Synthesis and antimicrobial evaluation of acyl derivatives of 16-membered macrolide antibiotics related to tylosin

A large number and wide variety of acyl derivatives of the tylosin-related macrolides 23-demycinosyltylosin (DMT), 23-demycinosyloxytylosin (DMOT) and 5-O-mycaminosyltylonolide (OMT) were synthesized and evaluated. This encompassed conversion of the hydroxyl groups at 2',4' and 23 of the appropriate macrolides to the corresponding esters, in which a variety of different substitution patterns were examined. A wide range of acyl substituents was investigated, particularly for 23-O-acyl derivatives of OMT, since these were substantially more active in vitro than OMT itself. However, the acyl derivatives which were prepared demonstrated no substantial improvement in oral efficacy or bioavailability over the parent macrolides.     

Microbiological and pharmacokinetic studies on flomoxef in ophthalmologic field

Microbiological and pharmacokinetic studies were carried out on flomoxef (FMOX, 6315-S), a new oxacephem parenteral antibiotic, in the ophthalmologic field. The results obtained are summarized as follows. FMOX has a broad antimicrobial activity spectrum against Gram-positive and Gram-negative bacteria. The MIC distribution against Staphylococcus aureus isolated from clinical cases was less than or equal to 0.20 - greater than or equal to 100 micrograms/ml with the peak value of 0.39 micrograms/ml. Concentrations of FMOX in aqueous humor and ocular tissues were determined after intravenous injection of 50 mg/kg to rabbits. FMOX showed a peak level of 2.2 micrograms/ml in the aqueous humor at 1/2 hour after administration with the ratio to serum level of 3.4%. Levels of FMOX in external and internal ocular tissues were 12.7 - 76.5 micrograms/g, less than 0.8 - 34.4 micrograms/g (ml) at 1/2 hour after administration, respectively. From these results, we concluded that FMOX may be expected to be a useful and valuable agent against infections in the ophthalmologic field.     

Chemical modification of tylosin. Thioether derivatives of tylosin and demycarosyltylosin

Thioether derivatives of tylosin and demycarosyltylosin were synthesized by Michael-type addition of thiol to C-11 of the enone moiety on the aglycone. Some of tylosin derivatives were effective to macrolide resistant Staphylococcus aureus, and their in vivo activities were same or superior than that of tylosin.     

New amidino-benzimidazolyl derivatives of tylosin and desmycosin

New amidino-benzimidazolyl derivatives of antibiotics tylosin and desmycosin are prepared in the reaction of corresponding amidino-substituted o-phenylendiamine with tylosin respectively desmyicosin on the 20-C aldehyde group. The reaction was carried out in absolute ethanol in the presence ofp-benzoquinone. On this way are prepared: 20-[5-(N-isopropylamidino)-2-benzimidazolyl]tylosin hydrochloride 9, 20-[5-(2-imidazolinyl)-2-benzimidazolyl]tylosin hydrochloride 10, 20-[5-(N-morpholinylamidino)-2-benzimidazolyl]tylosin hydrochloride 11, 20-[5-(N-isopropylamidino)-2-benzimidazolyl]desmycosin hydrochloride 12, 20-[5-(2-imidazolinyl)-2-benzimidazolyl]desmycosin hydrochloride 13, 20-[5-(N-morpholinylamidino)-2-benzimidazolyl]desmycosin hydrochloride 14. Their antimicrobial activity was tested on a series of microorganisms.     

Preparation and evaluation of 3,4'-ester derivatives of 16-membered macrolide antibiotics related to tylosin

A large group of ester derivatives of tylosin-related macrolides was prepared in which the hydroxyl groups at C-3 and C-4' were acylated by either chemical or biochemical methods. Most of the derivatives exhibited excellent in vitro antimicrobial activity. However, only the 3,4'-diacyl derivatives of tylosin and macrocin showed any significant improvements of in vivo efficacy against experimental infections in rodents.     

Microbiological, pharmacokinetic and clinical studies of rokitamycin dry syrup in the pediatric field

Rokitamycin (RKM), a newly developed macrolide antibiotic with a 16-membered ring, dissolves well under acidic conditions. It has been improved over other macrolides to minimize individual variations in its absorbability. We measured, using the GA-test, variations in gastric acidities of 43 children with ages between 1 to 14 years, and investigated the relationship between gastric acidities and pharmacokinetic values. Also activities (expressed in MICs) of antimicrobial agents were studied against clinically isolated 229 bacterial strains using an inoculum size of 10(6) cells/ml. Tested organisms included Streptococcus pyogenes (77 strains), Streptococcus agalactiae (29), Streptococcus pneumoniae (2), as Gram-positive cocci, and Haemophilus influenzae (1), Haemophilus parainfluenzae (1), Bordetella pertussis (12), Salmonella sp. (4) and Campylobacter jejuni (103) as Gram-negative bacilli. Against stock strains of bacteria, MICs of 10 drugs (RKM, erythromycin (EM), josamycin (JM), midecamycin (MDM), midecamycin acetate (MOM), clindamycin (CLDM), amoxicillin (AMPC), cefaclor (CCL), minocycline, ofloxacin (OFLX] were determined. Against isolates from patients who underwent treatment with RKM, MICs of only 4 drugs (RKM, EM, JM, MOM) were determined. Measurements were made on plasma and urinary concentrations of RKM and its urinary recovery rates after patients including 6 boys with ages between 5 years 1 month and 11 years 6 months were administered with RKM (dry syrup). Two groups of 6 boys were administered between meals with RKM at dose levels of 5 and 10 mg/kg, respectively. Clinical and bacteriological effects of RKM were evaluated for 175 patients including 5 cases of pharyngitis, 3 tonsillitis, 32 pneumonia, 17 mycoplasmal pneumonia, 34 atypical pneumonia, 28 streptococcal infections, 29 Campylobacter enteritis, 4 Salmonella gastroenteritis, and 23 enteritis due to unknown organisms. Five drop-out cases were excluded from the evaluations. In the evaluable cases, an average dose level used was 31.8 mg/kg/day, with a daily dose divided into 3 to 4 administrations and with an average treatment duration of 9 days. Adverse reactions of RKM and its effects on laboratory test values were investigated in these patients including the drop out cases. Obtained results of these studies are summarized below. 1. The GA-test produced pH values indicating that amounts of gastric acid were mostly either normal or high in 42 of the 43 subjects tested (97.7%), and only one low acid case (2.3%) was observed.(ABSTRACT TRUNCATED AT 400 WORDS)     

Quantum chemical studies on clonidine and related derivatives

The ground state geometry of the protonated form of clonidine was established by CNDO/2 (complete neglect of differential overlap) calculations. For the interplanar angle of this molecule we found a value of about 40 degrees. The interplanar angles of a number of clonidine related derivatives, both bases and protonated forms, were calculated on the basis of the results obtained for clonidine by taking into account the bond lengths and van der Waals radii of the substituents present at the ortho positions of the phenyl ring. The preferred conformations of the free bases and protonated forms were used as inputs for the semi-empirical PPP-MO (Pariser, Parr and Pople molecular orbital) calculation procedure in order to obtain several quantum chemical parameters. Excellent correlations resulted in relating some of the calculated parameters with the experimentally determined pK'a of the molecules. The results show the ability of MO-calculations to predict the basicity in this series of congeneric molecules and furthermore support the reliability of the calculation procedure in providing the quantum chemical parameters reported in this paper.     

Skin permeation of acyl derivatives of stobadine

Stobadine is a model drug with pyridoindole structure with cardioprotective and antioxidant properties. Permeation properties of its acyl derivatives were studied to find a proper prodrug form. The experimental study of transdermal delivery of derivatives was combined with the theoretical approach in which the partition coefficients of substances were estimated by means of fragmentation or quantum chemical calculations. All modes applied showed differences in the transport properties of derivative S1 (N-acetyl stobadine). The experimental results obtained for the flux of S1 were higher by one order of magnitude than for the other derivatives and the parent drug. The results are discussed from the point of view of physicochemical properties of derivatives. We concluded that the exceptional permeation value of S1 derivative results from the concurrence of partitioning coefficient, dissociation constant, and arrangement of permeation set.     

New derivatives of tylosin: chemical and electrochemical oxidation products of desmycosin

Chemical and electrochemical oxidation of dienonic moiety of desmycosin were carried out. Successive chemical oxidation of desmycosin with m-chloroperbenzoic acid afforded a family of 12,13-dihydro-12,13-dihydroxy derivatives. Indirect electrochemical oxidation via hypobromite as an intermediate gave rise to the new bicyclo derivative of desmycosin, 13-hydroxy-3-dehydroxy-3,12-oxa-desmycosin.     

Synthesis and anti-inflammatory activity of acyl derivatives of taraxasterol

Acylation of taraxasterol with acid chloranhydrides in the presence of N-dimethylaminopyridine yielded the new compounds 3β-acetoxy-20-methylidenetaraxastane, 3β-trifluoroacetoxy-20-methylidenetaraxastane, and 3β-benzoyl-20-methylidenetaraxastane. The antiphlogistic activities of taraxasterol and its acyl derivatives were studied. All study compounds had anti-inflammatory activity comparable to that of reference agent prednisolone. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 42, No. 6, pp. 12–14, June, 2008.     

HPLC法测定泰乐星中的相关物质

目的建立泰乐星中相关物质的测定方法。方法采用高效液相色谱法,紫外检测器,检测波长290nm;C18不锈钢色谱柱(200mm×4.6mm,5μm);柱温35℃;流动相为200g/L高氯酸钠∶乙腈(60∶40)并用1mol/L HCl调节pH至2.5;流速1.0ml/min;进样量20μl,峰面积归一化法计算。结果各相关物质峰保留时间及峰面积的RSD分别为0.65%和2.25%;各峰的分离度均不小于1.5。结论本法简便、灵敏、专属。