A novel class of inhibitors for human and rat steroid 5alpha-reductases: synthesis and biological evaluation of indoline and aniline derivatives. III

While searching for novel nonsteroidal inhibitors of human and rat prostatic 5alpha-reductases, we found a new series of indoline and aniline derivatives that showed potent inhibitory activities for both enzymes. Among them, 3-chloro-4-?[1-(4-phenoxybenzyl)indolin-5-yl]oxylbenzoic acid (2e, YM-36117) showed a more potent inhibitory activity for the human enzyme than ONO-3805 with an IC50 value of 5.3 nM and a reduced rat prostatic dihydrotestosterone (DHT) concentration by oral administration. The synthesis and the structure-activity relationships of these indoline and aniline derivatives are presented.     

Studies on cardiotonic agents. VII. Potent cardiotonic agent KF15232 with myofibrillar Ca2+ sensitizing effect

A series of novel 4,5-dihydro-5-methyl-6-(2 or 4-substituted 7-quinazolinyl)-3(2H)-pyridazinones was synthesized and examined for cardiotonic activity in anesthetized dogs. The 4-substituted aminoquinazolines generally showed potent and long-lasting inotropic activity. Fall in the activity was observed on the introduction of substituent at the 2-position of the quinazoline ring. The 3-substituted 4 (3H)-quinazolinimines generally exhibited weak activity. Ca2+ sensitizing effect of the 4-substituted amino derivatives was also examined in chemically skinned fiber from papillary muscle of guinea pig. The alkylamino derivatives exhibited small sensitizing effect, while the benzylamino derivatives exhibited large effect. Among them, KF15232 (Ix) was found to have the most potent cardiotonic and Ca2+ sensitizing activities.     

A novel class of inhibitors for human steroid 5alpha-reductase: synthesis and biological evaluation of indole derivatives. II

In a search for novel nonsteroidal inhibitors of human prostatic 5alpha-reductase, we found a new series of indole derivatives that showed potent inhibitory activities for the human enzyme. Among them, 4-[(1-benzyl-1H-indol-5-yl)oxyl-3-chlorobenzoic acid (2d, YM-32906) showed more potent inhibitory activity than finasteride with an IC50 value of 0.44 nM. 3-Chloro-4-[[1-(4-phenoxybenzyl)-1H-indol-5-yl]oxy]benzoic acid (2m) showed inhibitory activities for both human and rat prostatic 5alpha-reductase with IC50 values of 2.1 and 73 nM, respectively. The synthesis and structure-activity relationships of these indole derivatives are presented.     

Studies on antiallergic agents. I. Synthesis and antiallergic activity of novel pyrazine derivatives.

Various pyrazine derivatives were synthesized and their antiallergic activity was examined. The inhibitory activity on allergic histamine release of the compounds bearing a 5-tetrazolyl group was more potent than that of the corresponding carboxyl derivatives. The introduction of -CONH- or -NHCO- between the pyrazine ring and the 5-tetrazolyl group as a spacer greatly enhanced the activity. N-(1H-Tetrazol-5-yl)-2-pyrazinecarboxamide (I-3) was estimated to exhibit nearly the same potency as disodium cromoglycate (DSCG). The structure-activity relationship among various derivatives modified by introducing some substituents onto the 3-, 5- or 6-position of the pyrazine ring of I-3 was investigated. The activity remained unchanged or was reduced when such substituents as methyl, chloro, methoxy, methylamino and dimethylamino were introduced at the 3- or 5-position. In contrast, 6-substitution with various alkylamino groups more or less increased the activity. Among them, the 6-dimethylamino (I-17c) and 6-(1-pyrrolidinyl) (I-34) derivative were proved to be most potent. The IC50 values (concentration which produces 50% inhibition of the allergic histamine release) of I-17c and I-34 were determined to be 4.7 x 10(-10) and 4.6 x 10(-10) M, respectively. These two compounds produced a potent inhibitory activity on passive cutaneous anaphylaxis (PCA) in rat, not only by the intravenous route (ED50 = 0.0096 mg/kg for both compounds) but also by the oral route (ED50 = 0.19 and 0.18 mg/kg, respectively). On the other hand, when the pyrazine ring of some representative compounds was replaced with a pyridine ring, the inhibitory activity on histamine release was significantly reduced.     

Syntheses and Anti-cancer Activities of Derivatives of Tetrandrine and Fangchinoline

A series of derivatives of tetrandrine and fangchinoline was designed and synthesized to find more active anti-cancer compounds. Their anti-cancer activities were tested against human hcpatocellular carcinoma BEL-7402 and PLC/PRF/5 cells, human lung adenocarcinoma A549 cells as well as human leukaemia K562 cells, and the structure-activity relationship（SAR） was also studied. All the compounds except BI exhibited superior inhibitory ac- tivities against PLC/PRF/5 cells with half maximal inhibitory conccntration（ICs0） values of less than 15 μmol/L, and compounds A2, A4, B2 and B4 showed IC50 values of less than 9 pmol/L. Compounds A2, A6, B2 and B4 showed potent anti-cancer activities against all the tested cells with 1C5o values of less than 10 pmol/L. The results show that terandrine and fangchinoline derivatives are potential suppressors to human cancer.     

N-substituted hydroxyureas as urease inhibitors

In order to seek a urease inhibitor more potent than hydroxyurea (1), its alkyl- or phenyl-substituted derivatives were synthesized and evaluated for their effect on the jack bean urease. Of 16 compounds tested, m-methyl- (10) and m-methoxy-phenyl substituted hydroxyurea (13) showed the most potent inhibitory activities against the enzyme.     

哒嗪酮类新衍生物的合成及其对血小板聚集的抑制作用

6-(4-取代苯基)哒嗪酮类衍生物具有较强的抑制血小板聚集作用.设计并合成了6-(4-取代苯基)-5-甲基-4,5-二氢-3(2H)哒嗪酮类化合物.以乙酰苯胺为原料,经付-克酰化反应、氰化、水解、水合肼环化反应合成目标化合物,并参考Born方法进行体外药理实验.目标化合物通过1H NMR,MS,IR,元素分析等证实了其结构.体外药理实验表明,目标化合物对二磷酸腺苷(ADP)诱导的人血小板聚集均有较强的抑制作用.     

Synthesis and antiallergic activity of N-[4-(4-diphenylmethyl-1-piperazinyl)butyl]-1,4-dihydro-4-oxopyridine-3 - carboxamides

A new series of oxopyridinecarboxamide derivatives 3a--g and 5a were synthesized and evaluated for their antiallergic activity. 1,4-Dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxamides 3a and 5a exhibited potent antiallergic activity (inhibitory rates of 80.7 and 88.3%, respectively, at 20 mg/kg, p.o.) in the rat passive cutaneous anaphylaxis (PCA) test and also exhibited much more potent in vitro inhibitory activity than caffeic acid against the enzyme 5-lipoxygenase (5-LO). Their in vitro antihistamine activity, however, was weaker than that of ketotifen. Compounds 3a and 5a are viewed as promising candidates for antiallergic agents.     

Synthesis of 4H-benzo[a]phenoselenazin-4-ones as near-ir dyes

The condensation of 2-bromo- or 2, 6-dibromo-4, 8-bis(alkylamino)-1, 5-naphthoquinones with zinc 2-amino-benzeneselenolates gave 1, 5-bis(alkylamino)-4H-benzo[a]phenoselenazin-4-one and the 3- and/or 10-substituted compounds. These phenoselenazone derivatives absorb nearly infrared light and can be used as optical recording media for a laser beam.     

吡唑并嘧啶-4-酮衍生物的合成与除草活性

吡唑并嘧啶-4-酮衍生物的合成与除草活性;吡唑[3; 4-d]并嘧啶酮;苯氧丙酸酯;aza-Wittig反应;合成;除草活性     

Acrylamide derivatives as antiallergic agents. III. Synthesis and structure-activity relationships of N-[4-(4-diphenylmethyl-1-piperazinyl)butyl]- and N-[4-(4-diphenylmethylene-1-piperidyl)butyl]-3-heteroarylacry lamides

A new series of 3-heteroarylacrylamides 2 and 4 was prepared and the inhibitory activities against the rat passive cutaneous anaphylaxis (PCA) reaction and the enzyme 5-lipoxygenase (5-LO) were tested. Most of the compounds exhibited an anti-PCA activity superior to or equivalent to ketotifen and had a 5-LO inhibitory activity. The 3-heteroarylacrylamide derivatives including 3-(3-pyridyl)acrylamides represent a new structural class of compound that exhibits not only an in vivo anti-PCA activity but also an in vitro 5-LO inhibitory activity.     

1,3,4-Oxadiazole N-Mannich Bases: Synthesis,Antimicrobial, and Anti-Proliferative Activities

The reaction of 5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thione 3 with formaldehyde solution and primary aromatic amines or 1-substituted piperazines, in ethanol at room temperature yielded the corresponding N-Mannich bases 3-arylaminomethyl-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thiones 4a–l or 3-[(4-substituted piperazin-1-yl)methyl]-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thiones 5a–d, respectively. The in vitro inhibitory activity of compounds 4a–l and 5a–d was assessed against pathogenic Gram-positive, Gram-negative bacteria, and the yeast-like pathogenic fungus Candida albicans. The piperazinomethyl derivatives 5c and 5d displayed broad-spectrum antibacterial activities the minimal inhibitory concentration (MIC) 0.5–8 μg/mL) and compounds 4j, 4l, 5a, and 5b showed potent activity against the tested Gram-positive bacteria. In addition, the anti-proliferative activity of the compounds was evaluated against prostate cancer (PC3), human colorectal cancer (HCT-116), human hepatocellular carcinoma (HePG-2), human epithelioid carcinoma (HeLa), and human breast cancer (MCF7) cell lines. The optimum anti-proliferative activity was attained by compounds 4l, 5a, 5c, and 5d.     

Discovery of Novel Boron-Containing N-Substituted Oseltamivir Derivatives as Anti-Influenza A Virus Agents for Overcoming N1-H274Y Oseltamivir-Resistant

To address drug resistance to influenza virus neuraminidase inhibitors (NAIs), a series of novel boron-containing N-substituted oseltamivir derivatives were designed and synthesized to target the 150-cavity of neuraminidase (NA). In NA inhibitory assays, it was found that most of the new compounds exhibited moderate inhibitory potency against the wild-type NAs. Among them, compound 2c bearing 4-(3-boronic acid benzyloxy)benzyl group displayed weaker or slightly improved activities against group-1 NAs (H1N1, H5N1, H5N8 and H5N1-H274Y) compared to that of oseltamivir carboxylate (OSC). Encouragingly, 2c showed 4.6 times greater activity than OSC toward H5N1-H274Y NA. Moreover, 2c exerted equivalent or more potent antiviral activities than OSC against H1N1, H5N1 and H5N8. Additionally, 2c demonstrated low cytotoxicity in vitro and no acute toxicity at the dose of 1000 mg/kg in mice. Molecular docking of 2c was employed to provide a possible explanation for the improved anti-H274Y NA activity, which may be due to the formation of key additional hydrogen bonds with surrounding amino acid residues, such as Arg152, Gln136 and Val149. Taken together, 2c appeared to be a promising lead compound for further optimization.     

Acrylamide derivatives as antiallergic agents. I. Synthesis and structure-activity relationships of N-[(4-substituted 1-piperazinyl)alkyl]-3-(aryl and heteroaryl)acrylamides

A new series of acrylamide derivatives (7-10) were synthesized. Antiallergic activity of these compounds was evaluated and their structure-activity relationships were examined. Compound 10d, N-[4-(4-diphenylmethyl-1-piperazinyl)butyl]-3-(3-pyridyl)acrylamid e, showed antiallergic activity equivalent or superior to that of ketotifen in the rat passive cutaneous anaphylaxis (PCA) test by oral administration. Compound 10d, unlike ketotifen, had more potent in vitro 5-lipoxygenase inhibitory activity than caffeic acid, whereas its in vitro antihistamine activity was weaker than that of ketotifen. In addition, its inhibitory activity against histamine release from rat mast cells was approximately two-thirds as potent as that of disodium cromoglycate (DSCG). Compound 10d is a promising agent for treating a variety of allergic diseases.     

Synthesis of Sulfonamides Incorporating Piperidinyl-Hydrazidoureido and Piperidinyl-Hydrazidothioureido Moieties and Their Carbonic Anhydrase I,II, IX and XII Inhibitory Activity

Here we report a small library of hydrazinocarbonyl-ureido and thioureido benzenesulfonamide derivatives, designed and synthesized as potent and selective human carbonic anhydrase inhibitors (hCAIs). The synthesized compounds were evaluated against isoforms hCA I, II, IX and XII using acetazolamide (AAZ) as standard inhibitor. Several urea and thiourea derivatives showed inhibitory activity at low nanomolar levels with selectivity against the cytosolic hCA II isoform, as well as the transmembrane, tumor-associated enzymes hCA IX and XII. The thiourea derivatives showed enhanced potency as compared to urea analogues. Additionally, eight compounds 5g, 5m, 5o, 5q, 6l, 6j, 6o and 6u were selected for docking analysis on isoform I, II, IX, XII to illustrate the potential interaction with the enzyme to better understand the activity against the different isoforms.     

Synthesis and bioactivity of novel 3-(1-hydroxyethylidene)-5-substituted-pyrrolidine-2,4-dione derivatives

Ten novel 5-substituted derivatives of 3-(l-hydroxyethylidene)pyrrolidine-2,4-dione were synthesized.The compounds were confirmed by IR,:H NMR,MS and elemental analysis.The bioassay indicated that these compounds showed noticeable herbicidal activities,and compounds 6f and 6j exhibited excellent inhibitory activities against the stalk of Echinochloa crusgalli,with EC50 values of 94.4 and 72.7 mg/L,respectively.     

Syntheses of 2-(3,4-dimethoxyphenyl)ethylamine derivatives and their antiulcer activities.

A series of acyl derivatives of 2-(3,4-dimethoxyphenyl)ethylamine (4) were synthesized and evaluated for their effectiveness to prevent water-immersion stress-induced gastric ulceration when given intraperitoneally to rats. Among them N-[2-(3,4-dimethoxyphenyl)ethyl]-2-phenylaminoacetamide hydrochloride (15) had significant antiulcer activity. Further modification of the four parts of 15 revealed that only the introduction of a carbamoyl group into 2- or 3-position of the phenylamino part gave compounds (49-51, 54 and 55) which retained antiulcer activity comparable to the lead compound. However, the compounds (49-51 and 54) did not exert a prophylactic effect when administered orally except for the 3-substituted bezamide derivative 55. Alkyl substitution on the nitrogen of benzamide gave 3-[[[2-(3,4-dimethoxyphenyl)ethyl]carbamoyl]methyl] amino-N-methylbenzamide (66, DQ-2511) and the related compounds (67, 70, 74 and 77) which all had potent antiulcer activities at oral doses of 50-400 mg/kg.     

Synthesis and Anticancer Activities of Some Thiazole Derivatives

In this study, 2-substituted 4-[3/4-(4-arylthiazole-2-yl)aminophenyl]thiazole derivatives and 2-[4-[2-substituted 4-methylthiazole-5-yl]thiazole-2-yl]amino-5-arylidenethiazoline-4-one derivatives have been synthesized. The cytotoxic and/or growth inhibitory effects of the 16 selected compounds were evaluated in vitro against approximately 66 human tumor cell lines derived from nine neoplastic diseases. Some of the compounds were found to act as anticancer agents.     

Synthesis and Biological Evaluation of Novel Uracil and 5-Fluorouracil-1-yl Acetic Acid-Colchicine Conjugate

A series of novel uracil and 5-fluorouracil-1-yl-acetic acid-colchicine derivatives(6a-6n) was synthesized via coupling uracil and 5-fluorouracil(5-FU) with C-10 analogues of colchicine. The antitumor activities of the target compounds against human hepatocellular carcinoma(BEL7402) cells, human ovary carcinoma(A2780) cells, human lung adenocarcinoma(A549) cells and human breast carcinoma(MCF7) cells were tested in vitro, and the structure-activity relationship(SAR) of the compounds was also studied. The bioassay results demonstrate that most of the tested compounds display significant activity and particularly, compounds 6a, 6e, 6h and 6l show more potent cytotoxic activities than 5-fluorouracil and colchicine. The results show that the new derivatives of colchicine are potential suppressors on human cancer.     

Synthesis and antibacterial activity of C-2(S)-substituted pleuromutilin derivatives

<正>In order to probe the effect of C-2(S)-substituted groups in the antibacterial activity,a series of novel C-2(S)-substituted pleuromutilin analogues of SB-225586 were synthesized and evaluated for their in vitro antibacterial activity.The results of antibacterial activities indicated that C-2(S)-substituted pleuromutilin derivatives retained appreciable antibacterial activity,and the 2-fluorination compounds 6a and 6b are more potent than the corresponding 2-hydroxylation analogues 7a and 7b.