N-methyl-D-aspartate receptors in the retina: 3-[(+/-)-2-carboxypiperazin- 4-yl]-propyl-1-phosphonic acid (CPP) binding studies.

3-[(RS)-2-Carboxypiperazin-4-yl]-propyl-1-phosphonic acid (CPP) has been known for some years as one of the most selective antagonists at the N-methyl-D-aspartate (NMDA) receptor in the brain. The characteristics of the binding of [3H]CPP to chick retinal membranes were studied from the biochemical and pharmacological point of view. Magnesium induced a dose-dependent increase in the binding of [3H]CPP (EC50 = 4 microM). In the absence of this ion, a single population of receptors was found (KB = 431 nM; Bmax = 9.5 pmol/mg protein), which was not modified by the addition of 1 mM MgCl2. An additional, high affinity site (KB = 59 nM; Bmax = 2.2 pmol/mg protein) became evident in the latter condition. Saturation curves of the binding of [3H]CPP, using 1 mM AMPA [(RS)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate] or L-aspartate, as displacers in the presence of Mg2+, showed a KB = 200 and 395 nM, respectively. The relative potency of some analogues of excitatory amino acids, for displacing bound CPP in the absence of Mg2+, was AMPA = APH greater than L-glutamate = CPP; Mg2+ significantly increased the potency of AMPA, APH and L-glutamate. These results showed that CPP bound to high affinity (Mg(2+)-dependent) and low affinity sites and that AMPA and L-aspartate compete with this compound only at the low affinity sites. These findings suggest that either the binding of CPP in the retina shows different properties from those described in the brain or alternatively, that AMPA is not as specific for the quisqualate receptor in this organ.     

Synthesis and pharmacological activity of 6-[(E)-2-(2,6,6-trimethyl-1-cyclohexen-1-yl)ethen-1-yl]- and 6-(1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-naphthyl)-2-naphthalenecarboxylic acids

6-[(E)-2-(2,6,6-Trimethyl-1-cyclohexen-1-yl)ethen-1-yl]- and 6-(1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-6-naphthyl)-2-naphthalenecarboxylic acids (4 and 8) have been synthesized and show significant activity in reversing the keratinization process in hamster tracheal organ culture and in inhibiting the induction of ornithine decarboxylase in mouse skin by 12-O-tetradecanoylphorbol-13-acetate, two assays used to measure retinoid activity. The 2-naphthalenecarboxylic acid 8 was more active than 4.     

1-(7-Chloroquinolin-4-yl)-2-[(1H-pyrrol-2-yl)methylene]hydrazine: a potent compound against cancer

Heteroaromatic derivatives (3a–f) have been synthesized and evaluated for their activity against four cancer cell lines. Among the studied compounds, 1-(7-Chloroquinolin-4-yl)-2-[(1H-pyrrol-2-yl)methylene]hydrazine (3e) exhibited an excellent cytotoxic activity against the referred lines, and especially on melanoma cells (MDAMB-435). In this case, compound 3e is four times more active than the standard substance Doxorubicin. Together with other results from our group, 7-chloro-4-quinolinylhydrazones derived from chloroquine could be considered a relevant finding toward the rational design of new leads for antitumor compounds.     

1-(1H-1,2,4-三唑-1-基)-(2,4-二氟苯基)-3-取代-2-丙醇类化合物的合成及其抗真菌活性

目的研究不同取代哌啶和环仲胺侧链的引入对三唑醇类化合物抗真菌活性的影响。方法以氟康唑为先导化合物,设计合成了9个三唑醇类新化合物,化合物的结构均通过核磁、红外光谱确证;选择8种真菌为实验菌株,根据美国国家临床实验室标准委员会(NCCLS)推荐的标准化抗真菌敏感性实验方法,进行体外抑菌活性测试。结果目标化合物对8种真菌特别是深部真菌均有一定的抑制作用,其中化合物4、5对白色念珠菌的MIC80值小于或等于0.125μg.mL-1,是氟康唑活性的4倍以上,与伊曲康唑活性相当。结论立体化学因素的改变对该类化合物体外抑菌活性有较大影响。     

Discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (TAK-385) as a potent, orally active, non-peptide antagonist of the human gonadotropin-releasing hormone receptor

We previously discovered an orally active human gonadotropin-releasing hormone (GnRH) receptor antagonist, thieno[2,3-d]pyrimidine-2,4-dione derivative 1 (sufugolix). To reduce the cytochrome P450 (CYP) inhibitory activity and improve in vivo GnRH antagonistic activity, further optimization of this scaffold was carried out. We focused our synthetic efforts on chemical modification at the 5 and 3 positions of the thieno[2,3-d]pyrimidine-2,4-dione ring based on computational modeling, which resulted in the discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (16b) as a highly potent and orally active GnRH antagonist. Compound 16b showed potent in vitro GnRH antagonistic activity in the presence of fetal bovine serum (FBS) without CYP inhibition. Oral administration of 16b maintained the suppressive effect of the plasma luteinizing hormone levels in castrated cynomolgus monkeys at a 3 mg/kg dose for more than 24 h. Compound 16b is currently under clinical development with the code name of TAK-385.     

Synthesis and structure-activity relationships of 5-amino-6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methylquinolonecarboxylic acid antibacterials having fluorinated 7-[(3R)-3-(1-aminocyclopropan-1-yl)pyrrolidin-1-yl] substituents

A series of novel 5-amino-6-fluoro-1-[(1R,2S)-2-fluorocyclopropan-1-yl]-8-methylquinolones bearing fluorinated (3R)-3-(1-aminocyclopropan-1-yl)pyrrolidin-1-yl substituents at the C-7 position (2-4) was synthesized to obtain potent drugs for infections caused by Gram-positive pathogens, which include resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), and vancomycin-resistant enterococci (VRE). These fluorinated compounds 2-4 exhibited potent antibacterial activity comparable with that of a compound bearing a non-fluorinated (3R)-3-(1-aminocyclopropan-1-yl)pyrrolidine moiety at the C-7 position (1) and had at least 4 times more potent activity against representative Gram-positive bacteria than ciprofloxacin (CPFX), gatifloxacin (GFLX), or moxifloxacin (MFLX). Among them, the 7-[(3S,4R)-4-(1-aminocyclopropan-1-yl)-3-fluoropyrrolidin-1-yl] derivative 3 (=DQ-113), which showed favorable profiles in preliminary toxicological and nonclinical pharmcokinetic studies, exhibited potent antibacterial activity against clinically isolated resistant Gram-positive pathogens.     

叔丁基三唑醇类衍生物的合成及其抗真菌活性

目的设计合成具有叔丁基结构的三唑醇类化合物并研究其体外抗真菌活性。方法以一氯频那酮、三氮唑为原料,经多步反应合成目标化合物,化合物结构经IR、^1H-NMR谱确证;选择8种真菌为实验菌株,按国际标准抗真菌敏感性实验方法测定其体外抗真菌活性。结果设计合成了10个新化合物,所有化合物对8种真菌均有一定的抑制活性。结论立体化学因素对该类化合物的体外抑菌活性有较大影响。     

叔丁基三唑衍生物的合成及抗真菌活性研究

目的研究具有叔丁基结构的三唑醇类化合物的抗真菌活性以及各种4-(4-烷氧基苯基)哌嗪侧链的引入对抗真菌活性的影响.方法以一氯频那酮、三氮唑为原料,经多步反应合成目标化合物,化合物结构经IR、1H-NMR谱确证;选择8种真菌为实验菌株,按国际标准抗真菌敏感性实验方法测定其体外抗真菌活性.结果设计合成了10个新化合物.10个目标化合物对8种真菌均具有一定的抑制活性,其中,有4个化合物对白色念珠菌的MIC80值小于或等于0.125 mg·L-1,是氟康唑的4倍以上,与伊曲康唑相当.结论可以通过引入更多的疏水基团设计三唑醇类化合物,立体化学因素对该类化合物的体外抑菌活性有较大影响.     

Design, synthesis, and QSAR study of novel 2-(2,3-dioxo-2,3-dihydro-1H-indol-1-yl)-N-phenylacetamide derivatives as cytotoxic agents

This study deals with the synthesis of novel 2-(2,3-dioxo-2,3-dihydro-1H-indol-1-yl)-N-phenylacetamide derivatives (6a–j) from isatin (3) and 5,7-dibromoisatin (4). All newly synthesized compounds were characterized using IR, ¹H NMR, MS, and elemental analysis followed by evaluation of their cytotoxic activity by XTT assay on breast cancer cell line MCF-7 and non-cancer African green monkey cell line VERO. Correlation study for QSAR and in vitro assay was performed. The outcomes indicated that electron withdrawing substitutions at para position of phenyl ring and 5, 7 positions of isatin ring and increasing lipophilicity of the compound increased the cytotoxic activity. The 2-(5,7-dibromo-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)-N-(4-nitrophenyl)acetamide (6b) was found to be the most active compound in the series and demonstrated higher selectivity toward MCF-7 cell line. The IC₅₀ values were 1.96 and 1.90 μM for test compound (6b) and vinblastin (reference drug), respectively. This indicates compound (6b) may possess equipotent cytotoxic activity to vinblastine. The compound (6b) is particularly promising, since it could kill cancer cells 19–20 times more effectively than the non-cancer cells. This property of (6b) may enable us to effectively control tumors with low side effects. Hence, we propose that 2-(5,7-dibromo-2,3-dioxo-2,3-dihydro-1H- indol-1-yl)-N-(4-nitrophenyl)acetamide may be used as lead for further development.     

1-(1H-1,2,4-三唑-1-基)-2-(2,4-二氟苯基)-3-[(4-取代)-哌嗪-1-基]-2-丙醇的合成及其抗真菌活性

目的研究不同取代哌嗪侧链的引入对三唑醇类化合物抗真菌活性的影响.方法设计合成了13个三唑醇类新化合物;选择8种真菌为实验菌株,进行体外抑菌活性测试.结果目标化合物对8种真菌特别是深部真菌均有一定的抑制活性,其中有8个化合物对白色念珠菌的MIC80值小于或等于0.125μg/mL,是氟康唑活性的4倍以上,与酮康唑活性相当.结论脂水分配系数和立体化学因素的改变对该类化合物体外抑菌活性有较大影响.     

1-(1H-1,2,4-三唑-1-基)-2-叔丁基-3-[(4-取代苄基)-哌嗪-1-基]-2-丙醇的合成及其抗真菌活性的研究

目的研究具有叔丁基结构的三唑醇类化合物的抗真菌活性以及各种4-（取代苄基）哌嗪侧链的引入对该类化合物抗真菌活性的影响。方法设计合成了13个未见文献报道的目标化合物，所有化合物结构均经^1H-NMR谱确证，部分经过IR、MS确证；选择8种真菌为实验菌株，测定其体外抗真菌活性。结果所有化合物对8种真菌均有一定的抑制作用。其中，Ⅲ7的抑菌活性优于氟康唑。结论引入叔丁基和哌嗪侧链设计的目标化合物都具有抗真菌活性，侧链取代基的电性效应和立体化学特征的改变对该类化合物的抑菌活性有一定的影响。     

The autoradiographic studies on the distribution of 14C-labelled sodium 7-[D(-)-alpha-(4-ethyl-2, 3-dioxo-1-piperazinecarboxamido)-alpha-(4-hydroxyphenyl)-acetamido]-3-[(1-methyl -1 H-tetrazol-5-yl) thiomethyl]-3-cephem-4-carboxylate (14C-cefoperazone) in rats and mice

The distribution of cefoperazone (CPZ), a new semisynthetic cephalosporin antibiotic, was studied by macroautoradiography following a single intravenous or subcutaneous administration of 100 mg/kg 14C-CPZ to rats, mice, pregnant mice and experimental pyelonephritic mice. (1) In whole body autoradiograms of rats administered subcutaneously and mice administered subcutaneously and intravenously, their distribution patterns of the radioactivity were found to be similar to each case. The radioactivity was distributed at high concentration in liver, kidney, lung, tongue, salivary gland, skin, gastrointestinal tracts and retina. The radioactivity was rapidly excreted in urine and bile. And it was observed that the radioactivity excreted through bile was not reabsorbed from gastrointestinal tracts. (2) In pregnant mice administered intravenously, the radioactivity was observed the same level as whole blood level in placenta, while was hardly observed in fetuses. (3) In the experimental pyelonephritic mice administered intravenously, a considerable radioactivity was concentrated on the acute inflammatory area.     

Anti-HIV-1 screening of (2E)-3-(2-chloro-6-methyl/methoxyquinolin-3-yl)-1-(aryl)prop-2-en-1-ones

Biological studies of two series of 38 quinolinyl chalcones (4a–s and 5a–s) were investigated for their in vitro anti-HIV-1 and cytotoxic activities. Out of 38 compounds, seventeen compounds were observed as good anti-HIV-1 agents with EC₅₀ values less than 20 μM. Compounds 4a, 4l, 4o, 5e, 5h, 5l, 5o, and 5r displayed potent anti-HIV-1 activity with EC₅₀ values less than 5 μM. Among these, compound 5h emerged as the best anti-HIV-1 agent (EC₅₀ = 1.1 μM). Compounds 4d, 4n, 4q, 4r, 4s, 5n, and 5r showed no toxicity in human lymphocytes. Bioassay results show that the type(s) and position(s) of the substituents seem to be critical for their cytotoxic and anti-HIV-1 activities. These results could be useful in the invention of new anti-HIV agents through structural modification.     

Synthesis of new 1-(amino)-3-[(1,5-diphenyl-1H-1,2,4-triazol-3-yl) oxy] propan-2-ol and 1-[(1,5-diphenyl- 1H- 1,2,4-triazol-3-yl) oxy]-3-(4-arylpiperazin-1-yl) propan-2-ol derivatives with an expected beta-adrenolytic activity

3-(Oxiran-2-ylmethoxy)-l ,5-diphenyl-lH-1,2,4-triazole [I] was obtained in the reaction of 1,5-di-phenyl-IH-1,2,4-triazol-3-ol with 2-(chloromethyl) oxirane. Then I was converted into the corresponding aminoalkanol derivatives of 1,5-diphenyl-IH-1,2,4-triazol-3-ol, IIa,b -VIIa,b. Molecular structure of I was confirmed by an X- ray structure analysis. The receptor affinities for IVa, VIIa were determined.     

Structural features of the glutamate binding site in recombinant NR1/NR2A N-methyl-D-aspartate receptors determined by site-directed mutagenesis and molecular modeling

We have used site-directed mutagenesis of amino acids located within the S1 and S2 ligand binding domains of the NR2A N-methyl-D-aspartate (NMDA) receptor subunit to explore the nature of ligand binding. Wild-type or mutated NR1/NR2A NMDA receptors were expressed in Xenopus laevis oocytes and studied using two electrode voltage clamp. We investigated the effects of mutations in the S1 and S2 regions on the potencies of the agonists L-glutamate, L-aspartate, (R,S)-tetrazol-5yl-glycine, and NMDA. Mutation of each of the corresponding residues found in the NR2A receptor subunit, suggested to be contact residues in the GluR2 alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit, caused a rightward shift in the concentration-response curve for each agonist examined. None of the mutations examined altered the efficacy of glutamate as assessed by methanethiosulfonate ethylammonium potentiation of agonist-evoked currents. In addition, none of the mutations altered the potency of glycine. Homology modeling and molecular dynamics were used to evaluate molecular details of ligand binding of both wild-type and mutant receptors, as well as to explore potential explanations for agonist selectivity between glutamate receptor subtypes. The modeling studies support our interpretation of the mutagenesis data and indicate a similar binding strategy for L-glutamate and NMDA when they occupy the binding site in NMDA receptors, as has been proposed for glutamate binding to the GluR2 AMPA receptor subunit. Furthermore, we offer an explanation as to why "charge conserving" mutations of two residues in the binding pocket result in nonfunctional receptor channels and suggest a contributing molecular determinant for why NMDA is not an agonist at AMPA receptors.     

Improved synthesis of an ester-type prodrug, 1-acetoxyethyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-[(Z)-1- propenyl]-3-cephem-4-carboxylate (BMY-28271)

1-Acetoxyethyl 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3- [(Z)-1-propenyl]-3-cephem-4-carboxylate (BMY-28271) is an ester-type prodrug of cephalosporin for oral use. Methods suitable for large scale preparation were investigated. The yield was improved by esterification of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-trityloxyiminoacetamido]cep hem-4-carboxylic acid (11) followed by removal of the trityl group and, in addition, column chromatographic purification at each step was eliminated by optimization of the reaction conditions.     

4-[[1-[(4-氟苯基)甲基]-1H-2-苯并咪唑基]氨基]-1-哌啶甲酸乙酯的合成

以邻苯二胺为起始原料，经过缩合、氯代、烷基化和取代反应来合成4-[[1-[（4-氟苯基）甲基]-1H-2-苯并咪唑基]氨基]-1-哌啶甲酸乙酯。该合成方法操作简单，总收率达到30．7％。     

Verbindungen mit potentiell positiv inotroper Wirkung, 2. Mitt. Synthese von 3,4-Dihydro-2-[(3-oxo-1-cyclopenten-1-yl)amino]-1(2H)-phenanthron und 3-(1,2,3,4-Tetrahydro-1-hydroxy-2-phenanthrylamino)-2-cyclopentenon

Compounds with Potentially Positive Inotropic Activity, II: Synthesis of 3,4-Dihydro-2-[(3-oxo-1-cyclopenten-1-yl)amino]-1(2H)-phenanthrone and 3-(1,2,3,4-Tetrahydro-1-hydroxy-2-phenanthrylamino)-2-cyclopentenone The synthesis of the title compounds from 1,3-cyclopentanedione and 2-amino-3,4-dihydro-1(2H)-phenanthrone and 2-amino-1,2,3,4-tetrahydro-1-phenanthrole is described.