavidine and zalcitabine. The structure-activity relationship (SAR) analysis indicated that2-pyridone scaffold of these inhibitors was indispensable for their anti-HIV-1activity, and substitution of halogen at the3-position of the2-pyridone ring would decrease the anti-HIV activity. Further biological evaluation demonstrated that IA-7d, IA-7c, IB-7a and IB-7b inhibited the replication of HIV-1primary isolated BK132(X4) or92TH001(R5) strains in cord blood mononuclear cells (CBMCs) at submicromolar level. ELISA based RT enzyme inhibition assay revealed that IA-7d possessed anti-RT activity with an IC50value of5.2μM. Quantitative PCR analysis of viral DNA experience showed that IA-7d, IA-7c, IB-7a and I7-8b could highly effectively reduce the late RT DNA product to1.1%、11.7%、2.1%and2.8%, respectively, compared with the DMSO control group (100%). These results proved these2-pyridone typed DAPY-IOPY hybrid derivatives to be a highly promising NNRTI scaffold, which may serve as a new platform for further modification in search for more potent candidates for anti-HIV chemotherapy
Section Two:The Structural Optimization of DAPY Derivatives by Introducing Piperidyl, Morpholinyl or Piperazinyl Group into the NNIBP Tolerant Region
Based on the crystallographic studies and molecular modeling investigations of DAPYs, we focus our attention on exploiting the tolerant region I and II of NNIBP by incorporating hydrophilic piperidyl, morpholinyl or piperazinyl group into the pyridine-and pyrimidine-typed DAPY derivatives, with an aim to develop additional interactions between the inhibitors and NNIBP, as wells as to improve the drug solubility.
The antiviral activity evaluation results showed that, the most potent compounds of Series ⅡA, viz. ⅡA-8c2, IIA-8c3, IIA-8c4and IIA-8b3could effectively inhibit HIV-1NL4-3strains in MT-4cells with EC50values of0.1nM,0.05nM,0.8nM and0.3nM, respectively, accompanied with excellent SI values ranging from20349to242800. The anti-HIV-1ⅢB activities of IIA-8c2, IIA-8c3, IIA-8c4and IIA-8b3were low to9.1nM,7.4nM,9.3nM and7.8nM, respectively (SI=168-1283), much superior to FDA-aproved drug of NVP,3TC and DLV, and comparable to ETV, AZT and EFV. Additionally, compounds IIA-8b2and IIA-8b3showed good performance against the serious RES056(K103N+Y181C) mutant strains with the EC50values of6.2μM and6.8μM, respectively. The SAR analysis of Series IIA demonstrated that replacement of the2,4,6-trimethyl group on left-wing phenyl ring with4-CN-2,6-dimethy group led to improved potency, and incorporation of OCH3group into the6-position of pyridine instead of the Cl group yielded less active compounds. The substitutions at the Nj position of the right-wing piperidyl contributed to the anti-HIV-1activity in the following order:4-SO2NH2-phenyl>4-SO2Me-phenyl> pyridn-4-yl>4-CONH2-phenyl> phenyl> cyclopropyl or cyclobutyl.
The anti-HIV-1NL4-3assay results of Series IIB indicated that the extra morpholinyl or piperazinyl group which was introduced into the lead DAPY derivatives could be well adopted by the NNIBP tolerant site, without significantly reducing the compounds'anti-HIV activities. The most compound IIB-8b possessed an EC50value of9.1nM, with SI value of2596. These compounds of series IIB were expected to possess improved solubility and pharmacokinetic profile, due to the favorable hydrophilic properties of morpholinyl and piperazinyl group.
Section Three:Design, Synthesis and Biological Evaluation of N2, N4-Disubstituted-1,1,3-trioxo-2H,4H-pyrrolo[1,2-b][1,2,4,6]thiatriazine Derivatives as Novel HIV-1NNRTIs
In an effort to explore derivatives of N2, N4-2,4-disubstitued-1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazines (TTDs) as potent HIV-1NNRTIs, we had designed and synthesized a classes of N2, N4-disubstitued-1,1,3-trioxo-2H,4H-pyrrolo[1,2-6][1,2,4,6]thiatriazine derivatives (PTTDs), which displayed good activities against HIV-1virus. As a continuation of our research, we incorporated diverse groups into the N2position to further investigate the S AR patterns of PTTDs. An alternative synthetic strategy was attempted to firstly prepare PTTD ring, which subsequently underwent regioselectivce N-alkylation at its N2and N4positions, respectively, to give the target PTTDs. However, extensive effort to conduct this strategy eventually lead to the production of another new heterocycle, viz.1,1,3-trioxo-2H-pyrrolo[1,2-6][1,2,5]thiadiazole, rather than the expected PTTD ring. We proposed a plausible reaction mechanism for formation of1,1,3-trioxo-2H-pyrrolo[1,2-6][1,2,5]thiadiazole. Finally, we utilized the improved synthesis route of PTTDs to synthesize the PTTD target compounds.
Unfortunately, the biological evaluation results showed that only compound ⅢB-10a10had inhibition activity against wide type HIV-1ⅢB strains. ⅢB-10a10shares a ubiquitous privileged fragment of3,5-dimethyl-allyl group at its N2substitutions with many reported potent NNRTIs, including tetrahydromidazo (TIBO), thiocarboxanilid, diarylamines (Het-NH-Ph-U) and benzothiadiazepines. The molecular modeling study revealed that the3,5-dimethyl-allyl group of ⅢB-10a10generally overlapped the same group of8-TIBO, and occupied the same hydrophobic sub pocket defined by the residues of Y188and Y188. In some extent, this result demonstrated that the intrinsic relationships between the structural similarity of the ubiquitous privileged fragments and their pharmacophoric similarities, which encourages further exploring of bioactive substitutions of PTTDs based on the database of privileged fragments ubiquitous in known NNRTIs with high potency against WT and drug-resistant variants.
In summary, taking the DAPYs, IOPYs and PTTDs as leads,75compounds which belong to three categories of novel NNRTIs were designed and synthesized. The new, simple, and convenient synthetic approaches to the title compounds were developed, or improved and optimized. Lastly, through biological evaluation, we find several high potent antiviral compounds which had anti-HIV-1activity ranging from picomolar to nanonolar levels, and some of them also exhibit good performance against the serious resistant strains bearing variants of Y181C and K103N. Additionally, these compounds were expected to have improved pharmacokinetic profiles due to the incorporation of favorable fragments which benefit the drug solubility, which are worth further investigation and development.
本论文第一部分研究将选取对HIV-1病毒具有高效抗耐药性NNRTIs—二芳基嘧啶类(Diarylpyridine, DAPY)上市药物TMC125(Etrivirine)和3-碘基-4-苯氧基吡啶酮类(3-iodo-4-phenoxy-2-pyridinones, IOPY)衍生物R221239为先导,基于两者结合模式和药效基团的类似性,根据它们与RT结合的晶体复合物分子叠合结果,运用分子杂合的药物设计策略,将两类抑制剂的优势结构片段进行合理组合,设计了一类新型DAPY-IOPY杂合体:NNRTIs:(1)以IOPY类衍生物的2-吡啶酮为母核,以保持其与K101和K103氨基酸残基骨架的氢键作用,同时在2-吡啶酮3位上引入卤素,以与V179和Y188形成静电作用；(2)将DAPY类化合物右翼的苯胺基团迁移到吡啶酮6位,并在芳环对位引入不同的取代基,考察其对活性的影响；(3)将DAPY类化合物的优势取代基—2,4,6-三取代苯氧基和IOPY类化合物的优势取代基—3,5-二甲基苯氧基分别迁移2-吡啶酮的4位。由此设计了一系列3-卤代-4-苯氧基-6-苯胺基-1H-2-吡啶酮衍生物(Series IA)。同时,对Series IA化合物右翼芳环与中心杂环之间的NH接基团以CH2取代,设计了第二系列DAPY-IOPY杂合体衍生物—3-碘-4-苯氧基-6-苄基-1H-2-吡啶酮衍生物(Series IB)。
经过定向合成我们得到了两个系列31个目标化合物,活性结果显示,大部分Series IA化合物对野生型HIV-1(ⅢB)毒株表现出亚微摩尔到微摩尔水平的活性,其中活性最好的化合物IA-7d对野生型HIV-1IIIB毒株的EC5o值为0.15μM,优于DLV(EC50=0.91μM)、ddC(EC50=1.39μM)和NVP(EC50=0.113DAPY-IOPY杂合衍生物Series IA的构效关系研究显示：(1)2-吡啶酮母环对保持活性非常重要,以2-氯吡啶或2-甲氧基吡啶取代吡啶酮环活性降低,在吡啶酮3位上引入卤素活性下降,3位取代基对活性的贡献顺序为H>I>Br/Cl;(2)两翼取代基的SAR特征同DAPY类化合物一致,与IOPY类化合物不同：右翼芳环上活性最高的取代基为CN,左翼芳环的最优取代基为TMC125的活性取代基—4-氰基-2,6-二甲基,但被R221239的优势取代基—3,5-二甲基取代时化合物活性完全丧失。与Series IA不同,Series IB化合物表现出与IOPY类衍生物类似的构效关系。尤其左翼芳环为3,5-二甲基取代的化合物IB-7a(EC50＝0.22μM),不仅其抗HIV-ⅢB活性高于2,4,6-三甲基取代的化合物IB-7b(EC50＝0.32μM),而且对RES056(K103N+Y181C)双突变严重耐药毒株也具有较好的活性(EC50=1.71μM)。我们对DAPY-IOPY杂合体衍生物Series IA和Series IB代表性化合物进行了分子对接研究,结果发现Series IA NNRTIs衍生物与RT的结合模式更加类似于TMC125,而Series IB杂合体NNRTIs与RT的结合模式基本与R221239相一致,与构效关系研究的结论相互印证。
我们对DAPY-IOPY杂合体NNRTIs体外抗HIV-1ⅢB活性最好的4个化合物,进行了进一步的活性研究。在脐带血单个核细胞系(cord blood mononuclear cells, CBMC)的抗HIV-1活性测试表明,IA-7d、IA-7c、IB-7a和IB-7b对病人体内分离的原始R5毒株和R4毒株的活性处于亚微摩尔级；ELISA双抗夹心法抗HIV-1逆转录酶活性测试显示,化合物IA-7d和IA-7c对RT的抑制活性分别为5.2μM和39μM；定量PCR分析MT-4细胞单轮感染HIV-1NL4-3毒株后细胞内病毒总DNA含量表明,化合物IA-7d、IA-7c、IB-7a或IB-7b浓度为10μM时,对病毒逆转录晚期DNA产物的抑制率达99.2%,88.6%,98.3%和97.5%,验证了本研究所设计DAPY-IOPY杂合化合物的通过抑制RT逆转录过程而发挥抗HIV-1活性。
本论文第二部分研究根据DAPY类化合物与NNIBP晶体结构的解析和分子对接模拟研究,在对NNIBP中可容纳区域Ⅰ和可容纳区域Ⅱ两个结构修饰有利位点的契合适配性分析基础上,通过在吡啶类DAPY衍生物的右翼芳环和中心毗啶环之间插入哌啶胺极性基团,并在右翼末端芳环上引入-SONH2等极性基团,以开发与NNIBP中可容纳区域Ⅰ周围氨基酸残基的氢键作用力,并改善药物溶解度,设计了一系列具有哌啶胺柔性侧链的吡啶类DAPY衍生物(Series IIA)。同时,本研究在嘧啶和吡啶类DAPY衍生物的中心杂环和右翼芳环上位于NNIBP可容纳区域Ⅰ和可容纳区域Ⅰ的位置,引入水溶性较高的吗啉或哌嗪基团,设计了第二系列吗啉和哌嗪基团修饰的吡啶和嘧啶类DAPY衍生物(Series IIB),并分别用分子对接研究验证了Series IIA和Series IIB化合物设计的合理性。
对定向合成得到的两个系列29个化合物的体外抗HIV-1病毒活性测试结构表明,化合物IIA-8c2, IIA-8c3, IIA-8c4和IIA-8b3抑制HIV-1NL4-3毒株的ECso值分别为0.1rM、0.05nM、0.8nM和0.3nM(SI=20349-242800);对HIV-ⅢB野生毒株的活性分别为9.1nM、7.4nM、9.3nM和7.8nM(SI=168-1283),远远好于上市药物NVP、3TC与DLV(EC50=0.29μM,3.1μM,0.61μM),并与上市药物ETV、AZT和EFV的活性(EC50=7.0nM,6.8nM,9.5nM)相当。此外,化合物IIA-8b2、ⅡA-8b3对具有严重耐药性的RES056(K103N+Y181C)毒株也表现出一定的活性(EC50=6.2μM,6.8μM)。Series IIA衍生物的构效关系研究表明,左翼苯环上取代基R1对活性的贡献顺序为4-CN-2,6-二甲基>2,4,6-三甲基；吡啶环6位取代基R3对活性的贡献顺序为C1>OCH3;右翼哌啶胺基团N1位取代基R2对活性的贡献顺序为4-S02NH2-苯基>4-SO2Me-苯基>吡啶-4-基>4-CONH2-苯基>苯基>环丙基或环丁基。Series ⅡB化合物的抗病毒活性结果表明,在NNIBP的可容纳区域Ⅰ和Ⅱ引入水溶性较好的吗啉或者哌嗪基团,基本上可以保持先导化合物原有的活性。该系列活性最好的化合物IIB-8b抑制HIV-1NL4-3毒株的EC5o值为9.1nM(SI=2596),同时有望具有改善的药代动力学性质。
本论文第三部分工作是在本课题组前期N2,N4-双取代-吡咯[1,2-b][1,2,4,6]噻三嗪-1,1,3-三酮衍生物(PTTDs)研究的基础上,进一步探讨该类化合物N2位上多样性取代基引入对构效关系的影响(Seires Ⅲ)。本研究尝试对PTTD类化合物合成采用了新的合成路线,阐明了其可能的反应机制。对所合成PTTD类目标化合物进行了体外抗HIV活性试验。结果表明化合物ⅢB-10a10具有抗野生型HIV-1毒株的活性,其N2位的3,5-二甲基丙烯基为已报道的多种活性NNRTI分子结构中的普遍存在的优势基团。分子对接研究显示,ⅢB-10a10N2位上的3,5-二甲基丙烯基与TIBO化合物的3,5-二甲基丙烯基在NNIBP中的位置基本叠合,都处于Y181和Y188形成疏水亚口袋中。该研究结果体现了NNRTIs优势结构片段的类似性和结合模式的类似性之间具有内在联系,为下一步继续基于NNRTIs的分子结构多样性以及结合模式和优势结构基团的类似性,进行PTTD类衍生物的结构优化提供了重要思路。
综上所述,本课题设计以先导化合物/RT复合物的三维结构解析和构效关系为研究起点,充分考虑先导化合物与结构多样的NNRTIs药效团上类似性,以优势结构片段为导向,变换中心杂环的骨架结构、修饰侧链取代基及边链,以开发与RT结合位点的附加作用力,并提高溶解度；药物设计综合运用生物电子等排体、分子杂合、片段迁移等经典药物设计手段,并与计算机辅助药物设计的应用相结合。最后经定向合成了三个系列75个化合物,经过活性测试发现了多个抗HIV-1活性达到纳摩尔甚至皮摩尔水平的抑制剂,并有3个化合物(IB-7a、 IIA-8b2、IIA-8b3)对多药耐药毒株RES056(K103N+Y181C)表现出良好的活性。同时,本课题在优化抗病毒活性和抗耐药性的同时,通过引入哌啶胺、吗啉、哌嗪等水溶性较好环杂烷基团以提高化合物的溶解度。因此所获得的化合物在具有高效抗HIV-1活性的同时,有望获得改善的药代动力学性质,具有进一步研究开发的价值。
In the life cycle of human immunodeficiency virus type1(HIV-1), reverse transcriptase (RT) is responsible for the conversion of single-stranded viral RNA into double-stranded proviral DNA, a prerequisite for integration into host DNA. Due to its important role in the HIV-1life-cycle, RT has been identified as a prime target for anti-HIV drug discovery. Among currently available RT inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs) represent an important component of drug combination therapy for the treatment of HIV-infected patients. Up to date, five NNRTIs have been approved for clinical application by FDA:nevirapine (NVP), delavirdine (DLV), efavirenz (EFV), etravirine (ETV) and rilpivirine (RPV). First generation of NNRTIs, NVP and EFV, are suffered from severe side-effects over long periods of therapy, as well as inevitable emergence of HIV-1resistant strains. Though the second generation of NNRTIs, DLV, ETV, and RPV perform well against a variety of variants bearing clinically prevalent mutations, the development of novel NNRTIs families are still demanded to address issues of side effects, poor solubility, cross-resistance, and virologic failure
The NNRTI is a class of specific HIV-1RT inhibitors with diverse structures but share some inherent similarities in their pharmacophoric elements and binding mode with the NNRTI binding pocket (NNIBP), which provides valuable information for the lead discovery and drug optimization. More importantly, the extensive crystallgraphic investigations on the NNRTI/RT complexes help to interpret the ligand-enzyme interactions and reveal some important structure features to maintain the antiviral activity against mutant HIV-1strains. In this thesis, we focus our research interest on developing of novel NNRTIs using the structure-based approaches using a combination of traditional medicinal chemistry, structural biology, and computational chemistry. My research work could be divided into three sections, which are summarized as follows:
Section One:The Design, Synthesis and Biological Evaluation of DAPY-IOPY Hybrid Derivatives
Based on the pharmacophoric similarity and crystallographic overlaps of TMC125and R221239, we designed a novel series of DAPY-IOPY hybrid derivatives through combining their privileged structural features using molecular hybridization strategy:i)2-pyridone ring of IOPY was kept as the central scaffold to develop hydrogen-bondings with K103and K101. Meanwhile, halogen atoms were introduced to the3-position of the2-pyridone ring, respectively, to evaluate their impacts on antiviral activity; ii) Fragment switching of the2-aniline group of DAPY into the6-position of2-pyridione template and modified the substituents at this phenyl ring; iii) Introduction of the favorable substitutions of4-phenoxy moiety of DAPY and IOPY into the4-position of novel2-pyridone template, respectively, to probe the substitution SAR patterns of these novel DAPY-IOPY hybrid derivatives.
In total, we synthesized31target compounds which could be classified into two series (Series IA and Series IB). The biological testing results showed that most compounds possessed submicromolar to micromolar level of inhibition activities against HIV-1Ⅲb strains in MT-4cell cultures. The most potent compound IA-7d showed anti-HIV-1IIIB activity with an EC50value of0.15μM, comparable to that of nevirapine, but superior to those of delavidine and zalcitabine. The structure-activity relationship (SAR) analysis indicated that2-pyridone scaffold of these inhibitors was indispensable for their anti-HIV-1activity, and substitution of halogen at the3-position of the2-pyridone ring would decrease the anti-HIV activity. Further biological evaluation demonstrated that IA-7d, IA-7c, IB-7a and IB-7b inhibited the replication of HIV-1primary isolated BK132(X4) or92TH001(R5) strains in cord blood mononuclear cells (CBMCs) at submicromolar level. ELISA based RT enzyme inhibition assay revealed that IA-7d possessed anti-RT activity with an IC50value of5.2μM. Quantitative PCR analysis of viral DNA experience showed that IA-7d, IA-7c, IB-7a and I7-8b could highly effectively reduce the late RT DNA product to1.1%、11.7%、2.1%and2.8%, respectively, compared with the DMSO control group (100%). These results proved these2-pyridone typed DAPY-IOPY hybrid derivatives to be a highly promising NNRTI scaffold, which may serve as a new platform for further modification in search for more potent candidates for anti-HIV chemotherapy
Section Two:The Structural Optimization of DAPY Derivatives by Introducing Piperidyl, Morpholinyl or Piperazinyl Group into the NNIBP Tolerant Region
Based on the crystallographic studies and molecular modeling investigations of DAPYs, we focus our attention on exploiting the tolerant region I and II of NNIBP by incorporating hydrophilic piperidyl, morpholinyl or piperazinyl group into the pyridine-and pyrimidine-typed DAPY derivatives, with an aim to develop additional interactions between the inhibitors and NNIBP, as wells as to improve the drug solubility.
The antiviral activity evaluation results showed that, the most potent compounds of Series ⅡA, viz. ⅡA-8c2, IIA-8c3, IIA-8c4and IIA-8b3could effectively inhibit HIV-1NL4-3strains in MT-4cells with EC50values of0.1nM,0.05nM,0.8nM and0.3nM, respectively, accompanied with excellent SI values ranging from20349to242800. The anti-HIV-1ⅢB activities of IIA-8c2, IIA-8c3, IIA-8c4and IIA-8b3were low to9.1nM,7.4nM,9.3nM and7.8nM, respectively (SI=168-1283), much superior to FDA-aproved drug of NVP,3TC and DLV, and comparable to ETV, AZT and EFV. Additionally, compounds IIA-8b2and IIA-8b3showed good performance against the serious RES056(K103N+Y181C) mutant strains with the EC50values of6.2μM and6.8μM, respectively. The SAR analysis of Series IIA demonstrated that replacement of the2,4,6-trimethyl group on left-wing phenyl ring with4-CN-2,6-dimethy group led to improved potency, and incorporation of OCH3group into the6-position of pyridine instead of the Cl group yielded less active compounds. The substitutions at the Nj position of the right-wing piperidyl contributed to the anti-HIV-1activity in the following order:4-SO2NH2-phenyl>4-SO2Me-phenyl> pyridn-4-yl>4-CONH2-phenyl> phenyl> cyclopropyl or cyclobutyl.
The anti-HIV-1NL4-3assay results of Series IIB indicated that the extra morpholinyl or piperazinyl group which was introduced into the lead DAPY derivatives could be well adopted by the NNIBP tolerant site, without significantly reducing the compounds'anti-HIV activities. The most compound IIB-8b possessed an EC50value of9.1nM, with SI value of2596. These compounds of series IIB were expected to possess improved solubility and pharmacokinetic profile, due to the favorable hydrophilic properties of morpholinyl and piperazinyl group.
Section Three:Design, Synthesis and Biological Evaluation of N2, N4-Disubstituted-1,1,3-trioxo-2H,4H-pyrrolo[1,2-b][1,2,4,6]thiatriazine Derivatives as Novel HIV-1NNRTIs
In an effort to explore derivatives of N2, N4-2,4-disubstitued-1,1,3-trioxo-2H,4H-thieno[3,4-e][1,2,4]thiadiazines (TTDs) as potent HIV-1NNRTIs, we had designed and synthesized a classes of N2, N4-disubstitued-1,1,3-trioxo-2H,4H-pyrrolo[1,2-6][1,2,4,6]thiatriazine derivatives (PTTDs), which displayed good activities against HIV-1virus. As a continuation of our research, we incorporated diverse groups into the N2position to further investigate the S AR patterns of PTTDs. An alternative synthetic strategy was attempted to firstly prepare PTTD ring, which subsequently underwent regioselectivce N-alkylation at its N2and N4positions, respectively, to give the target PTTDs. However, extensive effort to conduct this strategy eventually lead to the production of another new heterocycle, viz.1,1,3-trioxo-2H-pyrrolo[1,2-6][1,2,5]thiadiazole, rather than the expected PTTD ring. We proposed a plausible reaction mechanism for formation of1,1,3-trioxo-2H-pyrrolo[1,2-6][1,2,5]thiadiazole. Finally, we utilized the improved synthesis route of PTTDs to synthesize the PTTD target compounds.
Unfortunately, the biological evaluation results showed that only compound ⅢB-10a10had inhibition activity against wide type HIV-1ⅢB strains. ⅢB-10a10shares a ubiquitous privileged fragment of3,5-dimethyl-allyl group at its N2substitutions with many reported potent NNRTIs, including tetrahydromidazo (TIBO), thiocarboxanilid, diarylamines (Het-NH-Ph-U) and benzothiadiazepines. The molecular modeling study revealed that the3,5-dimethyl-allyl group of ⅢB-10a10generally overlapped the same group of8-TIBO, and occupied the same hydrophobic sub pocket defined by the residues of Y188and Y188. In some extent, this result demonstrated that the intrinsic relationships between the structural similarity of the ubiquitous privileged fragments and their pharmacophoric similarities, which encourages further exploring of bioactive substitutions of PTTDs based on the database of privileged fragments ubiquitous in known NNRTIs with high potency against WT and drug-resistant variants.
In summary, taking the DAPYs, IOPYs and PTTDs as leads,75compounds which belong to three categories of novel NNRTIs were designed and synthesized. The new, simple, and convenient synthetic approaches to the title compounds were developed, or improved and optimized. Lastly, through biological evaluation, we find several high potent antiviral compounds which had anti-HIV-1activity ranging from picomolar to nanonolar levels, and some of them also exhibit good performance against the serious resistant strains bearing variants of Y181C and K103N. Additionally, these compounds were expected to have improved pharmacokinetic profiles due to the incorporation of favorable fragments which benefit the drug solubility, which are worth further investigation and development.
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