Synthesis,cytotoxic activity,and 2D‐ and 3D‐QSAR studies of 19‐carboxyl‐modified novel isosteviol derivatives as potential anticancer agents

Two series of novel acylthiosemicarbazide and oxadiazole fused‐isosteviol derivatives were synthesized based on the 19‐carboxyl modification. The target compounds were evaluated for their cytotoxicities against three cancer cell lines (HCT‐116, HGC‐27, and JEKO‐1) using an MTT assay. Lead compounds from the acylthiosemicarbazides ( 4 ) showed IC₅₀ values in the lower micromolar range. For example, compounds ( 4i , 4l , 4m , 4r, and 4s ) exhibited significant inhibitory activities against the three cell lines with IC₅₀ values of 0.95–3.36 μm . Furthermore, 2D‐HQSAR and 3D‐topomer CoMFA analyses were established, which could be used to develop second generation of isosteviol derivatives as anticancer agents.     

In vitro metabolic stability and biotransformation of isosteviol in human and rat liver fractions

Isosteviol is a lead compound whose cardioprotective property has been partly explained by its regulation of ion channels and interference with signalling pathways in the metabolism of some fatty acids. This study determined the metabolic stability of isosteviol in human liver microsomes and H9c2 cell line, and the identity of its metabolites in human and rat liver fractions. Isosteviol was largely unmetabolized in H9c2 cells and in NADPH-only supplemented human liver fractions, suggesting a very limited contribution of phase I biotransformation to its hepatic clearance. The in vitro half-life of isosteviol in UDPGA-only supplemented medium was observed to be 24.9 min with an estimated intrinsic clearance of 0.349 mL/min/kg in man. Analysis by LC-MS/MS and Q-tof showed that isosteviol is mainly metabolised to its acyl-β-D-glucuronide in humans and rats. Mono-hydroxy-isosteviol and dihydroisosteviol were also identified. Rat liver fraction, however, generated dihydroxy-isosteviol in addition to two mono-hydroxy derivatives. Further studies confirmed that dihydroisosteviol is subsequently biotransformed to its acyl-β-D-glucuronide in man and rat. These findings suggest that future studies of the efficacy and toxicity of isosteviol might have to consider xenobiotics that alter the glucuronidation pathways significantly in man.     

Synthesis and antituberculous activity of 9-aminoacridine azomethines

Condensation of 9-aminoacridine with p-substituted aromatic aldehydes led to the synthesis of the corresponding azomethines at yields of 60–78%. 9-Aminoacridine azomethines were found to have in vitro antituberculous activity against Mycobacterium tuberculosis H₃₇R_v at a concentration of 6.25 μg/ml. Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 42, No. 10, pp. 27–28, October, 2008.     

The effects of isosteviol against myocardium injury induced by ischaemia-reperfusion in the isolated guinea pig heart

1. This study aimed to investigate the protective effects of isosteviol against myocardial ischaemia-reperfusion (IR) injury and its effects on mitochondrial adenosine triphosphate (ATP)-sensitive potassium channel (mitoK(ATP)) activity in vitro. 2. Groups of eight guinea pigs were treated as follows: constant perfusion control (PC), IR control, ischaemic preconditioning (IPC) + IR, isosteviol (50, 250 or 500 nmol) + IR, 5-hydroxydecanoate acid (5-HD) (5 micromol) + isosteviol (500 nmol) + IR. The guinea pig heart was isolated and perfused in Langendorff mode with modified Tyrode solution at a flow rate of 10 mL/min. Ischaemia was introduced for 30 min followed by reperfusion for 20 min. Cardiac function, coronary arterial flow rate, lactate dehydrogenase (LDH) and creatine kinase (CK) activities in the perfusate were measured prior to ischaemia and at the end of reperfusion. 3. There were no significant (P > 0.05) changes in cardiac function or markers of cell damage (i.e. activities of LDH and CK) in the PC group. In contrast, cardiac function was adversely affected in the IR group, with significant (P < 0.05) decreases in left ventricular developing pressure (LVDevP), dP/dt(max) and dP/dt(min) compared with baseline and the PC group. In addition, there were increases in activity of LDH (20%) and CK (67%) compared with baseline and the PC group. 4. Ischaemic preconditioning and pretreatment with isosteviol, at all dose levels, resulted in a significant (P < 0.05) attenuation of IR injury. Lactate dehydrogenase and CK activities were not significantly (P < 0.05) different compared with baseline. Isosteviol did not increase coronary flow, suggesting that the protective effect of isosteviol on the myocardium was not mediated by dilation of the coronary blood vessels. 5. Pretreatment with the mitoK(ATP) blocker 5-HD partially antagonized the effects of 500 nmol isosteviol, with a statistically significant attenuation of its protective effects on HR, LVDevP, dP/dt(max) and dP/dt(min) compared with isosteviol alone pretreatment. 6. The IR injury on the Langendorff perfused guinea pig heart was alleviated by isosteviol, which appears to mediate its effects through mitoK(ATP) channels. Future research might aim to investigate the interaction of isosteviol with mitoK(ATP) channels in order to clarify its mechanism of action.     

Design,synthesis and cytotoxic evaluation of nitric oxide‐releasing derivatives of isosteviol

Twenty‐six novel isosteviol derivatives coupled with two types of nitric oxide (NO) donors (furoxans and NONOates) were synthesized and screened for cytotoxic activities against four human cancer cell lines with sunitinib as the positive control. The results showed that seven furoxan‐based derivatives ( 8a , 8b , 8c , 8d , 8e , 9e , and 9f ) exhibited desirable cytotoxic activities, while NONOate‐based derivatives displayed poor potency because of unstability. Compared with sunitinib, compounds 8a and 8e were more active on all tested cell lines, especially in HCT116 ( 8a , IC₅₀ = 0.48 ± 0.02 μm ; 8e , IC₅₀ = 0.94 ± 0.01 μm ); compounds 8b and 8d were more potent on HCT116 (IC₅₀ = 3.39 ± 0.06 and 3.29 ± 0.03 μm ), HepG2 (IC₅₀ = 1.05 ± 0.03 and 5.37 ± 0.08 μm ), and SW620 (IC₅₀ = 1.33 ± 0.02 and 4.11 ± 0.05 μm ) cell lines, and 8c exhibited higher activities on HepG2 cells with an IC₅₀ = 4.76 ± 0.14 μm . NO‐releasing experiment of compounds 8a – e , 17a , 18a , 19a , and 21a reminded us that NO‐releasing amount of this series of isosteviol derivatives positively correlates with their cytotoxic activities.     

异甜菊醇抗豚鼠离体心脏缺氧复灌损伤作用

目的　拟证实双萜类化合物异甜菊醇抗豚鼠离体心脏缺氧复灌损伤作用及与线粒体ATP敏感性钾通道 (mito KATP)的关系。方法　Langendorff装置逆向心脏灌注。预先灌注异甜菊醇 1,5和 10μmol·L- 1,5min ,流速约为 9.5mL·min- 1,全心停灌 30min ,复灌 2 0min ,观察心脏舒缩功能、冠脉流出液酶学和心肌组织学改变。结果异甜菊醇预处理有效减轻缺氧复灌引起的左室舒缩功能下降 ,降低冠脉流出液中乳酸脱氢酶和肌酸激酶浓度 ;延迟停灌后心脏出现挛缩的时间。mito KATP关闭剂 5 羟基癸酸 10 0 μmol·L- 1可部分逆转异甜菊醇 10 μmol·L- 1的心肌保护作用。光学和电子显微镜观察结果表明 ,异甜菊醇预处理可减轻缺氧复灌引起的心肌纤维和线粒体损伤。结论　异甜菊醇 1～ 10 μmol·L- 1预灌注可有效减轻豚鼠离体心肌缺氧复灌引起的损伤 ,该作用可能与mito KATP的开放有关。     

甜菊苷及其衍生物的生物活性研究进展

甜菊苷是一种常用天然甜味剂,属于四环二萜糖苷类。药理学研究表明,甜菊苷及其水解产物甜菊醇、异甜菊醇和甜菊双糖苷等具有降血糖、降血压、抗炎、抗肿瘤、止泻、抗菌和免疫调节等多种生物活性。综述甜菊苷、甜菊醇、异甜菊醇、甜菊双糖苷及相关衍生物的生物活性研究进展。     

Synthesis and Biological Evaluation of Novel FtsZ‐targeted 3‐arylalkoxy‐2,6‐difluorobenzamides as Potential Antimicrobial Agents

Novel series of 3‐O‐arylalkylbenzamide and 3‐O‐arylalkyl‐2,6‐difluorobenzamide derivatives were synthesized and evaluated for their on‐target activity and antibacterial activity. The results indicated that the 3‐O‐arylalkyl‐2,6‐difluorobenzamide derivatives possessed much better on‐target activity and antibacterial activity than the 3‐O‐arylalkylbenzamide derivatives. Among them, 3‐O‐chlorobenzyl derivative 36 was the most effective in antibacterial activity (0.5, 4, and 8 μg/mL) against Bacillus subtilis ATCC9372, methicillin‐resistant Staphylococcus aureus ATCC29213, and penicillin‐resistant Staphylococcus aureus PR, while 3‐O‐methylbenzyl derivative 41 only exhibited the most potent activity (2 μg/mL) against Staphylococcus aureus ATCC25923.     

Synthesis and Antibacterial Activity of Novel 4″‐O‐Carbamoyl Erythromycin‐A Derivatives

Novel 4″‐O‐carbamoyl erythromycin‐A derivatives were designed, synthesized, and evaluated for their in‐vitro antibacterial activities. All of the 4″‐O‐carbamoyl derivatives showed excellent activity against erythromycin‐susceptible Staphylococcus aureus ATCC25923, Streptococcus pyogenes, and Streptococcus pneumoniae ATCC49619. Most of the 4″‐O‐arylalkylcarbamoyl derivatives displayed potent activity against erythromycin‐resistant S. pneumoniae encoded by the mef gene and greatly improved activity against erythromycin‐resistant S. pneumoniae encoded by the erm gene or the erm and mef genes. In particular, the 4″‐O‐arylalkyl derivatives 4c–4e and 4g were found to possess the most potent activity against all the tested erythromycin‐susceptible strains, which were comparable to those of erythromycin, clarithromycin, or azithromycin. 4″‐O‐Arylalkyl derivatives 4e and 4g were the most effective against erythromycin‐resistant S. pneumoniae encoded by the mef gene (0.25 and 0.25 µg/mL). 4″‐O‐Arylalkyl derivatives 4a and 4b exhibited significantly improved activity against erythromycin‐resistant S. pneumoniae encoded by the erm gene. In contrast, the 4″‐O‐alkylcarbamoyl derivatives hardly showed improved activity against all the tested erythromycin‐resistant strains.     

Evaluation of New Indole and Bromoindole Derivatives as pp60c‐Src Tyrosine Kinase Inhibitors

A series of N‐benzyl‐indole‐3‐imine‐, amine derivatives and their 5‐bromo congeners were synthesized and their biological activity were evaluated against the pp60^c‐Src tyrosine kinase target. To afford the imine derivatives, aldehydes were reacted with substituted benzylamines and the corresponding amine derivatives were obtained by NaBH₄ reduction of these imines. Except insoluble N‐benzyl‐indole‐3‐imine derivatives, all the derivatives showed some activity against the kinase target. Screening of these compounds for their biological activity revealed that among N‐benzyl‐indole derivatives, those bearing 5‐bromo substitution have the enhanced potency, where the amine derivatives were more active than imines.     

Synthesis and antimicrobial and antifungal activity of derivatives of the diterpenoid isosteviol and the glycoside steviolbioside containing onium nitrogen atoms

Previously unknown derivatives of the diterpenoid isosteviol and the glycoside steviobioside containing onium nitrogen atoms were synthesized. The antimicrobial and antifungal activities of these compounds were studied.     

Synthesis and Antimicrobial Activity of Some New Quinazolin-4(3H)-one Derivatives

A new series of 6-iodo-2-phenylquinazolin-4(3H)-one derivatives was prepared and screened for antimicrobial activity. The thioureide derivatives 4–6, the carbohydrazide derivatives 19–21 and 24 displayed excellent broad-spectrum antimicrobial activity. Some compounds showed moderate activity against Candida albicans and Pseudomonas aeruginosa. None of the tested compounds was as active as the reference standard drugs ampicillin and clotrimazole. The detailed synthesis, antimicrobial activity, and the minimum inhibitory concentrations (MIC) are reported.     

Synthesis of 1,2,5(6)-Trisubstituted Benzimidazoles and Evaluation of Their Antimicrobial Activities

A series of 22 benzimidazoles, having several substituents on the azole and benzene nuclei, were prepared and evaluated in vitro for antimicrobial activity. At first 2-chloro or 2-chloromethyl-5(6)-substituted-1H-benzimidazoles were synthesized, which were then substituted at C-2 with several piperazine or piperidine derivatives. The antibacterial activity of these compounds against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa, and the antifungal activity against Candida albicans, Candida stellatoidea, Candida parapsilosis, and Candida pseudotropicalis were determined as the MIC values. Since compound 12 exhibits good activity, in order to clarify the effect of substituents at C-1 on the activity, benzimidazole derivatives having ethyl, allyl, benzyl, and p-fluorobenzyl substituents at C-1 were prepared, and slightly increased activity was seen.     

丹参新酮C环酚酯衍生物的设计合成及抗肿瘤活性研究

目的：通过对丹参新酮C环邻醌位点的结构修饰,改变其脂水分配系数(CLogP),获得系列丹参新酮酚酯衍生物,进而评价其抗肿瘤活性。方法：采用氢化还原、酰化、脱保护基等方法对丹参新酮的邻醌位点进行修饰,通过引入不同酸酐、氨基酸取代基,得到丹参新酮C环酚酯衍生物,在此基础上以前列腺癌Lncap和Du145细胞株对部分化合物进行抗肿瘤活性评价。结果：共合成了9个新的丹参新酮酚酯衍生物,其中1个化合物表现出较好的抗肿瘤活性。结论：脂水分配系数的改变对丹参新酮衍生物抗肿瘤活性影响很大,适当提高水溶性,有助于增强其抗肿瘤活性,改善成药性。     

Relationships Between the Chemical Structure of Antimycobacterial Substances and Their Activity Against Atypical Strains. Part 14: 3-Aryl-6,8-dihalogeno-2H-1,3-benzoxazine-2,4(3H)-diones

A set of eight derivatives of 6,8-dichloro-3-phenyl-2H-benzoxazine-2,4(3H)-dione and nine derivatives of 6,8-dibromo-3-phenyl-2H-1,3-benzoxazine-2,4(3H)-dione, substituted on the phenyl ring, was prepared by the reaction of the corresponding salicylanilides with ethyl chloroformate. The compounds were evaluated in vitro for antimycobacterial activity against Mycobacterium tuberculosis, Mycobacterium kansasii, and Mycobacterium avium. Their activity increases with increasing hydrophobicity and electron-withdrawing ability of the substituents on the phenyl ring.     

Synthesis and Antimycobacterial Activity of Novel Thiadiazolylhydrazones of 1‐Substituted Indole‐3‐carboxaldehydes

A series of novel thiocarbohydrazones of substituted indoles and their corresponding thiadiazole derivatives were prepared, and their structures were confirmed by different analytical and spectroscopic methods. The derivatives were prepared by a sequential synthetic strategy including substitution at N‐1 position of indole ring by various aliphatic and benzylic substituents, followed by condensation with thiocarbohydrazide, and finally cyclization by triethyl orthoformate. The derivatives were tested for their antimycobacterial activity against Mycobacterium bovis BCG, and the results revealed that among the synthesized compounds, thiadiazole derivatives 4e , 4f , 4n , 4p , 4q , and 4t exhibited the highest activity with IC₅₀ value of 3.91 μg/mL. The results indicate that the thiadiazole moiety plays a vital role in exerting antimycobacterial activity.     

In vitro Antiviral Effects and 3D QSAR Study of Resveratrol Derivatives as Potent Inhibitors of Influenza H1N1 Neuraminidase

The anti-influenza virus activities of 50 resveratrol (RV: 3, 5, 4′-trihydroxy-trans-stilbene) derivatives were evaluated using a neuraminidase (NA) activity assay. The results showed that 35 compounds exerted an inhibitory effect on the NA activity of the influenza virus strain A/PR/8/34 (H1N1) with 50% inhibitory concentration (IC₅₀) values ranging from 3.56 to 186.1 μm . Next, the 35 RV derivatives were used to develop 3D quantitative structure–activity relationship (3D QSAR) models for understanding the chemical–biological interactions governing their activities against NA. The comparative molecular field analysis (CoMFA r² = 0.973, q² = 0.620, q_test² = 0.661) and the comparative molecular similarity indices analysis (CoMSIA r² = 0.956, q² = 0.610, q_test² = 0.531) were applied. Afterward, molecular docking was performed to study the molecular interactions between the RV derivatives and NA. Finally, a cytopathic effect (CPE) reduction assay was used to evaluate the antiviral effects of the RV derivatives in vitro. Time-of-addition studies demonstrated that the RV derivatives might have a direct effect on viral particle infectivity. Our results indicate that the RV derivatives are potentially useful antiviral compounds for new drug design and development for influenza treatment.     

Novel Pirfenidone Analogs as Antifibrotic Agents: Synthesis and Antifibrotic Evaluation of 2-Pyridones and Fused Pyridones

A new series of substituted 1-(2-ethylphenyl)-2-oxo-1,2-dihydropyridine-3-carbonitriles have been synthesized. Moreover, substituted bicyclic derivatives e.g. thieno[3,4-c]pyridone, pyrido[3,4-c]pyridone, benzo[c]pyridone, and tricyclic derivatives, chromeno[3,4-c]pyridones have been prepared and evaluated for their antifibrotic activity. Among the tested compounds, compounds 4d and 5a exhibited potent antifibrotic activity without harmful side effects on liver and kidney functions. Detailed synthesis, spectroscopic and biological data are reported.     

Synthesis and antimicrobial activity of mono-and biquaternized derivatives of dipyridylethanes and dipyridylethylenes

A series of mono-and biquaternized derivatives of dipyridylethanes and dipyridylethylenes has been synthesized and characterized with respect to antimicrobial activity. The new compounds exhibit structure-dependent antimicrobial action on both Gram-negative (E. coli) and Gram-positive (St. aureus) bacterial species. Monoquaternized dipyridylethane and dipyridylethylene derivatives show a higher antimicrobial activity than compounds with two onium nitrogen atoms; derivatives of dipyridylethane are less active than the analogous derivatives of dipyridylethylene. A high antimicrobial activity (MIC ∼ 1 mg/ml) was observed for 1-[N-cetyl-(4-pyridinium)]-2-(4-pyridyl)ethylene. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 40, No. 4, pp. 19–22, April, 2006.     

Novel Steroidal 1,4-Diketones and Pyridazine Derivatives as Potential Antiestrogens

A series of steroidal 1,4-diketone derivatives was synthesized by acid-catalyzed condensation of 2-acetylestradiol-17β-acetate with substituted phenylglyoxals. Conversion of the products into the corresponding pyridazine derivatives was achieved by reaction with hydrazine hydrate. The synthesized compounds were evaluated for their uterotrophic, antiuterotrophic, and antifertility activities in mature female albino rats. Among the compounds tested, the phenyl 2 , p-bromophenyl 3 , and p-methoxyphenyl 5 diketone derivatives displayed uterotrophic activity of 72%, 72%, and 91%, respectively. The gradation of antiestrogenic activity was assessed in vivo by the inhibition of the estrone-stimulated uterine growth. Compounds 2–5 showed moderate antiestrogenic activity of 53–56%. None of the tested compounds elicited antifertility activity as assessed by the post-coital antiimplantation activity test.