Anti-Helicobacter pylori agents. 1. 2-(Alkylguanidino)-4-furylthiazoles and related compounds.

A series of 2-(alkylguanidino)-4-[5-(acetamidomethyl)furan-2-yl]thiazoles and related compounds were synthesized and evaluated for antimicrobial activity against Helicobacter pylori, inhibitory effect on gastric acid secretion, and histamine H2-receptor antagonist activity. Introduction of alkyl substituents on the guanidino moiety resulted in a significant increase in antimicrobial activity, which was associated with the alkyl chain length. Of the compounds obtained, the n-hexylguanidino derivative 13 demonstrated a 250-fold improvement in activity (MIC = 0.11 micrograms/mL) over the unsubstituted guanidino derivative 7. Alkyl-substituted guanidino derivatives also displayed gastric antisecretion and H2-antagonist activities. However, a simple correlation between the alkyl chain length and the activities was not found in these assays. Replacement of the guanidine with other bioisosteric groups (thiourea, urea, or (dimethylamino)methyl) resulted in loss of all activities tested. Thus the guanidino moiety was found to be essential for activity in this series of compounds.

Anti-Helicobacter pylori agents. 4. 2-(Substituted guanidino)-4-phenylthiazoles and some structurally rigid derivatives.

In order to find a new class of anti-Helicobacter pylori (H. pylori) agents, a series of 4-[(3-acetamido)phenyl]-2-(substituted guanidino)thiazoles and some structurally rigid analoges were synthesized and evaluated for antimicrobial activity against H. pylori. Among the compounds obtained, high anti-H. pyrori activities were observed in benzyl derivative 34 (MIC = 0.025 microg/mL) and phenethyl derivatives 35 and 36 (MIC = 0.037 microg/mL and 0.017 microg/mL). Though alkyl derivatives generally showed lower activity, the 2-methoxyethyl derivative 28 preserved significant activity (MIC = 0.32 microg/mL) and also exhibited more potent gastric antisecretory activity than ranitidine. Structural restriction by bridging between the thiazole and the phenyl rings with an alkyl chain did not improve the activity in this series.

Anti-Helicobacter pylori agents. 3. 2-[(Arylalkyl)guanidino]-4-furylthiazoles.

A series of 2-[(arylalkyl)guanidino]-4-[(5-acetamidomethyl)furan-2-yl]thiazole s and some 4-acetamidomethyl positional isomers were synthesized and evaluated for antimicrobial activity against Helicobacter pylori. Among the compounds that had potent antimicrobial activity (MIC < 0. 1 microgram/mL), compounds 31 and 36 additionally possessed H2 antagonist and gastric antisecretory activities. Though compound 51, an analogue incorporating a methyl group onto the furan nucleus of 36, and compound 54, a positional isomer of 51, also showed potent anti-H. pylori activity, the H2 antagonism profile was eliminated from these compounds. Thus, two types of potent anti-H. pylori agents could be derived from the same scaffold.

Studies of 7 beta-[2-(aminoaryl)acetamido]-cephalosporin derivatives. III. Synthesis and structure-activity relationships in the aminothiadiazole series.

The synthesis and in vitro antibacterial activity of 7 beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-oxyiminoacetamido] cephalosporins with various substituents at the 3-position in the cephem nucleus are described. Aminothiadiazolyl cephalosporins having pyridiniomethyl groups at the 3-position exhibited excellent activity against all organisms, particularly against Pseudomonas aeruginosa.

Synthesis and antibacterial activity of 7 beta-[1-(2-aminothiazol-4-yl)-1-cyclopropanecarboxyamido]cephem derivatives.

The synthesis and antibacterial activity of several 7 beta-[1-(2-aminothiazol-4-yl)-1-cyclopropanecarboxyamido]cep hem derivatives (1) are described. The structure-activity relationships of 1 are also presented.

Studies on beta-lactam antibiotics. XIX. Structure-activity relationships of cephalosporins having a thiadiazolylthiomethyl group at the C-3 side chain.

The synthesis and antibacterial activity of 7 beta-[(Z)-2-(2-amino-4-thiazolyl)-2-(hydroxy or alkoxy)iminoacetamido]cephalosporins with various thiadiazolylthiomethyl moieties at the 3-position are discussed. Of the compounds (1a-1e, 7a-7d), 7 beta-[(Z)-2-(2-amino-4-thiazolyl)-2-hydroxyiminoacetamido]-3-[(1,2 ,4- thiadiazol-5-yl)thiomethyl]cephalosporin (1d: FK312) exhibited the highest activity against Gram-positive and Gram-negative bacteria, especially, against methicillin-resistant Staphylococcus aureus. Furthermore, the pharmacokinetic profiles of the compound 1d showed longer serum levels than that of ceftriaxone in rats.

Synthesis and structure determination of FR109615, a new antifungal antibiotic.

The structure of FR109615, a new antifungal antibiotic, was determined to be (1R,2S)-2-aminocyclopentane-1-carboxylic acid ((-)-cis-2-ACPC: 8a) by X-ray analysis. (-)-cis-2-ACPC (8a) was also synthesized via optical resolution of 3a and 3b derived from (+/-)-cis-2-ACPC hydrochloride (1). 8a showed potent antifungal activity, while its antipode (+)-cis-2-ACPC (8b) had no activity.

Studies of 7 beta-[2-(aminoaryl)acetamido]-cephalosporin derivatives. I. Synthesis and structure-activity relationships in the aminopyridine series.

The synthesis and in vitro activity of 7 beta-(2-aminopyridyl-2-alkoxyiminoacetamido)cephalosporins with various substituents at the 3-position are described. The effects of substitution pattern on the pyridine ring, oxime substituent and 3-substituent were studied as a function of the MIC values. Of these various kinds of derivatives, 7 beta-[2-(2-aminopyridin-6-yl)-2-alkoxyiminoacetamido]cephalo sporins exhibited significantly higher activity against most of micro-organisms.

Studies of 7 beta-[2-(aminoaryl)acetamido]-cephalosporin derivatives. II. Synthesis and structure-activity relationships in the aminopyrimidine series.

The synthesis and the antibacterial activity of 7 beta-[2-(aminopyrimidinyl)-2-oxyiminoacetamido]cephalosporin s with various substituents at the 3-position in the cephem nucleus are described. The 7 beta-[2-(4-aminopyrimidin-2-yl)-2 -methoxyiminoacetamido]cephalosporin derivative (1) showed significantly higher activity than the corresponding 2-aminopyrimidin-4-yl derivative (2) against Gram-negative bacteria. It was also higher in potency against Escherichia coli and Serratia marcescens than the aminopyridyl compound (4).

Synthesis and biological activity of 3-vinylthio- and 3-vinylthiomethylcephem derivatives.

The synthesis and biological properties of some 3-vinylthio- and 3-vinylthiomethylcephem derivatives are described. Both series possess potent antibacterial activity. Among them, 3-[(Z)-2-cyanovinylthiomethyl]cephem derivative was found to have an expanded antibacterial spectrum.

Structure activity relationships of synthetic antibiotic analogues of chryscandin.

Anti-yeast activity with a series of chryscandin derivatives showed that the O-methyl-L-tyrosyl moiety is not always required for activity at the target site. On the other hand, the adenyl-3'-aminoribofuranuronic acid moiety seems to be essential for biological activity. Therefore, the various acyl derivatives on the amino group of the sugar part of the nucleoside were synthesized. 1-(6-Amino-9H-purin-9-yl)-3-(S-benzyl-L-cysteinylamino)- 1,3-dideoxy-beta-D-ribofuranuronic acid (16) showed the highest efficacy among them against Candida albicans. It exhibited sixteen-fold enhanced activity in vitro compared with that of native chryscandin. The in vivo activity of 16 against experimental infection of C. albicans showed the almost same as that of 5-fluorocytosine and a superior to that of ketoconazole.

Synthesis and biological activity of 7 alpha-hydroxyethyl-1-oxacephem derivatives.

A series of 7 alpha-hydroxyethyl-1-oxacephems (1) was synthesized. The main focus of this study was to investigate biological activity relationships between 1-oxacephems (1) and the corresponding cephems (2). Replacement of the sulfur atom of 2 by the oxygen atom caused an enhancement of antibacterial activity, although the antibacterial activity of 1 was not high enough. Additionally 1 showed beta-lactamase inhibitory activity, especially against cephalosporinase. However, the potency was lower than that of 2.

Chryscandin, a novel peptidyl nucleoside antibiotic. II. Structure determination and synthesis.

The structure of chryscandin, a novel antifungal antibiotic, produced by Chrysosporium pannorum No. 4629 was deduced to be 1 from spectroscopic and chemical evidences. In order to confirm the structure and to determine the absolute configuration, the total synthesis of chryscandin was performed. D-Xylose was transformed into 10 in ten steps. After beta-glycosidation of silylated benzoyl adenine with 10, the resulting 11 was converted into 4, which was identical with the product obtained from chryscandin by alkaline hydrolysis. From the key intermediate 13, chryscandin was synthesized via peptide formation followed by removal of the protecting groups. Chryscandin (1) is the first naturally occurring nucleoside antibiotic possessing a 3-aminoribofuranuronic acid in the molecule.

Effects of metal combinations on cytotoxicity evaluation using a dynamic extraction method.

The effects of metal combinations on cytotoxicity were examined following dynamic extraction by freely gyrating two spherical metals in a glass vessel. The cell viabilities of an Au alloy, a Ag-Pd-Au alloy and Ti were little affected by combinations among three metals. Cell viability ranged between 60 and 80% when precious alloys were in combination with Co-Cr or Ni-Cr alloys. Ti showed a clear difference in cell viability either in combination with Co-Cr or Ni-Cr alloys. The cell viability of the Ti/Co-Cr alloy combination was the same as that of precious alloys/Co-Cr or Ni-Cr alloy combinations. However, in an analogy with Co-Cr alloy/Ni-Cr alloy combination, the Ti/Ni-Cr alloy combination depressed the cell viability below 20%. This suggested that when new metals are to be used in combination with dissimilar metals, the cytotoxicity of the metals could be evaluated in extraction conditions using the mutual dynamic contact of dissimilar metals.

[Studies on FK482 (Cefdinir). III. Synthesis and structure-activity relationships of 7 beta-[(Z)-2-aryl-2-hydroxyiminoacetamido]-3-vinyl-3- cephem-4-carboxylic acid derivatives].

The synthesis, antibacterial activity and oral absorption of the 7 beta-[(Z)-2-aryl-2-hydroxyiminoacetamido]-3-vinylcephalosporins (Ia--e) are described. All of these compounds exhibited excellent activity against Staphylococcus aureus. Against Gram-negative bacteria FK482 exhibited more excellent activity than the other compounds (Ia--e). These compounds except Ie showed good oral absorption. The relationship between the oral absorption rates and the lipophilicity of these cephalosporins is discussed.

[Studies on FK482 (Cefdinir). IV. Synthesis and structure-activity relationships of 7 beta-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]- 3-substituted cephalosporin derivatives].

The synthesis of 7 beta-[(Z)-2-(aminothiazol-4-yl)-2-hydroxyiminoacetamido] cephalosporins (Ia-i) modified at the C-3 position of a cephem nucleus and the effect of the C-3 substituents on the antibacterial activity and oral absorbability are discussed. The cephems (Ie, h and i) having a C-3 substituent such as 1-propenyl, ethylthio and vinylthio group as well as FK482 (cefdinir) exhibited excellent antibacterial activities against both gram-positive and gram-negative bacteria. However, those compounds showed poor absorption rate after oral administration in rats. It is concluded that the vinyl moiety at the 3-position is necessary to display fairly oral absorptivity in a series of 7 beta-[(Z)-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]c eph ems.

[Research and development of new oral cephems, cefixime and cefdinir].

This article reviews the structure-activity relationships, biological properties and synthesis of two new oral cephalosporin antibiotics, cefixime (CFIX) and cefdinir (CFDN). Our research into new oral cephalosporin antibiotics began in the late 1970's. The first goal of our research was to discover a new oral cephem possessing similar antibacterial activity and resistance to beta-lactamase as the 3rd generation injectable cephalosporins. We focused our attention on searching for a non-prodrug type cephem, that is, a new parent structure with high intrinsic absorption. We selected ceftizoxime (CZX) as a seed compound due to its relatively high excretion rate (8.5%) in the urine after oral administration to rats. We concentrated our research on the chemical modification of the oxime moiety in CZX based on our hypothesis for oral absorption, and discovered a lead compound with a carboxymethoxyimino group which displayed better urinary excretion (41.0%). Optimization studies led to a new oral cephem, CFIX. However, CFIX shows only low to moderate antibacterial activity against gram-positive bacteria such as S. aureus. Hence, the second goal of our research was to discover a new oral cephem with enhanced activity against gram-positive bacteria. From a consideration of structure-absorption relationships, we studied the activity and absorbability of cephems bearing other acidic functional groups at the oxime moiety of CFIX. As a result, we found a new oral cephem, CFDN with a hydroxyimino group at the 7-position. CFIX has excellent biological properties, displaying potent antibacterial activity against a wide range of gram-positive bacteria except S. aureus and gram-negative bacteria including opportunistic pathogens, high stability towards beta-lactamases and long acting efficacy. CFDN exhibits excellent and well balanced antibacterial activities against gram-positive and gram-negative bacteria. The pharmacokinetic of CFDN in healthy volunteers showed that serum levels were high enough to make CFDN as an effective antibacterial agent. The proposed mechanisms of intestinal absorption of CFIX and CFDN are briefly described. The efficient synthetic methods to CFIX and CFDN were achieved via a common intermediate, 7-amino-3-vinylcephalosporanic acid diphenylmethyl ester from 7-ACA.

[Studies on FK482. II. Synthesis and structure-activity relationships of 7 beta-[(Z)-2-(2-aminothiazol-4-yl)-2-substituted acetamido]-3-vinyl-3-cephem-4-carboxylic acid derivatives].

Various 7 beta-[2-(2-aminothiazol-4-yl)-2-substituted acetamido]-3-vinyl-3-cephem-4-carboxylic acid derivatives (Ia--e, IIa--g) were synthesized in order to find a new orally active cephalosporin improving the antibacterial activity of cefixime (CFIX) against Staphylococcus aureus. These derivatives include three types of alpha-substituted 2-(2-aminothiazol-4-yl)acetyl side chain; i) mono or non substituted acetyl moiety, ii) carboxyalkoxyimino acetyl moiety, iii) phosphonomethoxyimino and hydroxyimino acetyl moiety. Their structure-activity relationships and urinary recoveries in rats were studied. As a result, the compound with a hydroxyimino acetyl side chain (IIg, FK482) showed good oral absorption and excellent antibacterial activity against both gram-positive and gram-negative bacteria and was selected as a candidate for clinical trial.

[A new oral cephem, cefdinir: its structure-activity relationships and biological profile].

This article reviews structure-activity relationships and biological properties of a new oral cephem, cefidinir (CFDN). It also describes a hypothesis concerning the absorption mechanism from the intestine. Antibacterial activities and the oral absorption efficiencies were studied with regard to 3-vinyl cephalosporins with various 7-acyl side chains. From the study, 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetyl group was selected and various 3-substituents were screened. As a result, it was found that the vinyl compound, CFDN, showed excellent antibacterial activity and good oral absorption in rats. In vitro and in vivo antibacterial activities, the affinity for PBPs and the stability to beta-lactamases revealed that CFDN had well balanced antimicrobial activities against Gram-positive and Gram-negative bacteria and good biological properties. The pharmacokinetics of CFDN in healthy volunteers showed that serum concentration and half life were good enough to make CFDN an effective therapeutic agent. The mechanism of intestinal absorption of CFDN and related oral cephems are discussed and a hypothesis for molecular recognition by the carrier protein in the intestine is proposed.

Cellular and molecular studies of the effects of a selective COX-2 inhibitor celecoxib in the cardiac cell line H9c2 and their correlation with death mechanisms.

Cardiovascular disease is one of the leading causes of death worldwide, and evidence indicates a correlation between the inflammatory process and cardiac dysfunction. Selective inhibitors of cyclooxygenase-2 (COX-2) enzyme are not recommended for long-term use because of potentially severe side effects to the heart. Considering this and the frequent prescribing of commercial celecoxib, the present study analyzed cellular and molecular effects of 1 and 10 µM celecoxib in a cell culture model. After a 24-h incubation, celecoxib reduced cell viability in a dose-dependent manner as also demonstrated in MTT assays. Furthermore, reverse transcription-polymerase chain reaction analysis showed that the drug modulated the expression level of genes related to death pathways, and Western blot analyses demonstrated a modulatory effect of the drug on COX-2 protein levels in cardiac cells. In addition, the results demonstrated a downregulation of prostaglandin E2 production by the cardiac cells incubated with celecoxib, in a dose-specific manner. These results are consistent with the decrease in cell viability and the presence of necrotic processes shown by Fourier transform infrared analysis, suggesting a direct correlation of prostanoids in cellular homeostasis and survival.