具有肾保护活性的查尔酮衍生物的设计合成及活性评价

目的 设计合成11个查尔酮色氨酸衍生物,并进行肾保护和抗肿瘤活性测试.方法 以芳香醛与4-乙酰基苯甲酸为原料,经Claisen-Schmidt缩合、酰胺缩合、水解、酰胺缩合反应合成了11个查尔酮色氨酸衍生物.采用MTT法测定化合物改善顺铂诱导的肾细胞(HK-2)损伤活性;评价化合物对胃癌细胞(HGC-27)的抗增殖作用...     

基于磺酰胺药效团的查尔酮衍生物的合成与活性筛选

目的消除查尔酮α,β-双键的不利影响,发现多靶标受体酪氨酸激酶(RTKs)抑制剂。方法查尔酮骨架上引入磺酰胺,设计并合成14个查尔酮衍生物(SFA1～SFA14)。分别采用酪氨酸激酶检测试剂盒(ADP-Glo^TM)和四唑盐比色试验法(MTT)评价化合物对表皮生长因子受体(EGFR)、激酶插入区受体(KDR)和成纤维细胞生长因子受体1(FGFR1)以及乳腺癌细胞(MCF-7)、非小细胞肺癌细胞(A549)和白血病细胞(K562)的抑制活性。结果大部分化合物具有高效RTKs抑制活性和抗肿瘤活性,部分化合物活性接近阳性对照的水平。结论查尔酮磺酰胺衍生物具有潜在抗肿瘤活性。     

含三苯胺衍生物取代钌配合物的合成及其抗菌活性研究

目的 以三苯胺取代邻菲啰啉衍生物为主配体，合成了两种新型的抗菌钌配合物[Ru(phen)2PMA](PF6)2(Ru-1)和[Ru(dmphen)2PMA](PF6)2(Ru-2)。方法 通过¹HNMR、¹³CNMR和HRMS对两个化合物的结构进行了表征，并通过最低抑菌浓度，生长曲线，时间杀伤曲线，生物膜形成实验，耐药测试，溶血毒素分泌实验以及棋盘联用实验研究了化合物的抗菌活性；通过DAPI/PI染色实验以及蛋白质泄露实验研究了化合物的抗菌机制；最后通过大蜡螟幼虫研究了化合物的毒性。结果 两个化合物在体外对金黄色葡萄球菌均具有显著抗菌活性(MIC=0.0078～0.0156 mg/mL),0.031 mg/mL的Ru-2能在10 min杀灭超过99.0%的细菌。在亚抑菌浓度下，Ru-2不仅能有效抑制细菌生物膜的形成和溶血毒素的分泌，还能显著提升8种临床常用抗生素对金黄色葡萄球菌的敏感性(FICI<0.5)。抑菌机制研究结果表明，化合物Ru-2能破坏细菌细胞壁的完整性。此外，毒性研究也表明Ru-2具有良好的生物相容性；结论 具有膜破坏机制...     

3位酮基红霉衍生物的半合成及其抗菌活性研究

设计合成了３位酮基－９－（２－甲氧基异丙基）－肟红霉素及其中间体,抗菌活性检测表明,目标化合物及其中间体均有不同程度的抗菌活性,其中Ｋ３和Ｋｍ对革兰氏阳性菌抗菌活性与红霉素相似,而Ｋｍ对红霉素耐药菌有较强作用。     

氟哌酸衍生物的合成及抗菌活性

以氟哌酸为原料，合成了５种尚未见报道的衍生物，经体外抗菌试验验证，部分衍生物的活性优于氟哌酸，并对其结构与活性的关系作了探讨。     

N-取代苯基-5-取代苯基-3H-1,2,4-三唑-3-硫酮衍生物的合成及抗菌活性研究

目的 以苯甲酸为原料,经4步反应合成一系列N-取代苯基-5-取代苯基-3H-1,2,4-三氮唑-3-硫酮化合物并研究其抗菌活性。方法 基于课题组前期对新型潜在三唑类抗菌化合物6h的作用机制研究,筛选多个侧链基团,使用乙醇和碳酸钠作溶剂改善最后一步反应条件,通过硅胶柱色谱分离纯化目标化合物,合成一系列1,2,4-三唑类化合物并采用质谱(MS)和1H NMR、13C NMR进行结构表征。通过琼脂扩散法初步筛选所有化合物对肺炎克雷伯菌、金黄色葡萄球菌和铜绿假单胞菌3种常见菌株的抗菌活性,并通过微量稀释法进一步测定它们的最小抑菌浓度(MIC值)。结果 合成17个含有卤代苯基和其他侧链基团的目标化合物,其MS以及核磁共振谱图数据表明所有化合物结构正确。抗菌活性初步筛选可知化合物6a、6b、6d、6f、6g、6h、6k、6m和6p等9个化合物具有不错的抑菌能力,其MIC测试结果表明,大部分化合物对所测菌株的MIC值在25~100μg/mL范围内。尤其是化合物6h和6k对肺炎克雷伯菌的MIC值达到25μg/mL,抑菌活性与对照药物氨苄西林相当。结论 在前期作用机制研究基础上,通过对构效关系的阐述,发现一些侧链片段如间位卤代苯基或对位卤代苯基、三氟甲基苯基等具有吸电子基团的苯基、吡啶基等对1,2,4-三唑类衍生物的抗菌活性有明显增强作用,证实侧链基团与受体蛋白形成特异性协调作用和氢键作用从而发挥衍生物的抗菌活性。     

丙基桥联双二茂铁基查尔酮衍生物的合成

查尔酮及其衍生物是芳香醛酮发生交叉羟醛缩合的产物,是一类重要的药物活性化合物.本文以氢氧化钠为催化剂,合成了6个丙基桥联双二茂铁基查尔嗣衍生物.产物结构经1HNMR,IR及质谱进行了表征.此方法反应时间短,产率高且易于操作.     

二氢青蒿素-查尔酮杂合物的设计、合成及其抗肿瘤活性研究

目的设计合成二氢青蒿素-查尔酮杂合物,提高二氢青蒿素类化合物对白血病细胞的生长抑制活性。方法将取代查尔酮以醚键拼合到二氢青蒿素的C-10位,设计并合成了29个二氢青蒿素-查尔酮杂合物。采用细胞计数法测定目标化合物对人白血病HL-60细胞的生长抑制作用。结果得到了29个含有查尔酮侧链的二氢青蒿素衍生物,均为未见文献报道的新化合物,其结构经1H-NMR、MS和IR谱确证。所有目标化合物对人白血病HL-60细胞都有不同程度的生长抑制作用。结论所有目标化合物对HL-60细胞株的生长抑制活性均强于二氢青蒿素,GI50值均小于0.10μmol·L-1。连接链的改变、查尔酮A环和B环的调换以及取代基的改变对化合物活性的影响没有显著差异。     

红霉素衍生物的合成及抗菌活性

目的设计、合成红霉素4″-氨基甲酸酯衍生物,研究其抗菌活性。方法以阿奇霉素为起始原料,经1, 1′-羰基二咪唑处理以及胺解反应、曼尼希反应制备目标化合物,并以金黄葡萄球菌为试验菌进行体外抗菌活性研究。结果共合成了9个目标化合物,其结构经IR、13C NMR、1HNMR和元素分析得以证实,经体外抗菌活性试验发现化合物F-3和F-4显示较好抗金黄色葡萄球菌活性,所有化合物无体外杀菌活性。结论说明吡咯烷基或哌啶基可能有利于提高抗菌活性。     

New thiazolyl-pyrazoline derivatives bearing nitrogen mustard as potential antimicrobial and antiprotozoal agents

A new series of N-substituted pyrazoline derivatives 6a–g , 7a–g , 8a–g , and 9a–g was synthetized by reaction of hydrazine derivatives and chalcone–thiazole hybrids bearing nitrogen mustard 5a–g . The chalcones 5a–g were obtained by Claisen–Schmidt condensation of thiazole-2-nitrogen mustard 3 and selected acetophenones 4a–g . These new compounds 6/7/8/9a–g were screened for their antifungal activity against Cryptococcus neoformans, with IC₅₀ values of 3.9–7.8 µg/ml for the N-3,5-dichlorophenyl pyrazolines 9e – g . Interestingly, those compounds show low cytotoxic effects toward erythrocytes (RBC). In addition, N-acetyl ( 6a,b ) and N-formyl pyrazolines ( 7a , 7b , 7c , and 7g ) showed inhibitory activity against methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus, and vancomycin-intermediate S. aureus, with the most important minimum inhibitory concentration values ranging from 31.25 to 125 µg/ml. Regarding the antiprotozoal activity, thiazolyl-pyrazolines 9g , 8f , and 7c display high activity against Plasmodium falciparum, Leishmania (V) panamensis, and Trypanosoma cruzi, with EC₅₀ values of 11.80, 6.46, and 4.98 μM, respectively, and with 7c being approximately 2.6-fold more potent than benznidazole with a selectivity index of 1.61 on U-937 human cells, showing promising potential as a novel antitrypanosomal agent.     

Synthesis and anti-bacterial activity of some heterocyclic chalcone derivatives bearing thiofuran, furan, and quinoline moieties

36 Novel heterocyclic chalcone derivatives were synthesized and tested for their anti‐bacterial activity. Some compounds presented good anti‐microbial activities against Gram‐positive bacteria (including the multidrug‐resistant clinical isolates). This class of compounds presented high potency against Streptococcus mutans, among which the derivatives F2 with an MIC of 2 µg/mL was as active as the standard drug (norfloxacin) and less active than oxacillin. All the compounds did not inhibit the growth of Gram‐negative bacteria (Escherichia coli CCARM 1924 or Escherichia coli CCARM 1356) at 64 µg/mL.     

Synthesis and biological evaluation of novel 4,5-dihydropyrazole derivatives as potent anticancer and antimicrobial agents

A focused library of 4,5-dihydropyrazole dervivatives (4, 5, 6, 7a–h, 8, 9a–g, and 10a–g) were synthesized from novel 5-(2,6-difluorophenyl)-3-phenyl-4,5-dihydropyrazole-1-carbothioamide 4. The synthesized compounds were characterized using elemental analysis and spectral data (IR, mass spectra, ¹H and ¹³C NMR) and evaluated for antimicrobial activity by broth dilution method and in vitro anticancer activity. Among the synthesized compounds 7a, 9c, 9g, and 10d exhibit broad spectrum antimicrobial activity against tested microbial strains. The in vitro cancer results ascertain 7a, 9c, and 10d are most potent molecules in comparison to reference standard cisplatin.     

Synthesis and biological evaluation of andrographolide derivatives as potent anti-HIV agents

In an attempt to develop potent anti-HIV drugs, 20 andrographolide derivatives were designed, synthesized, and evaluated for their in vitro anti-HIV activity. The screening results revealed that five compounds showed potent anti-HIV activities with therapeutic indices (TI) above 10. The most promising compound 6f shows a significant TI close to 34.07, with the potency to be a new lead.     

Synthesis of certain mercapto-and aminopyrimidine derivatives as potential antimicrobial agents

Reaction of ethyl 4-chloro-2-phenylpyrimidine-4-carboxylate (4) with 5-chloro-2-methylthiophenol or 3-aryl-4-phenyl-1,2,4-triazole-5-thiol yielded the corresponding thioethers (5) and (8a, b), respectively. Careful alkaline hydrolysis of (5) yielded the corresponding carboxylic acid (6). Reaction of (4) withp-aminoacetophenone yielded compound (10) which was reacted with certain aromatic aldehydes to afford the α, β-unsaturated ketones (11a–d). Condensation of (11a–d) with malononitrile or phenylhydrazine yielded the 2-amino-3-cyanopyridines (12a–f) or the 2-pyrazolines (13a, b), respectively. Seven representative compounds were tested for theirin vitro antimicrobial activity against some pathogenic micro-organisms, some of them were proved to be active.     

Synthesis and evaluation of lysozyme derivatives exhibiting an enhanced antimicrobial action

In order to generate novel preservatives exhibiting a broad antimicrobial spectrum against Gram-positive as well as Gram-negative bacteria, lysozyme was modified by the covalent attachment of caffeic acid and cinnamic acid, respectively. Linkage of these organic acids to lysozyme was achieved by the constitution of amide bindings between the carboxyl group of ligands and primary amino groups of the enzyme mediated by a carbodiimide. Compared to nonmodified lysozyme, the lytic activity of all resulting conjugates was reduced. In contrast, bacterial growth of Escherichia coli (ATCC 8739) could be strongly inhibited by lysozyme–caffeic acid conjugates and to a lower degree also by lysozyme–cinnamic acid conjugates. The minimal inhibitory concentration against E. coli was 0.05% for the lysozyme derivative of the highest antimicrobial activity. However, the efficacy of lysozyme derivatives against Staphylococcus aureus (ATCC 6538) was slightly reduced. As the antimicrobial spectrum of lysozyme altogether could be substantially widened, these derivatives represent promising candidates as novel preservatives for various pharmaceutical and cosmetic formulations.     

Synthesis and biological evaluation of some 2,4,5-trisubstituted thiazole derivatives as potential antimicrobial and anticancer agents

We report on the synthesis and biological evaluation of two series of 2,4,5-polysubstituted thiazoles comprising the acid hydrazide functionality and some derived pharmacophores known to contribute to various chemotherapeutic activities. All newly synthesized compounds were subjected to in-vitro antibacterial and antifungal screening. Of the compounds tested, 13 derivatives displayed inhibitory effect on the growth of three Gram-positive strains while they lack activity against Gram-negative bacteria. Moreover, four compounds were able to exert antifungal activity against C. albicans. Potential antibacterial and antifungal activities were linked to the thiosemicarbazide function 6a-f and those substituted with both the thioureido and thiosemicarbazide moieties 12a-f. Compounds 6f and 12f (R = 4-F-C(6)H(4)) could be considered as the most active members in this investigation with a broad spectrum of antibacterial activity against three types of Gram-positive bacteria, together with an appreciable antifungal activity against C. albicans. Compounds 6d, 6f, and 12f were twice as active as ampicillin against B. subtilis. The best antifungal activity was shown by compound 6d 50% less active than clotrimazole. 17 compounds were selected and tested for their preliminary in-vitro anticancer activity according to the current one-dose protocol of the NCI. Three cell lines, non-small cell lung cancer Hop-92, ovarian cancer IGROV1, and melanoma SK-MEL-2, exhibited some sensitivity against most of the tested compounds. Compound 12f proved to be the most active anticancer member with a broad spectrum of activity against most of the tested subpanel tumor cell lines. Consequently, 12f was carried over to be tested in the five-dose assay.     

Synthesis and biological evaluation of sophocarpinic acid derivatives as anti-HCV agents

Chronic hepatitis C virus (HCV) infection has become a major public health burden worldwide. Twenty-two sophocarpinic acid or matrine derivatives were synthesized and their anti-HCV activities were evaluated in vitro. The structure-activity analysis revealed that (i) sophocarpinic acids with a D-seco 3-ring structure scaffold were more favorable than matrines with a 4-ring scaffold; (ii) the introduction of an electron-withdrawing group on the phenyl ring in 12-N-benzenesulfonyl Δ^βγ sophocarpinic acids was beneficial for the antiviral activity against HCV. Among them, compounds 9h and 9j exhibited the most potent inhibitory activities on HCV replication with selectivity indies of 70.3 and 30.9, respectively. Therefore, both were selected as antiviral candidates for further investigation.KEY WORDS: Sophocarpinic acid, Matrine, Anti-HCV, Antiviral activity, Structure−activity relationship     

Synthesis and biological evaluation of 2,5-diaminobenzamide derivatives as anti-proliferating agents

The screening of the chemical library for the anti-proliferative activity of the chemical library provided 2,5-diaminobenzamide as the initial hit. The confirmation and the optimization of hit were performed by synthesis followed by the evaluation of growth inhibitory activity against human cancer cell lines. The most active growth inhibitor showed IC₅₀ of 1.0 μM. The compound 7 increased not only sub-G1 population but also number of cells which are stained with Annexin V-FITC and 7-AAD, suggesting that compound 7 induced cell death is apoptosis.