Akira Manaka

Recent Developments in Macrolide Antimicrobial Research

Clarithromycin and azithromycin, which are more acid-stable than erythromycin A (EM), have been widely prescribed for the treatment of respiratory tract infections because of their high efficacy and safety. However, these macrolide antibiotics are only weakly active against pathogens with an efflux gene (mef) and are inactive against pathogens with a methyltransferase-inducible gene (erm) and constitutively resistant organisms. To address the drug resistance issue, tremendous efforts have been devoted to the modification of the macrolide structure. As a consequence, several types of decladinosyl derivatives, such as ketolide and acylides, have been recognized to be effective against mef-type resistant streptococci and methylase-inducible staphylococci. It has also been recognized that derivatives containing certain 11-, 6- or 4 -tethered aryl substituents, such as telithromycin (HMR 3647), cethromycin (ABT-773) and CP-544372, are effective against erm(B)-type resistant streptococci. Telithromycin was recently approved in several European countries for the treatment of respiratory tract infections and cethromycin is now in the final stage of clinical study. Macrolide antibiotics have been modified to address the issues of acid-instability and inactivity against resistant strains. In this review, we will summarize the progress in the macrolide research area and discuss the desirable features of the next generation macrolide antibiotics.

Synthesis of Aromatic Thioamide from Nitrile Without Handling of Gaseous Hydrogen Sulfide

Abstract A new method for synthesizing aromatic primary thioamides is described. Simple treatment of aromatic nitriles with sodium hydrogen sulfide and magnesium chloride in dimethylformamide (DMF) gave aromatic primary thioamides in yields of 80–99% without handling of hazardous hydrogen sulfide.

2-Acylimino-3H-thiazoline derivatives : A novel template for platelet GPIIb/IIIa receptor antagonists

In the course of our research for the low-molecular weight RGD peptide mimics, we have found that a rigid 2-acylimino-3H-thiazoline structure is suitable for the peptide backbone mimics. Introduction of amidinophenyl and beta-alanine moiety as arginine and aspartic acid side-chain surrogates to this backbone mimic resulted in a highly potent fibrinogen receptor antagonist 2-(4-amidinobenzoylimino)-3,4-dimethyl-N-(2-carboxyethyl)-3H-thiazoline-5-carboxamide (7c), namely PS-028 (Ki = 46.5 +/- 5.8 microM).

Synthesis and characterization of a potent and selective protein tyrosine phosphatase inhibitor, 2-[(4-methylthiopyridin-2-yl)methylsulfinyl]benzimidazole

The synthesis and biological activity of a series of 2-[(4-methylthiopyridin-2-yl)methylsulfinyl]benzimidazoles are described. These compounds have potent inhibitory effects against the protein tyrosine phosphatase activity of CD45. Enzymatic analysis with several phosphatases revealed that compound 5a had high specificity for CD45 compared with serine/threonine phosphatases (PP1, PP2A), tyrosine phosphatases (LAR, PTP1B and PTP-S2) and dual phosphatase (VHR).

TU-572, a Potent and Selective CD45 Inhibitor, Suppresses IgE-Mediated Anaphylaxis and Murine Contact Hypersensitivity Reactions

Background: CD45, receptor-type protein tyrosine phosphatases (PTPases) are essential components of signaling through both the T cell receptor and the B cell antigen receptor. However, the functional significance of CD45 in the signaling pathway through the high-affinity immunoglobulin (Ig) E receptor has not yet been established. In this study, we demonstrate that the potent CD45 inhibitor negatively regulates IgE-dependent anaphylaxis and contact hypersensitivity reactions. Method: We have previously found that TU-572, 2-[(4-methylthiopyridin-2-yl)methylsulfinyl]-5-isopropoxybenzimidazole, had a potent and selective inhibitory effect against PTPase activity of CD45. Using a CD45 inhibitor, we examined in vitro and in vivo IgE-mediated responses. Results: TU-572 potently inhibited histamine release from rat peritoneal mast cells and mouse systemic anaphylaxis reaction using monoclonal anti-dinitrophenyl (DNP) IgE and DNP-BSA. TU-572 also suppressed the immediate-type hypersensitivity response induced by repeated epicutaneous application of trinitrochlorobenzene in BALB/c mice. Conclusion: These findings revealed that the PTPase activity of CD45 played a critical role in signal transduction of IgE-mediated anaphylaxis in vitro and in vivo. PTPase inhibitors such as TU-572 are useful in the treatment of allergic diseases.

Synthesis and antibacterial activity of 6-O-(heteroaryl-isoxazolyl)propynyl 2-fluoro ketolides.

Macrolide antibiotics are widely prescribed for the treatment of respiratory tract infections; however, the increasing prevalence of macrolide-resistant pathogens is a public health concern. Therefore, the development of new macrolide derivatives with activities against resistant pathogens is urgently needed. A series of novel 6-O-(heteroaryl-isoxazolyl)propynyl 2-fluoro ketolides has been synthesized from erythromycin A. These compounds have shown very promising in vitro and in vivo antibacterial activities against key respiratory pathogens including erythromycin-susceptible/resistant strains.

Asymmetric synthesis of the sulfoxide metabolite of ON-579 by the kagan protocol

Abstract A synthesis of both enantiomers of bio-active metabolite of ON-579; 4-[2-(4-chlorophenyl-sulfonylamino)-ethylsulfinyl]-2,6-difluorophnoxyacetic acid was accomplished by the asymmetric oxidation of ON-579 methyl ester followed by hydrolysis. Difference in TXA 2 receptor antagonizing activity was noted for the enantiomers in an U46619-induced rabbit platelet aggregation inhibitory activity.

In vitro antibacterial activity of .ALPHA.-methoxyimino acylide derivatives against macrolide-resistant pathogens and mutation analysis in 23S rRNA

We characterized in vitro activities of α-methoxyimino acylides against macrolide-resistant clinical isolates of Streptococcus pneumoniae, Streptococcus pyogenes and Mycoplasma pneumoniae with ribosome modification or substitution and selected acylide-resistant mutants to clarify the binding point of the acylides. The acylides had low MICs against erm(B) gene-containing S. pneumoniae and S. pyogenes (MIC90s, 1–4 μg ml−1). For M. pneumoniae, although they had poor potencies against macrolide-resistant strains with the A2058G (Escherichia coli numbering) mutation in 23S rRNA (MICs, >32 μg ml−1), one of them showed in vitro activities against macrolide-resistant strains with the A2058U or A2059G mutations (MICs, 0.5–1 μg ml−1). These A2058U and A2059G mutant strains were used for the selection of acylide-resistant mutants. A genetic analysis showed that new point mutations in acylide-resistant mutants were found at G2576 in domain V of 23S rRNA and at Lys90 in L22 ribosomal protein. Furthermore, a molecular modeling study revealed that G2505/C2610, which enables stacking with G2576, might interact with a pyridyl moiety or an α-methoxyimino group at the 3-position of acylides. The α-methoxyimino acylides were shown to possess a tertiary binding point at G2505/C2610 in 23S rRNA. Our results suggest that α-methoxyimino acylides represent significant progress in macrolide antimicrobials.