Synthesis of 5-substituted 2'-deoxyuridines

A series of thymidylate synthetase inhibitors was synthesized, some of which were potential irreversible inhibitors. 5-Formyl-2'-deoxyuridine (9) and its dithiolane derivative 11 were prepared by condensation of the bis(trimethylsilyl) derivative of 5-formyluracil dimethyl acetal and the protected chloro sugar followed by saponification of the protective groups. 5-Acetyl-2'-deoxyuridine (15) was prepared in the same way from 5-acetyluracil. Treatment of the diester of 5-allyl-2'-deoxyuridine (17 or 22) with m-chloroperbenzoic acid gave the corresponding epoxide. Dimethylamine removed the ester groups and opened the epoxide to give the amino alcohol 24. The diester of 5-chloromethyl-2'-deoxyuridine (27) treated with methanol or sodium azide gave 5-methoxymethyl- (29) and 5-azidomethyl- (31) 2'-deoxyuridines. Compound 27 also was converted to 5-iodoacetamidomethyl-2'-deoxyuridine by treatment with ammonia, chloroacetyl chloride, base saponification, and finally sodium iodide.     

Synthesis and structure-activity relationships of 7-(2-aminoalkyl)morpholinoquinolones as anti-Helicobacter pylori agents

A series of the titled compounds was synthesized and tested for anti-Helicobacter pylori activities. We discovered Y-34867 having the most potent activity against Helicobacter pylori among the quinolones tested along with high photostability. Furthermore, Y-34867 showed an excellent therapeutic effect in the experimental Helicobacter pylori infected Mongolian gerbil model.     

Synthesis and structure-activity relationships of 2-pyridones: II. 8-(Fluoro-substituted pyrrolidinyl)-2-pyridones as antibacterial agents

The 8-position side chain of 2-pyridones is believed to be involved in the binding with bacterial DNA gyrase to form the ternary complex, making them very important for the activity of 2-pyridones. A series of 2-pyridones having fluoro-substituted amines at the 8-position has been synthesized and their antibacterial activities and parmacokinetic properties are reported.     

1-Phenyl-3-(aminomethyl)pyrroles as potential antipsychotic agents. Synthesis and dopamine receptor binding

A series of 1-phenyl-3-(aminomethyl)pyrroles were prepared in two steps from aniline and their affinities for D2, D3, and D4 dopamine receptor subtypes determined. A 15-fold selectivity for cloned human D4 receptors over cloned African Green monkey D2 receptors was observed with 1-(2-pyridyl)-4-[[3-(1-phenylpyrrolyl)]methyl]piperazine.     

2-Phenyl-4-(aminomethyl)imidazoles as potential antipsychotic agents. Synthesis and dopamine D2 receptor binding

A series of 2-phenyl-4-(aminomethyl)imidazoles were designed as conformationally restricted analogs of the dopamine D2 selective benzamide antipsychotics. The title compounds were synthesized and tested for blockade of [3H]YM-09151 binding in cloned African green monkey dopamine D2 receptor preparations. The binding affinity data thus obtained were compared against that of the benzamides and a previously described series of 2-phenyl-5-(aminomethyl)-pyrroles.     

Synthesis and antimyoctic properties of 1-(2-alkyl-2-phenylethyl)-1H-imidazoles

The synthesis of 1-(2-alkyl-2-phenylethyl)-1H-imidazoles was accomplished starting from the corresponding phenylacetonitriles. Via alkylation, esterification, and sodium borohydride reduction-in the presence of lithium iodide-beta-phenylalconols were obtained. Mesylation of these alcohols and refluxing with imidazole in dimethylformamide furnished title compounds, which were active in vitro against dermatophytes, yeasts, other fungi, and gram-positive bacteria and in vivo as well as in vitro against Candida albicans.     

Synthesis of 2'-aminomethyl derivatives of N-(2-(phosphonomethoxy)ethyl) nucleotide analogues as potential antiviral agents

A series of purine and pyrimidine N-(2-(phosphonomethoxy)ethyl) derivatives bearing aminomethyl, (dimethylamino)methyl, morpholinomethyl, and (trimethylammonio)methyl groups at the 2'-position were synthesized. The compounds were prepared by alkylation of the heterocyclic bases with appropriately substituted (aminoalkyl)oxiranes followed by condensation of the resulting intermediates with dialkyl ((p-tolylsulfonyl)oxy)methanephosphonate and subsequent treatment of the obtained diester with bromotrimethylsilane. 9-(3-Amino-2-(phosphonomethoxy)propyl)adenine (2a) proved active against varicella zoster virus (VZV), cytomegalovirus (CMV), and Moloney murine sarcoma virus (MSV) in the concentration range of 7-35 micrograms/mL. None of the other aminoalkyl derivatives demonstrated significant antiviral activity against herpes simplex virus type 1 and 2 (HSV-1 and HSV-2), VZV, (CMV), vaccinia virus (VV), MSV, and human immunodeficiency virus type 1 and 2 (HIV-1 and HIV-2).     

Synthesis of 5-chloro-3'-nitro-4'-substituted salicylanilides, a new series of anthelmintic and antimicrobial agents

A number of 5-chloro-3'-nitro-4'-substituted salicylanilides (6--23) have been synthesized by treating 4',5-dichloro-3'-nitrosalicylanilide (5) with various sodium aryl oxides, alkoxides, or amines. These compounds have been tested against Hymenolepis nana infection in rats and have also been evaluated for their in vitro antimicrobial activity against various strains of bacteria and fungi. In the former test 17 was the most active cestodicidal agent showing activity at 30 mg/kg. In the antimicrobial screening, 22 inhibited the growth of all the bacteria and fungi used while 6 was active against the penicillin resistant Staphylococcus aureus at a minimum inhibitory concentration of 0.00609 microgram/mL.     

2,6-dialkylpiperazines. VIII (1)-N1-arylalkyl-N4-(2'-pyridyl)-2,6-dimethylpiperazines as adrenolytic and vasodilator agents

A series of cis and trans N1-arylalkyl-N4-(2'-pyridyl)-2'6-dimethylpiperazines were synthetized and tested as adrenolytic and vasodilator agents. The N1-substitution with the 3,4-dimethoxyphenethyl group seems the most promising with regard to pharmacological activity, which was found to reside mainly in the trans isomer (3-II b). The adrenolytic activity of (3-II b) is comparable with that of the related 2-methyl derivative (1-III), while it is higher than that of (IV) in which the piperazine nucleus is C-unsubstituted.     

Synthesis, local anaesthetic and antiarrhythmic activity of methyl N-(2-substituted aminopropanoyl)-3-cyanoanthranilates

A series of methyl N-(2-substituted aminopropanoyl)-3-cyanoanthranilates (4a-i), that are structurally-related to tocainide and lidocaine, was synthesized and was found to be active when evaluated for local anaesthetic activity using the frog-foot withdrawal reflex, the guinea pig wheal derm and the rabbit corneal reflex tests. A selected numbers of the series were preliminarily evaluated for antiarrhythmic activity using CaCl2-induced arrhythmia test. Compounds 4a, 4c and 4f at lower doses completely protected the animals against the induced arrhythmias.     

Synthesis and structure-activity relationships of a new series of benzimidazoles as H1-antihistaminic agents

New 2-(4-(4-azolylbutyl)piperazinyl)-, 2-(4-(4-azolylbutyl) piperazinylmethyl)-, 2-(4-(-azolylbutyl)homopiperazinyl)- and 2-(4-(4-azolylbutyl)homopiperazinylmethyl)benzimidazoles were synthesized, characterized and tested for in vitro and in vivo H1-antihistaminic activity. Structure-activity relationships implied that the best antihistaminic activity required the simultaneous presence of a homopiperazinylbenzimidazole system (or a methylene linker between the benzimidazole and the piperazine rings) and an unsubstituted pyrazole ring. 1-(2-Ethoxyethyl)-2-?4-[4-(pyrazol-1-yl)butyl] homopiperazin-1-yl?benzimidazole (17), as its dimaleate salt, has been chosen for further development.     

2-substituted quinoline alkaloids as potential antileishmanial drugs

Ten 2-substituted quinoline alkaloids isolated from a plant used for treatment of New World cutaneous leishmaniasis have antileishmanial in vitro activities against the extracellular forms of Leishmania spp. BALB/c mice infected with Leishmania amazonensis PH8 or H-142 or Leishmania venezuelensis were treated 1 day after the parasitic infection with a quinoline alkaloid (100 mg/kg of body weight per day) or with reference drug N-methylglucamine antimonate (Glucantime) (56 mg of pentavalent antimony [Sbv] per kg per day) for 14 days. Lesion development was the criterium used to assess disease severity. Two three-carbon chain quinolines [2-n-propylquinoline and 2-(1',2'-trans-epoxypropyl)quinoline (chimanine D)] were more potent than N-methylglucamine antimonate against L. amazonensis PH8, and five quinoline alkaloids [2-(3,4-methylenedioxyphenylethyl)quinoline, cusparine, 2-(3,4-dimethoxyphenylethyl)quinoline, 2-(E)-prop-1'-enylquinoline (chimanine B), and skimmianine] were as effective as the reference drug. Single treatment near the site of infection, 14 days after infection with L. amazonensis, with 2-n-propylquinoline or chimanine B reduced the severity of lesions but less notably than N-methylglucamine antimonate. 2-n-Propylquinoline exhibited significant activity against the virulent strain L. venezuelensis. The active products did not show any apparent toxicities during the experiment. This study is, to our knowledge, the first to show the activity of 2-substituted quinoline alkaloids for experimental treatment of New World cutaneous leishmaniasis. Further investigations of these compounds might yet prove helpful for the development of new antileishmanial drugs.     

2-substituted (2SR)-2-amino-2-((1SR,2SR)-2-carboxycycloprop-1-yl)glycines as potent and selective antagonists of group II metabotropic glutamate receptors. 2. Effects of aromatic substitution, pharmacological characterization, and bioavailability

In this paper we describe the synthesis of a series of alpha-substituted analogues of the potent and selective group II metabotropic glutamate receptor (mGluR) agonist (1S,1'S,2'S)-carboxycyclopropylglycine (2, L-CCG 1). Incorporation of a substitutent on the amino acid carbon converted the agonist 2 into an antagonist. All of the compounds were prepared and tested as a series of four isomers, i.e., two racemic diastereomers. On the basis of the improvement in affinity realized for the alpha-phenylethyl analogue 3, in this paper we explored the effects of substitution on the aromatic ring as a strategy to increase the affinity to these compounds for group II mGluRs. Affinity for group II mGluRs was measured using [3H]glutamic acid (Glu) binding in rat forebrain membranes. Antagonist activity was confirmed for these compounds by measuring their ability to antagonize (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid-induced inhibition of forskolin stimulated cyclic-AMP in RGT cells transfected with human mGluR2 and mGluR3. Meta substitution on the aromatic ring of 3 with a variety of substituents, both electron donating (e.g., methyl, hydroxy, amino, methoxy, phenyl, phenoxy) and electron withdrawing (e.g., fluorine, chlorine, bromine, carboxy, trifluoromethyl) gave from 1.5- to 4.5-fold increases in affinity. Substitution with p-fluorine, as in 97 (IC50 = 0.022 +/- 0.002), was the exception. Here, a greater increase in affinity was realized than for either the ortho- or meta-substituted analogues; 97 was the most potent compound resulting from monosubstitution of the aromatic. At best, only modest increases in affinity were realized for certain compounds bearing either two chlorines or two fluorines, and two methoxy groups gave no improvement in affinity (all examined in a variety of substitution patterns). Three amino acids, 4, 5, and 104, were resolved into their four constituent isomers, and affinity and functional activity for group II mGluRs was found to reside solely in the S,S,S-isomers of each, consistent with 1. With an IC50 = 2.9 +/- 0.6 nM, the resolved xanthylmethyl compound 168 was the most potent compound from this SAR. Amino acid 168 demonstrated high plasma levels following intraperitoneal (i.p.) administration and readily penetrated into the brain. This compound, however, had only limited (approximately 5%) oral bioavailability. Systemic administration of 168 protected mice from limbic seizures produced by the mGluR agonist 3,5-dihydroxyphenylglycine, with an ED50 = 31 mg/kg (i.p., 60 min preinjection). Thus, 168 represents a valuable tool to study the role of group II mGluRs in disease.     

Synthesis and biological investigations of 1-(tetrahydropyran-2'-yl)- and 1-(tetrahydrofuran-2'-yl)benzimidazoles and 1/2-(tetrahydropyran-2'-yl)- and 1/2-(tetrahydrofuran-2'-yl)benzotriazoles

Sets of benzimidazole and benzotriazole derivatives bearing on position 1 or 2 a tetrahydrofuranyl or tetrahydropyranyl moieties were prepared through the addition of the suitable benzazoles on 2,3-dihydrofuran and 3,4-dihydro-2H-pyran. The reactions were carried on either without solvent or in carbon tetrachloride solution. In the last case some peculiar chlorinated side products were isolated and characterized. Twenty compounds were screened for in vitro antitumoral and anti-HIV-1 activities and found poorly active or completely inactive. On the other hand several compounds exhibited good tracheal relaxant activity in vitro; compound 8, 11, 16, 24 and 26 resulted more active than theophylline in this test, while compound 11 was comparable to amrinone till the concentration of 3 micrograms/ml. Finally, compound 5 resulted endowed with a strong diuretic and saluretic activity at the dose of 3 mg/Kg, thus representing a new lead for discovering new diuretic agents.     

Synthesis of 11-substituted androstenediones and testosterones as human decidual cell growth inhibitors

11 alpha-Hydroxytestosterone (1a), 11 beta-hydroxytestosterone (1b), 11 alpha-methoxytestosterone (1c), 11 beta-methoxytestosterone (1d), 11-ketotestosterone (1e), and delta 9(11)-testosterone (1f) were synthesized from hydrocortisone (4b) or 11-epi-hydrocortisone (4a). The six target compounds, together with 11 alpha-methoxyandrostenedione (2c), 11 beta-methoxyandrostenedione, (2d) and their lead compound, testosterone (1), were found to effectively inhibit the growth and differentiation of human decidual cells in culture. There is no observable binding of these compounds to estrogen receptor of rabbit uterus. The introduction of a polar group (e.g., hydroxyl and carbonyl) to C-11 of androstenes decreases both the relative binding affinities to progesterone receptor and the inhibitory effects on human decidual cell growth, while the methylation of 11-hydroxyl group minimizes these effects. The similar effects of a polar group at C-11 of testosterone (1) on the inhibitory effects on human decidual cell growth and the relative binding affinities to progesterone receptor of rabbit uterus may suggest that one of the mechanisms of human decidual cell growth inhibition by these compounds is the anti-progestational activity of these androgens.     

Synthesis of 1-(beta-D-glycopyranosyl)-3-deazapyrimidines from 2-hydroxy and 2-mercaptopyridines

The synthesis of new 4- and 5-substituted-3-cyanopyridine nucleosides has been performed by reacting the silylated pyridines and penta-omicron-acetyl-alpha -D-glycopyranose in dichloroethane in the presence of SnCl4. The free nucleosides were tested for their potential activity against HIV and different types of tumor.     

1 beta-Methyl-2-(5-substituted pyrrolidin-3-ylthio)carbapenems. 3. Synthesis and antibacterial activity of BO-2727 and its related compounds

The synthesis and biological activity of (1R,5S,6S)-2-[(3S,5S)- 5-substituted pyrrolidin-3-ylthio]- 6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid in which hydroxy-substituted aminoethyl, aminopropyl, and aminobutyl groups were introduced as substituents, are described. These derivatives showed potent antibacterial activity against Gram-positive and Gram-negative bacteria including P. aeruginosa. Among them, lenapenem (BO-2727, 7b), carrying an (R)-1-hydroxy-3-(N-methylamino)propyl group, was selected as a development candidate.     

SO2-4/TiO2-WO3催化合成丁醛1,2-丙二醇缩醛

以固体超强酸SO2-4/TiO2-WO3为催化剂,对以丁醛和1,2-丙二醇为原料合成丁醛1,2-丙二醇缩醛的反应条件进行了研究.实验表明SO2-4/TiO2-WO3是合成丁醛1,2-丙二醇缩醛的良好催化剂,研究了醛醇摩尔比、催化剂用量、反应时间诸因素对收率的影响.最佳反应条件为n(丁醛)/n(1,2-丙二醇)=1/1.4,催化剂用量为反应物料总质量的0.5%,环己烷为带水剂,反应时间50 min.上述条件下,丁醛1,2-丙二醇缩醛的收率可达84.6%.     

Synthesis and biological evaluation of substituted flavones as gastroprotective agents

Flavone (1) was found to protect against ethanol-induced gastric damage in rats; however, it is known that certain compounds in the flavone class, including flavone itself, are inducers of hepatic drug metabolizing enzymes. With the hope of identifying gastroprotective flavones that have minimal effects on drug metabolizing enzymes, we have synthesized and evaluated selected flavone analogs. Gastroprotective potency in the ethanol model was retained by methoxy substitution in the 5-position (4) and by methoxy (12) or methyl (14) substitution in the 7-position. A number of substituted analogs of the potent molecule 5-methoxyflavone (4) were also synthesized, and in many cases, these substitutions provided gastroprotective molecules. In order to assess liver enzyme induction potential, two of the gastroprotective flavones, 7-methoxyflavone (12) and 5-methoxy-4'-fluoroflavone (26), were examined for their effect on liver microsomal cytochrome P450 and 7-ethoxyresorufin O-dealkylase (CYP1A) activity. These two compounds caused minimal changes in the cytochrome P450 concentration and were considerably less potent than beta-naphthoflavone as inducers of CYP1A enzyme activity. Furthermore, following oral administration to rats, 5-methoxy-4'-fluoroflavone (26) was found to protect against indomethacin-induced gastric damage. These results indicate that, through appropriate substitution, flavones can be obtained that are gastroprotective but have minimal effects on drug-metabolizing enzymes.     

SO4^2-／TiO2-WO3催化合成丁醛1，2-丙二醇缩醛

以固体超强酸SO4^2-／TiO2-WO3为催化剂，对以丁醛和1，2-丙二醇为原料合成丁醛1，2-丙二醇缩醛的反应条件进行了研究。实验表明：SO4^2-／TiO2-WO3是合成丁醛1，2-丙二醇缩醛的良好催化剂，研究了醛醇摩尔比、催化剂用量、反应时间诸因素对收率的影响。最佳反应条件为：n（丁醛），n（1，2-丙二醇）：1／1．4，催化剂用量为反应物料总质量的0．5％，环己烷为带水剂，反应时间50min。上述条件下，丁醛1，2-丙二醇缩醛的收率可达84．6％。