Yoshihisa Akiyama

Peptidyl α-keto thiazole as potent thrombin inhibitors

Abstract We report the synthesis and evaluation of α-keto thiazole derivatives such as D-Phe-Pro-Arg-thiazole 9 as a novel type of thrombin inhibitor. Tripeptidyl α-keto thiazole 9 exhibited the inhibitory activity of thrombin at nanomolar levels and showed a more potent prolongation effect on clotting time than argatroban at a dose of 3 mg/kg intravenously.

Design and synthesis of novel ring-expanded arbekacin analogues

Novel homologated aminoglycosides having a seven-membered ring were designed and synthesized by treatment of 5-keto arbekacin with diazomethane in CH 2 Cl 2 -Et 2 O. The ring-expanded arbekacin analogue showed good antibacterial activity against Staphylococcus aureus and Escherichia coli including aminoglycoside-resistant bacterial strain.

In vitro and in vivo antimicrobial activity of TS2037, a novel aminoglycoside antibiotic

To overcome serious methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa infections, we synthesized TS2037, 5,4″-diepi-arbekacin, a novel aminoglycoside antibiotic, and evaluated its biological properties. TS2037 showed broad-range, as well as robust antibacterial activities against Gram-positive and Gram-negative bacteria. The MIC50 and MIC90 of TS2037 against clinical isolates of MRSA (n = 54) were both 0.25 µg/mL, and no resistant strain was observed. The MIC50 and MIC90 of TS2037 against clinical isolates of P. aeruginosa (n = 54) were 1 and 4 µg/mL, respectively. TS2037 and arbekacin, anti-MRSA aminoglycoside, were more stable against AAC(6′)-APH(2″), aminoglycoside-6′-N-acetyltransferase and 2″-O-phosphotransferase, produced by resistant S. aureus than gentamicin. Therapeutic efficacies of TS2037 in the mouse models of systemic infection with MRSA were superior to those of arbekacin, vancomycin, and linezolid. The efficacy of TS2037 against systemic infection caused by P. aeruginosa producing AAC(6′)-II was superior to those of arbekacin and amikacin. In the nephrotoxicity risk screening, the release of free N-acetyl-β-d-glucosaminidase from the kidney epithelial cell line after treatment with TS2037 at 2.5 and 5.0 μM were 2.0 and 2.1 (U/L), respectively, which were about two times higher than those of arbekacin. In conclusion, TS2037 exhibited the most potent antibacterial activity among aminoglycosides tested against both MRSA and P. aeruginosa in vitro and in vivo, although its nephrotoxicity risk remains to be improved.