dl-7-(4,4-二甲基-3-氨甲基-吡咯烷-1-基)-喹诺酮类化合物的合成与抗菌作用

目的寻找新的高效抗革兰氏阳性菌的喹诺酮类药物。方法设计合成了dl-7-(4,4-二甲基-3-氨甲基-吡咯烷-1-基)-1-环丙基-6-氟-8-甲氧基-1,4-二氢-4-氧代喹啉-3-羧酸及其类似物，测定其体外活性。结果共合成10个目标化合物，经¹H NMR，MS确证其结构。目标化合物具有良好的抗革兰氏阳性菌的活性，尤其是化合物22不仅对4株革兰氏阳性耐药菌(两株MRSA，两株MRSE)的活性表现突出，MIC值为0.015～0.5 mg·L^-1，其活性是加替沙星(MIC值为0.125～16 mg·L^-1)的4～128倍，而且，对铜绿假单孢菌03-5的MIC值为0.008 mg·L^-1，其活性是加替沙星(MIC值为0.03 mg·L^-1)的4倍。结论化合物22值得进一步深入评价。     

7-(7-氨甲基-5-氮杂螺［2,4］庚烷-5-基)-1-环丙基-6-氟-8-甲氧基-1,4-二氢-4-氧代喹啉-3-羧酸及其类似物的合成与抗菌作用7-(7-氨甲基-5-氮杂螺［2,4］庚烷-5-基)-1-环丙基-6-氟-8-甲氧基-1,4-二氢-4-氧代喹啉-3-羧酸及其类似物的合成与抗菌作用

目的寻找新的广谱、高效、低毒喹诺酮类抗菌药物。方法设计合成7-(7-氨甲基-5-氮杂螺［2,4］庚烷-5-基)-1-环丙基-6-氟-8-甲氧基-1,4-二氢-4-氧代喹啉-3-羧酸及其类似物,测定其体内外活性。结果共合成了20个新化合物,经¹HNMR,MS和HRMS确证其结构。其中5个目标化合物(22～26)有广谱活性,尤其对革兰氏阳性菌具有很强的活性。其中化合物24对所试的13株革兰氏阳性菌的MIC值均0.03 mg·L^-1,其活性优于对照药克林沙星和加替沙星,对所试的6株革兰氏阴性菌,其活性相当于或低于对照药。结论化合物(22～26)值得进一步评价。     

7-[3-氨甲基-4-(脲亚氨基)吡咯烷-1-基]喹诺酮衍生物的合成与抗菌作用研究

目的 寻找新的喹诺酮类抗菌药.方法 设计合成7-位具有较强亲水性取代基的7个氟喹诺酮衍生物,测定其体外抗菌活性.结果 化合物10对金葡菌(包括MRSA)和表葡菌(包括MRSE)的活性(MIC:0.06～4μg/mL)与左氧氟沙星和吉米沙星基本相当.化合物11对肺炎链球菌08-2的活性(MIC:0.25μg/mL)分别是左氧氟沙星和吉米沙星的128倍和32倍,化合物12对肺炎克雷伯菌09-22和09-23的活性(MIC:1μg/mL)分别是左氧氟沙星和吉米沙星的16倍和4倍,但目标物对革兰阴性菌的活性普遍弱于对照药.结论 7-位取代基的水溶性并非决定喹诺酮抗菌活性的主要因素.     

5-氨基-8-甲氧基喹诺酮类化合物的合成及体内外抗菌作用

通过5-氨基-1-环丙基-6,7-二氟-8-甲氧基-1,4-二氢-4-氧代喹啉-3-羧酸与不同的环胺进行缩合反应,合成了5个未见文献报道的5-氨基-8-甲氧基喹诺酮类化合物。它们的结构均经核磁共振氢谱和高分辨质谱所确证。用环丙沙星及加替沙星作对照,测定了它们的体外抗菌活性,结果表明它们具有广谱活性,其中化合物5、7和9活性十分明显地优于对照药;化合物5和9进一步评价了其体内活性,结果表明化合物5和9分别比对照药加替沙星和莫西沙星具有更优秀的体内活性,值得深入研究。     

3-取代苯甲酰基-4H-色烯-4-酮的合成及其抗快速增殖分枝杆菌活性研究

目的 设计合成3-苯甲酰基-4H-色烯-4-酮类化合物,并测定其体外抗快速增殖分枝杆菌活性。 方法 以焦性没食子酸和取代苯甲酸为原料,经Friedel-Crafts酰基化、Baker-Venkataraman重排等反应合成目标化合物,初步测定了目标化合物的抗快速增殖分枝杆菌活性。结果 共合成8个3-苯甲酰基-4H-色烯-4-酮类化合物,其结构经核磁共振氢谱和质谱确证。化合物2a、2e呈现边缘抗快速增殖分枝杆菌活性。结论 在具有抗快速增殖分枝杆菌活性的天然产物(S)-3-(4-甲氧苄基)-7,8-亚甲二氧基二氢高异黄酮的2,3-位引入双键、7,8-位更换为甲氧基以及9位以羰基替代亚甲基均会导致抗快速增殖分枝杆菌活性的大幅降低。     

加替沙星治疗36例下呼吸道感染的临床观察

加替沙星是第四代新型喹诺酮类抗菌药,不仅对革兰氏阴性菌有良好活性,对革兰氏阳性菌尤其是链球菌属,对梭状芽胞杆菌属和拟杆菌属等厌氧菌及呼吸道感染常见的非典型病原菌肺炎支原体、肺炎衣原体和结核分枝杆菌、非结核分枝杆菌等也具有较强的抗菌活性。其组织分布广泛,在肺组织及尿液中的药物浓度为血浓度的12倍。本文随机对比观察加替沙星(治疗组)及环丙沙星(对照组)治疗下呼吸道感染各36例,结果报道如下。     

7-{4-［2-［2-取代-4-((5S)-5-乙酰胺甲基-2-氧代-噁唑烷-3-基)苯基］乙基］哌嗪-1-基}-氟喹诺酮类化合物的合成与抗菌活性

目的寻找新型的噁唑烷酮-氟喹诺酮类抗菌药物。方法设计合成了7-{4-［2-［2-取代-4-((5S)-5-乙酰胺甲基-2-氧代-噁唑烷-3-基)苯基］乙基］哌嗪-1-基}-氟喹诺酮类化合物，测定其体外抗菌活性。结果共合成20个目标化合物，经^{1H NMR和MS确证结构。目标化合物具有较好的体外抗菌活性，尤其是化合物22，对屎肠球菌的抑制活性分别是吗啉噁酮和诺氟沙星的16倍和64倍，对金葡菌的抑制活性为吗啉噁酮的4倍。结论某些带有氟喹诺酮结构片段的噁唑烷酮类化合物抗菌活性加强。}     

25-12 新的喹诺酮抗菌剂-DX619

至从发现喹诺酮母核的 6 -氟喹诺酮可提高抗菌活性以来 ,6 -氟喹诺酮类已成为一组主要的治疗剂 ,构效关系的研究已证明加替沙星和莫西沙星比环丙沙星和氧氟沙星具有更高的抗革兰氏阳性球菌的活性。而最近研究显示去掉 6 -氟基可提高活性并降低毒性。革兰氏阳性球菌多药耐药性不     

组蛋白去乙酰化酶抑制剂与加替沙星新缀合物的合成及抗肿瘤活性

目的 设计合成加替沙星-组蛋白去乙酰化酶抑制剂(histone deacetylase inhibitor, HDACi)缀合物，并探讨其抗肿瘤活性。方法 以第四代喹诺酮类药物加替沙星为原料，对其进行结构修饰，分别在其C-7哌嗪基和C-3位羧基引入辛二酰苯胺异羟肟酸(SAHA)单元，并采用HDACs试剂盒、微管蛋白试剂盒和MTT法对所合成的缀合物进行酶和抗肿瘤抑制活性测试。结果 合成了4个未见文献报道的新化合物10a~c和13，其结构均经过1H NMR、13C NMR和HRMS进行确证。初步的生物活性研究表明目标化合物能有效地抑制微管蛋白聚合和HDACs，并对5种肿瘤细胞有不同程度的抑制活性，其中SAHA类似物单元的侧链为6个亚甲基的缀合物10b和13对微管蛋白聚合和HDACs的抑制活性以及抗肿瘤活性强于其他衍生物。结论 将组蛋白去乙酰化酶抑制剂(HDACi)单元引入到加替沙星上，能提高其抗肿瘤活性。     

加替沙星对金黄色葡萄球菌的体外抗菌活性

考察加替沙星对金黄色葡萄球菌的体外抗菌活性以及抗MRSA的能力。采用药敏纸片法（K－B法），从129株临床分离的金黄色葡萄球菌筛选对甲氧西林和氟喹诺酮类药物的耐药菌株，用琼脂二倍稀释法对交叉耐药菌进行MIC测试，比较了加替沙星与环丙沙星等第二代氟喹诺酮类药物的耐药菌株，用琼脂二倍稀释法对交叉耐药菌进行MIC测试，比较了加替沙星与环丙沙星等第二代氟喹诺酮类药物的抗菌活性。用苯唑西林筛选三代自发突变株，比较环丙沙星、加替沙星对MRSA的抗菌活性。实验表明，苯唑西林、环丙沙星、氧氟沙星、左氧氟沙星对129株金黄色葡萄球菌的耐药率相似。体外活性表明，加替沙星比环丙沙星等第二代氟喹诺酮类药物的抗菌活性强，抗MRSA菌株的活性较强；敏感金黄色葡萄球菌发生加替沙星耐药的突变频率在所试药物中也是最低的。说明加替沙星比环丙沙星等第二代氟喹诺酮类药物的抗菌活性得到明显提高。     

Synthesis and in-vitro antimycobacterial activity of fluoroquinolone derivatives containing a coumarin moiety

A series of gatifloxacin, ciprofloxacin, and 8-OCH(3) ciprofloxacin coumarin derivatives with remarkable improvement in lipophilicity as compared to the parent fluoroquinolones was designed, synthesized, and characterized by (1) H-NMR, MS, and HRMS. These derivatives were evaluated for their in-vitro activity against Mycobacterium smegmatis CMCC 93202 and MTB H37Rv ATCC 27294. All of the synthesized compounds were less active than the parent compounds against M. smegmatis CMCC 93202, but the activity of compound 6 was found to be 2-8-fold more potent than ciprofloxacin, 8-OCH(3) ciprofloxacin, moxifloxacin, and rifampin, and comparable to gatifloxacin against MTB H37Rv ATCC 27294. These results indicated that the lipophilicity of the tested compounds is not the sole parameter affecting antimycobacterial activity.     

Design and synthesis of lipophilic phosphoramidate d4T-MP prodrugs expressing high potency against HIV in cell culture: structural determinants for in vitro activity and QSAR.

A series of new substituted-aryl phosphoramidate derivatives of the anti-HIV drug d4T were synthesized as membrane-soluble nucleotide prodrugs, to extend and quantify the SAR observed for an earlier series of related derivatives. All of the compounds were found to be significantly more potent against HIV in cell culture than the nucleoside analogue d4T, and most were also found to be significantly more potent than the parent phosphoramidate. A Hansch type QSAR analysis was applied to the combined series of 21 compounds. The results of this analysis revealed anti-HIV activity to be principally dependent on lipophilicity in a quadratic manner, with terms representing substituent steric bulk and electronic effects having a minimal significance.     

New hydrazide–hydrazones of isonicotinic acid: synthesis,lipophilicity and in vitro antimicrobial screening

This study describes the synthesis, lipophilicity and in vitro antimicrobial assays of 15 new hydrazide–hydrazones of isonicotinic acid. New derivatives were obtained on the basis of the condensation reaction of isonicotinic acid hydrazide with different aromatic aldehydes. The chemical structure of synthesized compounds was confirmed by spectral methods. Experimental lipophilicity of new isonicotinic acid derivatives was determined using reversed‐phase thin‐layer chromatography. All synthesized compounds were subjected to in vitro antimicrobial assays against reference strains of Gram‐positive bacteria, Gram‐negative bacteria and fungi belonging to Candida spp. Some of the synthesized hydrazide–hydrazones proved to be significant antibacterial compounds and more potent than commonly used chemotherapeutic agents.     

Synthesis and biological evaluation of fatty acyl ester derivatives of (-)-2',3'-dideoxy-3'-thiacytidine

A number of fatty acyl derivatives of (-)-2',3'-dideoxy-3'-thiacytidine (lamivudine, 3TC, 1) were synthesized and evaluated for their anti-HIV activity. The monosubstituted 5'-O-fatty acyl derivatives of 3TC (EC(50) = 0.2-2.3 μM) were more potent than the corresponding monosubstituted N(4)-fatty acyl (EC(50) = 0.4-29.4 μM) and 5'-O-N(4)-disubstituted (EC(50) = 72.6 to >154.0 μM) derivatives of the nucleoside. 5'-O-Myristoyl (16) and 5'-O-12-azidododecanoyl derivatives (17) were found to be the most potent compounds (EC(50) = 0.2-0.9 μM) exhibiting at least 16-36-fold higher anti-HIV activity against cell-free virus than 1 (EC(50) = 11.4-32.7 μM). The EC(90) values for 16 against B-subtype and C-subtype clinical isolates were several folds lower than those of 1. The cellular uptake studies confirmed that compound 16 accumulated intracellularly after 1 h of incubation with CCRF-CEM cells and underwent intracellular hydrolysis. 5'-O-Fatty acyl derivatives of 1 showed significantly higher anti-HIV activity than the corresponding physical mixtures against the B-subtype virus.     

Synthesis and aldose reductase inhibitory activity of pyridazine derivatives possessing acetic acid group.

N-acetic acid and S-acetic acid derivatives of 5-arylidene pyridazines were synthesized for evaluation as new aldose reductase inhibitors. Intrinsic activity for each compound was assessed by measuring inhibition of enzymatic activity in an isolated pig lens enzyme preparation. All prepared compounds exhibited a significant in vitro aldose reductase inhibitory effect (10(-5) M less than or equal IC50 less than or equal to 10(-4) M). It was found that lipophilicity was important in increasing activity. Furthermore, this activity (log 1/IC50) could be correlated directly to a lipophilic parameter (log kw) for the whole data set.     

N‐Benzylsalicylthioamides: Highly Active Potential Antituberculotics

A gseries of 29 new derivatives of N‐benzylsalicylthioamides was synthesized and the compounds were tested for in‐vitro antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii, and Mycobacterium avium. The activity was analyzed by quantitative structure‐activity relationship (QSAR). Activity increased with increasing lipophilicity and electron donating effect of the substituents in the acyl moiety and decreased with the electrophilic superdelocalizability of the molecules. The most active compounds are more active than isoniazid (INH) and are active against INH‐resistant potential pathogenic strains of mycobacterium.     

Optimization of the Schiff bases of N-hydroxy-N'-aminoguanidine as anticancer and antiviral agents

Hydroxyurea, hydroxyguanidine, and some thiosemicarbazones have been shown to have anticancer and antiviral activities. One of their possible sites of action is the enzyme ribonucleotide reductase (RR). Combination of the structural features of these compounds led to the design and synthesis of the Schiff bases of N-hydroxy-N'-aminoguanidine. Synthesis and structure-activity studies of some of these compounds point to increased size and lipophilicity as important factors for activity. To optimize the activities of this series of compounds, 13 derivatives of high lipophilicity and molecular size have been synthesized and their biological activities studied. The most active anticancer compounds against L1210 in vitro (compounds 9 and 12) are about 7 times more active than hydroxyguanidine and hydroxyurea. The most active antiviral compounds against Rous sarcoma virus transformation of chick fibroblasts in vitro (7, 9) are about 40 times more active than hydroxyguanidine. One of the compounds (4) shows promising activity in vivo (% T/C = 140 against P388 leukemia in mice) and is undergoing further studies by the National Cancer Institute (NCI). Studies of the inhibition of transformation of chick embryo cells by Rous sarcoma virus show that all these compounds inhibit transformation while some compounds inhibit viral replication as well.     

Antibacterial properties of 5-substituted derivatives of rhodanine-3-carboxyalkyl acids. Part II

Two series of rhodanine-3-acetic and rhodanine-3-propionic acids derivatives having benzylidene and cinnamylidene substituents with additional electron donating and withdrawing groups at the C-5 position, were synthesised. The structures of the obtained derivatives were confirmed by spectroscopic methods and their lipophilicity was screened. The crystal structures were determined for selected compounds. The antibacterial activity of the derivatives was depended on the type of carboxyalkyl group in the N-3 position and on the type of the substituent in the C-5 position. The derivatives of rhodanine-3-propionic acid demonstrated the highest activity against Gram-positive bacteria. However, none of tested derivatives showed activity against Gram-negative bacteria and yeast. We believe that the presence of the N,N-diethylamine group in the aromatic system and the number of carbon atoms in the carboxyalkyl group is more significant for the biological activity than the fact that the benzylidene or cinnamylidene substituent was present at the C-5 position.