Biological activity of 4-hydroxyisophthalic acid derivatives. Hydrazones with antimicrobial activity

The following hydrazono derivatives (I-XIX) of type (A) (sequence in text) where Rn = (sequence in text ) (I-XVII); (sequence in text) (XVIII); -CCl3 (XIX); and Xn = H (I); 2-Cl (II); 3-Cl (III); 4-Cl (IV); 2-NO2 (V); 3-NO2 (VI); 4-NO2 (VII); 2-OH (VIII); 3-OH (IX); 4-OH (X); 4-F (XI); 3,4-OCH3,OH (XII); 3,4,5-OCH3,OH,J (XIII); 3,4-OCH3,OCH3 (XIV); 2,4-Cl2 (XV); 3,4-Cl2 (XVI); 2,6-Cl2 (XVII); were prepared and characterized in an attempt to make available for testing a representative selection of hitherto unreported 4-hydroxyisophthalic acid derivatives. The new compounds in question were obtained in satisfactory yield by condensation of 4-hydroxyisophthalic acid hydrazide with the appropriate aldehydes. The prepared compounds were tested for their possible activity against Gram-positive (S. epidermidis, B. subtilis, B. anthracis) and Gram-negative bacteria (P. aeruginosa, B. melitensis, S. typhi O, S. typhi H, S. infantis, S. paratyphi B, E. coli Bb, E. coli 7075), and fungi (C. albicans, A. niger, S. cerevisiae). The "in vitro" antimicrobial assays were carried out using the paper disk technique (Kirby-Bauer modified). The influence of certain structural modifications on the antimicrobial activity was evaluated.     

Biological activity of 4-hydroxyisophthalic acid derivatives. II. Anilides with antimicrobial activity

A series of 1,3 -bis-anilides of 4-hydroxyisophthalic acid was prepared and tested for antibacterial and antifungal activity. The prepared compounds (I-XVIII), of general structure (A), (Formula: see text) where Xn = H (I); 2-F (II); 3-F (III); 4-F (IV); 2-Cl (V); 3-Cl (VI); 4-Cl (VII); 2-Br (VIII); 3-Br (IX); 4-Br (X); 2-J (XI); 3-J (XII); 4-J (XIII); 2,5-Cl2 (XIV); 2,4-Br2 (XV); 2,3,4-Cl3 (XVI), 2,4,5-Cl3 (XVII); 2,4,6-Cl3 (XVIII), were investigated for the purpose of determining the effect of halogen-substitution on the aniline rings of (A). All of these compounds were prepared in satisfactory hield by reaction of 4-hydroxyisophthalic acid with the appropriate aromatic amine at 175 degrees for 3 hours. The 1,3-bis-anilides prepared in this investigation were screened for antimicrobial activity by a disk-diffusion assay (Kirby-Bauer modified). The organisms used were laboratory cultures of S. aureus, B. subtilis, B. anthracis, M. paratuberculosis 607, E. coli Bb, S. typhi, S. typhimurium, S. paratyphi B, Pr. vulgaris, Kl. pneumoniae, Ps. aeruginosa, C. albicans, and A. niger. The results of this investigation indicated that most of the 1,3-bis-(halogen-anilides) of 4-hydroxyisophthalic acid had little or no antifungal activity "in vitro", while showed significant activity against Gram+ and Gram- bacteria. Some fluoro-derivatives showed inhibitory activity especially toward S. aureus and M. paratuberculosis. Iodo-derivatives showed broad-spectrum "in vitro" antimicrobial activity, and had some antifungal activity.     

Biological activity of 4-hydroxyisophthalic acid derivatives. III. Variously substituted anilides with antimicrobial activity

A series of 1,3-bis-anilides of 4-hydroxyisophthalic acid was prepared and investigated for antibacterial and antifungal activities. The prepared compounds (I-XIV), of the general formula (A), where Xn = 2-NO2 (I); 2,4-(NO2)2 (II); 2,4-NO2, Cl (III); 2,4-NO2,CF3 (IV); 3,4-NO2,Cl (V); 2,4-Cl,NO2 (VI); 2,5-Cl,NO2 (VII); 2,4,6-Cl,NO2,Cl (VIII); 2,4-Br, NO2 (IX); 2-CF3 (X); 3-CF3 (XI); 2,5-Cl,CF3 (XII); 2,5-CH3,Cl (XIII); 3,4-Cl,CH3 (XIV), were obtained in satisfactory yield by reacting 4-hydroxyisophthalic acid with the appropriate substituted aniline. (Formula: see text). The prepared compounds were tested for antimicrobial activity by a disk-diffusion assay (Kirby-Bauer modified). The organisms used were the following: S. aureus, B. subtilis, B. anthracis, M. paratuberculosis 607, E. coli Bb, S. typhi, S. typhimurium, S. paratyphi B, Pr. vulgaris, K1. pneumoniae, Ps. aeruginosa, C. albicans, and A. niger. The results of the antimicrobial screening showed that a number of substituted anilides exhibited varying degrees of activity against Gram-positive and Gram-negative bacteria, and fungi, nitro-halogen-derivatives being the most interesting members of the series.     

Microbial conversion of 5-sulfoisophthalic acid into 5-hydroxyisophthalic acid by Ochrobactrum anthropi S9

5-Hydroxyisophthalic acid-producing microorganisms were isolated from enrichment cultures using 5-sulfoisophthalic acid as a sulfur source. One bacterium, Ochrobactrum anthropi S9, had the highest 5-sulfoisophthalic acid-degrading activity, and stoichiometrically formed 5-hydroxyisophthalic acid, a raw material for polymer synthesis. Under optimum culture conditions, 1.3 mM 5-hydroxyisophthalic acid accumulated in the medium by 60 h. The addition of Na₂SO₄, l-methionine or l-cysteine at 2 mM inhibited the conversion of 5-sulfoisophthalic acid. O. anthropi S9 cells converted 5-sulfoisophthalic acid, benzenesulfonic acid, 3-sulfobenzoic acid, 4-aminobenzenesulfonic acid, naphthalene-1-sulfonic acid and naphthalene-2-sulfonic acid into the corresponding hydroxylated compounds.     

Renal amino acid excretion and aging

The urinary excretion and serum concentration of amino acids were studied in 62 healthy individuals aged 15 to 70 years. In elderly subjects (61-70 years), it was found that renal amino acid clearance per 100 ml GFR (fractional excretion, FE) rose significantly in the following amino acids: CYS, VAL, MET, ILE and LEU. Since the serum concentrations of these amino acids showed no significant changes, but the GFR was reduced, it can be concluded that the raised FE of these amino acids was due to a decrease in their effective tubular reabsorption. A significant correlation was found between FENa and FE of most amino acids including those mentioned above. The findings support the assumption that changes in tubular Na+ transport probably participate in the changes of tubular amino acid transport in elderly individuals.     

Absorption,metabolism and excretion of 3-acetyl don in pigs

The absorption, metabolism and excretion of 3-acetyldeoxynivalenol (3-aDON) in pigs were studied. Pigs with a faecal microflora known to be able to de-epoxidate trichothecenes were used in the experiment. The pigs were fed a commercial diet with 3-aDON added in a concentration of 2.5 mg/kg feed for 2.5 days. No traces of 3-aDON or its de-epoxide metabolite were found in plasma, urine or faeces. Deoxynivalenol (DON) was detected in plasma as soon as 20 min after start of the feeding. The maximum concentration of DON in plasma was reached after 3 h and decreased rapidly thereafter. Only low concentrations close to the detection limit were found in plasma 8 h after start of the feeding. A significant part of the DON in plasma was in a glucuronide-conjugated form (42 ± 7%). No accumulation of DON occurred in plasma during the 60 h of exposure. The excretion of DON was mainly in urine (45 ± 26% of the toxin ingested by the pigs) and only low amounts of metabolites of 3-aDON (2 ± 0.4%) were recovered in faeces. De-epoxide DON constituted 52 ± 15% of the total amount of 3-aDON-metabolites detected in faeces. The remaining part in faeces was DON. DON was still present in the urine and faeces at the end of the sampling period 48 h after the last exposure. The results show that no de-epoxides are found in plasma or urine in pigs after trichothecene exposure, even in pigs having a faecal microflora with a de-epoxidation activity. The acetylated form of the toxin is deacetylated in vivo. Furthermore, the experiment shows that the main part of DON is rapidly excreted and does not accumulate in plasma, but a minor part of the toxin is retained and slowly excreted from the pigs.     

Absorption and excretion of tablet disintegrating β-cyclodextrin polymer in rats

Absorption and excretion of a new tablet disintegrating agent, a crosslinked β-cyclodextrin polymer was investigated following per os administration in the rat. The polymer, which is insoluble but swells in water, was prepared from β-cyclodextrin by reacting with [2-¹⁴C]epichlorohydrin in an alkaline medium. Radioactivity of blood, urine, faeces, exhaled carbon dioxide and the gastrointestinal tract was determined by a liquid scintillation method. No radioactivity could be detected in the blood up to 24 h after the administration of the polymer. Radioactivity of urine and exhaled carbon dioxide together did not exceed 0·11% of the total administered radioactivity, 98% of which was found in the large intestine and the faeces. Therefore, it is assumed that β-cyclodextrin polymer could not be absorbed from the gastrointestinal tract.