Synthesis of 2-(Alkylthio)-1,2,4-triazolo[1,5-a]pyrimidines and 3-(Alkythio)-1,2,4-triazolo[3,4-a]pyrimidines and Their Vasodilator Activity

本文作者合成了新的５，７二甲基１，２，４三唑并［１，５ａ］嘧啶２苄硫醚类（Ｂ系列）５，７二甲基１，２，４三唑并［３，４ａ］嘧啶２苄硫醚类化合物（Ｄ系列），并测定了这两类化合物在体外对８５７ｍｍｏｌ·Ｌ１Ｋ＋和１０４ｍｍｏｌ·Ｌ１ＮＥ（ｎｏｒｅｐｉｎｅｐｈｒｉｎｅ）引起的血管条收缩的抑制作用。测定结果表明，Ｂ系列化合物的活性均高于Ｄ系列化合物，在苯环的对位有体积较大的疏水性基团有助于生物活性的提高。５，７二甲基１，２，４三唑并［１，５ａ］嘧啶２对溴苄硫醚表现出最好的扩张血管活性，在浓度为１０５ｍｏｌ·Ｌ１和１０４ｍｏｌ·Ｌ１时，对１０４ｍｍｏｌ·Ｌ１ＮＥ引起的离体血管条痉挛的抑制率均为１００％；对８５７ｍｍｏｌ·Ｌ１Ｋ＋引起的离体血管条痉挛的抑制率分别为４７％和１００％。     

Synthesis and antitumor screening of new series of pyrimido-[4,5-b]quinolines and [1,2,4]triazolo[2′,3′:3,4]pyrimido[6,5-b]quinolines

New series of pyrimido[4,5-b]quinolines and [1,2,4]triazolo[2′,3′:3,4]pyrimido[6,5-b]quinolines have been synthesized. Compounds 4a, 4e, 4f, 4h, 5b, 5d, 6a, 6d, 6e, 8c, 8d, 10c–e, 10h, 11a, 11b, and 12a were tested for in vitro antitumor activity against human breast carcinoma (MCF-7) cell line, where compound 8d was found to be the most active member with IC₅₀ value of 3.62 μM. The DNA-binding affinity for the same compounds showed that compounds 8d and 10d exhibited the highest affinity to DNA. The detailed synthesis, spectroscopic, and biological data are reported.     

Synthesis,Analysis, and Acute Toxicity of 9-(2-diethylaminoethyl)-2-phenylimidazo[1,2-α]benzimidazole Dinitrate

Pharmaceutical Chemistry Journal - The key synthetic stage (cyclization) of 9-(2-diethylaminoethyl)-2-phenylimidazo[1,2-α]benzimidazole dinitrate, which possesses antiulcer activity, was...     

Synthesis of novel 2-(3′-aryl-sydnon-4′-ylidene)-5′-substituted-[1,3,4]-thiadiazolylamines and [1,3,4]-thiadiazol-2′-yl-3-oxo-[1,2,4]-triazoles as antimicrobial agents

The title compounds (3g–n) and (6g–n) were synthesized using 3-arylsydnones as synthons, and the structures were confirmed by IR, ¹H NMR, FAB mass and CHN analysis. These compounds were evaluated for their antibacterial and the antifungal activities in terms of minimum inhibitory concentrations (MICs) against the bacterial strains E. coli, B. cereus, and the fungal strains A. niger, C. albicans. Some of the compounds have shown significant activities.     

Biologically active conformation of [Met5]- and [Leu5]enkephalin on δ opioid receptor

Investigations of the conformation of endogenous enkephalins are generally based on structural comparisons of enkephalins with other opiates and on experimental pharmacological studies. Based on such investigations, we now propose a model of the biologically active (receptor-bound) conformation of [Met⁵]- and [Leu⁵]enkephalin on the δ opioid receptor. The model helps with the design of new opioid analgesics.     

Synthesis of 6-[1-[4-(benzoxazol-2-yl)thiobuthyl]-1,2,3-triazole-4-yl]methylenepenam as β-lactamase inhibitors

The 6,6-dibromopenam6 was treated with CH₃MgBr and carbaldehyde5 to afford the 6-bromo-6-(1-hydroxy-1-methyl)penicillanate7, which was reacted with acetic anhydride to give acetoxy compound8. The deacetobromination of8 with zinc and acetic acid gave 6-exomethylenpenams, Z-isomer9 and E-isomer10, which were oxidized to sulfones11 and12 by m-CPBA. The p-methoxybenzyl compounds were deprotected by AlCl₃ and neutralized to give the sodium salts13, 14, and15.     

Synthesis and investigation of Nα-[3-di(2-chloroethyl)amino-4-methylbenzoyl]amino acids

Pharmaceutical Chemistry Journal -     

Uterotrophic assay,Hershberger assay,and subacute oral toxicity study of 4,4´-[1-[4-[1-(4-hydroxyphenyl)-1-methylethyl]phenyl]ethylidene]bis[phenol] based on the OECD draft protocols

We performed an uterotrophic assay, the Hershberger assay, and a 28-day repeated-dose toxicity study (enhanced OECD test guideline No. 407) of 4,4′-[1-[4-[1-(4-hydroxyphenyl)-1-methylethyl]phenyl]ethylidene]bis[phenol] based on the OECD draft protocols. In the uterotrophic assay, female SD rats were subcutaneously injected with the chemical at doses of 0, 100, 300, and 1,000 mg/kg on each of 3 days from postnatal day 20 to day 22, and the uterine weight of rats given the 1,000 mg/kg dose of the test chemical plus ethinyl estradiol decreased. In the Hershberger assay, the test chemical was orally administered at doses of 0, 100, 300, and 1,000 mg/kg day to castrated male SD rats for ten consecutive days beginning on postnatal day 56, and no changes were observed. On the other hand, when the test chemical was orally administered at doses 0, 100, 300, and 1,000 mg/kg day for at least 28 days, a decrease in LH values in rats of both sexes and a decrease in FSH and estradiol values in female rats were detected in the 1,000 mg/kg group, and abnormal estrous cycles, uterine glandular atrophy, persistence of ovarian corpora lutea, vaginal epithelial mucification, and mammary glandular hyperplasia were also observed in one female rat in the 1,000 mg/kg group. Therefore, the uterotrophic assay used in this study showed that the chemical has the estrogen–antagonist properties, and some potentially endocrine-mediated effects were detected in growing rats based on the results of the enhanced OECD test guideline No. 407. However, the changes were observed in rats given a high dose of the chemical, 1,000 mg/kg day.     

Synthesis of 6-[2-(Benzoxazol-2-ylmethylamino)ethoxy]-1-Alkyl-1H-lndole-2-Carboxylic acid and inhibitory activity on β-Amyloid aggregation

6-[2-(benzoxazol-2-ylmethylamino)ethoxy]-1-alkyl-1H-indole-2-carboxylic acids were designed and synthesized as beta-amyloid (Abeta) fibril assembly inhibitors. Their inhibitory activity on Abeta, aggregation was evaluated by thioflavin T assay although their activities were insignificant.     

Synthesis and in vitro antitumor activity of new quinoline, pyrimido[4,5-b]quinoline, [1,2,3]triazino[4,5-b]quinoline, and [1,2,4]triazolo[2′,3′:3,4]pyrimido[6,5-b]quinoline analogs

New series of quinoline, pyrimido[4,5-b]quinoline, [1,2,3]triazino[4,5-b]quinoline, and [1,2,4]triazolo[2′,3′:3,4]pyrimido[6,5-b]quinoline analogs have been synthesized and characterized by analytical and spectrometrical methods (IR, ¹H NMR, ¹³C NMR, MS). Fifteen of the newly synthesized compounds; namely, 3a, b, 4b, 6a, b, 10a–f, and 14a–d were evaluated for their in vitro antitumor activity at the National Cancer Institute (NCI) 60 cell lines panel assay. Compounds 4b and 10f are the most active members in this study, demonstrating significant broad spectrum antitumor activity against most of the tested sub-panel tumor cell lines. The detailed synthesis, spectroscopic, and biological data are described.     

2-[4-(2-甲氧基乙基)苯氧基甲基]环氧乙烷的制备

对甲氧乙基苯酚于30%碳酸钾水溶液中,在相转移催化剂PEG400参与下与氯甲基环氧乙烷于90℃反应6h,制得标题化合物,收率87%.     

Synthesis and antifungal activity of 9-aryl-8-(2-thienyl)-4,9-dihydrotetrazolo-[1′,5′-1,2]pyrimido[4,5-d]pyridazin-5(6 h)-ones

A series of 9-aryl-8-(2-thienyl)-4,9-dihydrotetrazolo[1′,5′-1,2]pyrimido[4,5-d]pyridazin-5(6H)-ones have been obtained by reaction of equivalent amounts of methyl esters of 7-aryl-6-(2-thienyl)-4,7-dihydrotetrazolo[1, 5-a]pyrimidine-5-carboxylic acids and hydrazine hydrate at 180–190°C in the absence of solvents. The structures of the synthesized compounds have been determined based on spectral data (PMR, IR, high-resolution mass spectrometry). The synthesized compounds were tested for antimicrobial activity.     

Synthesis and antitumor evaluation of acyclic 1-[ω-(N′-2-chloroethyl-N′-nitrosoureido)alkyl]thymidine nucleoside analogues

In the preparation of acyclic thymidine nucleoside analogues, K₂CO₃ (or NaH) treated thymine in DMSO was alkylated with ω-chloroalkyl nitrite (Cl-(CH₂)_n-CN; n=1, 2, 3, 4) to provide an isomeric mixture of 1-(ω-cyanoalkyl)thymine (2a-d) and 1,3-bis(ω-cyanoalkyl)thymine in approximately 5∶1 ratios. Reduction of the cyano function2a-d with NaBH₄/CoCl₂·6H₂O gave the corresponding 1-(ω-aminoalkyl)thymine (3a-d). The newly formed primary amino function in3a-d was directly reacted with 2-chloroethylisocyanate to afford the 1-[ω-(N′2-chloroethy-lureido) alkyl]thymine (4a-d) in good yields. Nitrosation of 1-[5-(N′-2-chloroethylureido)pentyl] thymine (4d) with glacial acetic acid and dry NaNO₂ powder in anhydrous CH₂Cl₂ gave two types of regioisomeric nitrosoureas, 1-[5-(N′-2-chloroethyl-N′-nitrosoureido)pentyl]thymine (5d) and 1-[5-(N′-2-chloroethyl-N-nitrosoureido)pentyl]thymine in approximately 5∶1 ratios. The in vitro cytotoxicity of the synthesized compounds (2a-d, 3a-d, 4a-d and5a-d) against three cell lines (K-562, P-388 and FM-3A) are measured as IC₅₀ values. Compounds3d and4c showed moderate activities against all three cell lines, and all other compounds were found to be not active.     

cis-trans-Isomerization of [E]-5-(2-bromovinyl)-2,2′-anhydrouridine in vivo in rats

1. [E]-5-(2-bromovinyl)-2,2′-anhydrouridine ([E]BVANUR) has considerable antiviral activity against herpes simplex virus type 1 (HSV-1).

2. [E]BVANUR is not a substrate of pyrimidine nucleoside phosphorylases, but it is an inhibitor of uridine phosphorylase (K_i=450 nM).

3. [E]BVANUR (trans-isomer, parent compound) undergoes isomerization to [Z]BVANUR (cis-isomer), the only metabolite in rat, which was identified by?h.p.l.c., mass spectra and n.m.r. spectroscopy.

4. Absorption of the drug from the gastrointestinal tract after oral administration is minimal. Absorption of [E]BVANUR from the abdominal cavity after i.p. administration was slow.     

Synthesis and Antiarrhythmic Activity of N-[2-(Adamantan-2-YL)Aminocarbonyl-Methyl-N′-(Dialkylamino)Alkylnitrobenzamides

Pharmaceutical Chemistry Journal - Novel 2-aminoadamantane derivatives, specifically N-[2-(adamant-2-yl)-aminocarbonylmethyl]-N′-(dialkylamino) alkylnitrobenzamides and their physiologically...     

Synthesis of a radiotracer for studying nicotinic acetylcholine receptors: (+/−)-exo-2-(2-[18F]fluoro-5-pyridyl)-7-azabicyclo[2.2.1]heptane

The radiochemical synthesis of (+/−)-exo-2-(2-[¹⁸F]fluoro-5-pyridyl)-7-azabicyclo[2.2.1]heptane ([¹⁸F] (UNDERLINE)1(/UNDERLINE) ) was accomplished by Kryptofix® 222 assisted nucleophilic no-carrier-added [¹⁸F]fluorination of (+/−)-exo-2-(2-bromo-5-pyridyl)-7-azabicyclo[2.2.1] heptane ( (UNDERLINE)3a(/UNDERLINE) ). The average radiochemical yield of the final product was 10% and the average specific activity was greater than >2000 mCi/μmol, calculated at end-of-synthesis. The stable fluorine ligand ([¹⁹F] (UNDERLINE)1(/UNDERLINE) ) was prepared by Kryptofix® 222 assisted nucleophilic fluorination of (+/−)-exo-2-(2-bromo-5-pyridyl) - 7 -methoxycarbonyl - 7 - azabicyclo[2.2.1]heptane ( (UNDERLINE)3b(/UNDERLINE) ) followed by acid deprotection.     

Synthesis and anti-microbial activity of some imidazo[ 1′,2′:5,6]pyrimido[ 4,5-c] pyridazines and related heterocycles

The synthesis of the title heterocycles was achieved using 3-amino-5,6-diphenylpyridazine-4-carbonitrile (4) as a starting material. This compound was converted into the corresponding 4-imidazolinyl derivative 5 which was then subjected to cyclization reactions to afford the title compounds.     

Studies on the synthesis,in vitro antitumor activity of 4H-benzo[h]chromene, 7H-benzo[h]chromene[2,3-d]pyrimidine derivatives and structure–activity relationships of the 2-,3- and 2,3-positions

Some 4H-benzo[h]chromene and 7H-benzo[h]chromeno[2,3-d]pyrimidine derivatives were prepared as potential cytotoxic agents. The in vitro cytotoxic activity of the synthesized compounds was investigated in comparison with the well-known anticancer standard drugs Vinblastine, Colchicine, and Doxorubicin using MTT colorimetric assay. It was found that compounds 23, 15, 20, and 21 showed the highest anticancer activity against the three tumor cell lines MCF-7, HCT, and HepG-2, compared with Vinblastine and Colchicine, while compound 23 was the most active against HepG-2 as compared with Doxorubicin. We explored the SAR of 4H-benzo[h]chromenes with modification at the 2-,3- positions and 7H-benzo[h]chromeno[2,3-d]pyrimidine at 2,3-positions. The structure–activity relationship (SAR) study revealed that the antitumor activity on 4H-benzo[h]chromene and 7H-benzo[h]chromeno[2,3-d]pyrimidine derivatives were significantly affected by the lipophilicity (hydrophobic or hydrophilic), of the substituent at 2-,3- and 2,3-positions. Structures of these compounds were established on the basis of spectral data, IR, ¹H NMR, ¹³C NMR, ¹³C NMR-DEPT, and MS data.