Novel 17-membered azalides of N-methylated amine type were synthesized and their antibacterial activity was evaluated.

A series of modifications to the terminal guanidine group of the arginine residue in tripropeptin C was performed, and the corresponding pyrimidine derivatives were synthesized as a part of a structure-activity relationship study. Some of the resulting compounds maintained excellent antibacterial activity. Our findings indicated that the guanidine group in tripropeptin C is not essential for the antibacterial activity of this compound, and the possibility of chemical modification of the guanidine group was demonstrated.

Arbekacin, an aminoglycoside antibiotic, is an important drug because it shows a potent efficacy against methicillin-resistant Staphylococcus aureus . However, resistance to arbekacin, which is caused mainly by the bifunctional aminoglycoside-modifying enzyme, has been observed, becoming a serious problem in medical practice. To create new arbekacin derivatives active against resistant bacteria, we modified the C-4″ and 6″ positions of its 3-aminosugar portion. Regioselective amination of the 6″-position gave 6″-amino-6″-deoxyarbekacin (1), and it was converted to a variety of 6″- N -alkanoyl derivatives (6a−z). Furthermore, regioselective modifications of the 4″-hydroxyl group were performed to give 4″-deoxy-4″-epiaminoarbekacin (2) and its 4″- N -alkanoyl derivatives (12 and 13). Their antibacterial activity against S. aureus , including arbekacin-resistant bacteria, was evaluated. It was observed that 6″-amino-6″- N -[( S )-4-amino-2-hydroxybutyryl]-6″-deoxyarbekacin (6o) showed excellent antibacterial activity, even better than arbekacin.

Synthesis and antibacterial activity of 1- N -[( S )-ω-amino-2-hydroxyalkyl] derivatives of dibekacin, 5-deoxydibekacin, 3′-deoxykanamycin A and gentamicin B

Methylene sp3 carbon–hydrogen bond activation of N-picolinoylcycloalkylamines provides a useful method for synthesizing cis-3-arylated cycloalkylamine derivatives. Pd(II) species catalyzed the γ-arylation of N-picolinoylcycloalkylamines with aryl iodides in the presence of silver carbonate to afford cis-3-arylated N-picolinoylalkylamines in up to 87% yield. Hydrolysis of the amide linkage to give the corresponding cis-3-arylated cycloalkylamines was also demonstrated.

Acidic treatment of a mixture of caprazamycins (CPZs) A–G isolated from a screen of novel antimycobacterial agents gave caprazene, a core structure of CPZs, in high yield. Chemical modification of the resulting caprazene was performed to give its various derivatives. The structure–activity relationships of the caprazene derivatives against several mycobacterial species and pathogenic Gram-positive and Gram-negative bacteria were studied. Although caprazene showed no antibacterial activity, the antibacterial activity was restored for its 1′′′-alkylamide, 1′′′-anilide and 1′′′-ester derivatives. Compounds 4b (CPZEN-45), 4d (CPZEN-48), 4f and 4g (CPZEN-51) exhibited more potent activities against Mycobacterium tuberculosis and M. avium complex strains than CPZ-B. These results suggest that caprazene would be a good precursor from which novel semisynthetic antibacterial antibiotics can be designed for the treatment of mycobacterial diseases such as tuberculosis and M. avium complex infection.

Synthesis and antibacterial activity of tripropeptin C derivatives modified at the carboxyl groups

Novel antibiotics, active against acid-fast bacteria, caprazamycins, were isolated from the culture broth of Streptomyces sp. MK730-62F2. The planar structures of the compounds were determined by 2D NMR spectroscopic study. Furthermore, the absolute structure of caprazamycin B (2) was established by NMR spectroscopy and X-ray crystallography of its degradation products and by total synthesis of the 5-amino-5-deoxy-D-ribose moiety. In the course of degradation studies of 2 under alkaline and acidic conditions, we obtained the two core components, caprazene (11) and caprazol (14), respectively, in high yield.Structurally, caprazamycins belong to a family of lipo-uridyl antibiotics, which have been discovered as specific inhibitors of a bacterial translocase.

Novel antibiotics, active against acid-fast bacteria, caprazamycins, were isolated from the culture broth of Streptomyces sp. MK730-62F2. The planar structures of the compounds were determined by 2D NMR spectroscopic study. Furthermore, the absolute structure of caprazamycin B (2) was established by NMR spectroscopy and X-ray crystallography of its degradation products and by total synthesis of the 5-amino-5-deoxy-D-ribose moiety. In the course of degradation studies of 2 under alkaline and acidic conditions, we obtained the two core components, caprazene (11) and caprazol (14), respectively, in high yield. Structurally, caprazamycins belong to a family of lipouridyl antibiotics, which have been discovered as specific inhibitors of a bacterial translocase.

Optically pure 1d-chiro-inositol (DCI) has been synthesized from optically inactive myo-inositol practically in four steps. The crystalline nature of most intermediates and the utilization of inexpensive reagents facilitate the economical mass production of DCI, which is expected to be used in the future for treatment of Type 2 diabetes and polycystic ovary syndrome (PCOS).

This paper describes the chemical transformation of the basic 16-membered macrolides, tylosin derivatives, into neutral macrolides having a 3'-methoxyl group. 2',4'-Di-O-acetyl-3,23-bis(O-tert-butyldimethylsilyl)mycaminosyltylon olide 9,20-bis(ethylene acetal) N-oxide (1b) was treated with Ac2O-pyridine in CH2Cl2 to afford the 3'-ketone 1c and the 3'-N-acetyl-3'-N-demethyl derivative 1d in 67 and 5% yield; respectively. Reduction of 1c with Zn(BH4)2 gave the 3'-alcohol 1e in 84% yield stereoselectively. O-Methylation of 1e with MeOTf and 2,6-di-tert-butylpyridine gave the 3'-methyl ether 1f in 49% yield in spite of the presence of the adjacent acetoxyl groups. Deprotection of 1f provided the desired neutral macrolide 1g. Similar synthetic routes were also used for transformation of the suitably protected 4'-deoxymycaminosyltylonolide 2b and desmycosin 3c into neutral macrolides having a 3'-methoxyl group. It was found that the mycinose moiety of a neutral macrolide plays an important role in its antimicrobial activity.

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