1. [Thrombin inhibitors which display antibacterial activity]
A A Poiarkov, N A Timoshok, N Ia Spivak, S A Poiarkova Ukr Biokhim Zh (1999). 2010 Jan-Feb;82(1):123-9.
The investigation of cytotoxicity and antibacterial activity of the novel thrombin inhibitors containing retro-D-sequences -D-Arg-D-Phe--modified by D-arginine amino group by the residues of lauric acid or chromone-contained substituent, in comparison with known cationic preservative Nalpha-lauroyl-L-arginine ethyl ester (LAE) have been carried out. It has been shown that compound Laur-D-Arg-D-Phe-OMe has a similar cytotoxicity with LAE, and Chrom-D-Arg-D-Phe-OMe has almost twice higher toxicity than it fatty moiety contained analogues. Antibacterial activity of Laur-D-Arg-D-Phe-OMe against Staphylococcus aureus and Bacillus subtilis is close in action to LAE. It is assumed that ability of thrombin inhibitors to suppress the growth of some microorganisms can be explained by their ability to suppress activity of trypsin-like serine proteinases, which participate in the infection process of Staphylococcus aureus and influence on Bacillus subtilis sporulation. These findings open new prospects for exploring efficient antimicrobial agents among synthetic low-molecular trypsin-like serine proteinase inhibitors.
2. [Analysis of the relationship between the reactivity of synthetic substrates and thrombin inhibitors and their structure]
V K Kibirev, A A Gershkovich, S B Serebrianyĭ Ukr Biokhim Zh (1978). 1983;55(3):271-6.
Kinetics of thrombin- and trypsin-catalyzed hydrolysis of diphenylacetyl-L-arginine esters was studied at pH 8.5 and 25 degrees C, and the antithrombin activity of in vitro synthesized compounds was examined. The anticlotting activity of arylsulphonyl-L-arginine methyl esters appeared to be higher than that of the derivatives of diphenyl arginine. Relations were found connecting polar (delta) and steric (Es) characteristics of substituent (R) in R-C6H4-SO2-Arg-OCH3 esters with their antithrombin activity in vitro or with efficiency of their thrombin-catalyzed hydrolysis. This gives supplementary possibilities for synthesis of new substrates and more potent thrombin inhibitors.
3. Thrombin inhibitors. 1. Ester derivatives of N alpha-(arylsulfonyl)-L-arginine
S Okamoto, K Kinjo, A Hijikata, R Kikumoto, Y Tamao, K Ohkubo, S Tonomura J Med Chem. 1980 Aug;23(8):827-30. doi: 10.1021/jm00182a003.
A series of N alpha-(arylsulfonyl)-L-arginine esters was prepared and tested as inhibitors of the clotting activity of thrombin. N alpha-Dansyl-L-arginine methyl ester was the most inhibitory of the N alpha-(arylsulfonyl)-L-arginine methyl esters. The most potent inhibitors were the n-propyl and n-butyl esters of N alpha-dansyl-L-arginine with an I50 of 2 X 10(-6) M. Esters of unsaturated straight-chain alcohols with a chain length of four carbons were also as inhibitory as the n-butyl ester. The inhibitors were hydrolyzed by thrombin and trypsin more slowly than N alpha-tosyl-L-arginine methyl ester.
