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 β-lactamase as the 3 rd 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 β-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.
This review summarizes selected 5 researches fitted to the present title : 1) the synthesis of 1α-hydroxyvitamin D3, 2) the synthesis of cis-2-cyclopentene-1, 4-diol, 3) the photochemical methods for the cyclobutane annelation to heteroaromatic compounds and for β-lactam synthesis, 4) the novel total synthetic method of modified nucleosides (e.g. C-nucleoside, N-nucleoside, and their carbocyclic derivatives) and its application to the synthesis of (-)-BCA [1R, 4S, 5R-(4, 5-bishydroxymethylcyclopent-2-en-1-yl)-9H-adenine] having anti-HIV activity, and 5) the creation of chiral 1, 3-dihetero six-membered ring compounds as novel synthetic intermediates for enantiomerically pure compounds. All the mothods described are practicable (e.g. easy to handle, applicable to large scale preparation, and wide applicability). Among researches 4 and 5, the followings are notable achivements. For 4, BCA is the first nucleoside analog having non-natural sugar moiety. The use of di-l-menthylacetoxymethylenemalonates as dienophiles has offered new cooperative concept in asymmetric Diels-Alder reactions. Reductive retrograde aldol reaction and sodium borohydride-mediated amide bond cleavage reactions developed in this study have been shown to have wide applicability. For 5, several chiral dihetero six-membered compounds (e.g. 1, 3-dioxin-4-ones, 1, 3-dioxane-4, 6-diones, and 1, 3-oxazine-4, 6-diones) have been synthesized and used successfully for the synthesis of a variety of biologically active compounds (e.g. iridoids, Corey lactone, carbocyclic C-nucleoside, etc.). New proposal involving n-σ* interaction has been put forward to account for the boat conformation of 1, 3-oxazine-4, 6-diones.
Thirteen species of Iridaceae plants were studied with the capability to induce HL-60 promyelocytic leukemia cells into macrophages. The neutrophil stimulating activity in these plants was also examined by measuring superoxide production. Both activities are known to be possessed by tumor promoters such as 12-O-tetradecanoylphorbol-13-acetate (TPA). Dried parts of Iridaceae plants were extracted with methanol. Then, each extract was added to a culture medium of HL-60 cells and cultured for two days. A morphological change of the cells from suspended to adherent state, which was reported to occur in the process of differentiation, was observed. Nine species, most of which belong to the Iris genus, had the activity to cause cell adhesion. Each of the cell adhesion-positive extract was applied to a silica gel column and eluted with chloroform, ethyl acetate and methanol in order. The activity was recovered only in the ethyl acetate eluate in all the cases. Those partially purified fractions also activated superoxide generation of neutrophils. When ethyl acetate fractions of Iris tectorum and Iris japonica were analyzed by HPLC, three active peaks different from TPA and teleocidins in UV spectra were detected. From these results, it was suggested that several plants of Iridaceae may contain TPA-type and yet structurally-different tumor promoters.
γ-Hydroxybutenolides possessing conjugated substituents at the β-position and their related compounds have been synthesized by the previously reported procedure with minor modifications and their antiulcer activities have been examined in the HCl-ethanol induced ulcer model often used for the evaluation of gastric mucosal protective factor enhancing effect. The compound A-1 5-hydroxy-4-[2-(2, 6, 6-trimethyl-1-cycohexenyl-1-yl)-(E)-ethenyl]-2 (5H)-furanone showed a pronounced effect at a low dosage of 5 mg/kg p.o. and some analogues compounds also exhibited potent inhibitory activity as compared with the reference drugs. The relationship between the structure of γ-hydroxybutenolides and the antiulcer effect has been also examined and then the 5-hydroxyl group has been found to be essentially functional one to have antiulcer activity.
To elucidate the mechanism of anthelmintic action of bithionol, the inhibitory effect of the drug on NADH-fumarate reductase (NADH-FR) of Ascaris lumbricoides suum was examined. NADH-FR, an enzyme of anaerobic carbohydrate metabolic pathway was solubilized from the mitochondria of the worm's muscle with deoxycholate, and then partially purified with the monoethanolamine-Sepharose 4B column chromatography. Rhodoquinone (RQ), which is required for the electron transfer from NADH to fumarate, was separated from the enzyme protein and phospholipids. Although the enzyme protein fraction eluted from the above column did not show NADH-FR activity, this enzyme was reactivated by the addition of purified RQ and phosphatidylcholine. The IC50 value of bithionol for reconstituted NADH-FR was 18±2μM. The inhibition type was competitive to RQ. Bithionol inhibited at most 30% NADH-ferricyanide reductase, which did not require RQ, even at high concentration of 150μM. These results suggest that the pharmacological action of bithionol, a phenolic anthelmintic, depends on the inhibition of the electron transport system by the competition with RQ.
Three new phenolic compounds were isolated from methanol extracts of the leaves of Daphne pseudo-mezereum (Thymelaeaceae) and characterized as (-)-pinoresinol di-O-glucoside (1), 5-hydroxy-7-methoxy coumarin 8-O-β-D-glucoside (2), diosmetin 7-O-β-D-xylopyranosyl (1→6) β-D-glucopyranoside (3), respectively, together with six known compounds, using 1H-and 13C-NMR spectra.
Oxidative reactions of o-nitrophenylthio substituted 2-phenyl-3 (2H)-pyridazinones (3, 4, 13) with hydrogen peroxide were examined and o-nitrophenylsulfinyl compounds (5, 7, 14) and o-nitrophenylsulfonyl compound (6) were obtained. As the results of antibacterial antifungal screening tests in vitro, 3, 5 and 6 revealed strong antitrichophyton activities.