The antibiotic resistance phenomenon which is uncontrollably spreading worldwide has already become a problem of global dimensions and as such gives pharmaceutical industry all the more reasons to investigate new potential antibacterial targets and develop new antibacterial agents. Emerging “superbugs” which have developed resistance against all known antibacterial agents has forced us into development of antibacterial agents with a unique mechanism of action. DNA gyrase has an important biological role in process of DNA replication and has unique ability of introducing negative supercoils into circular DNA. Structural similarity with topoisomerase IV, which is also involved in modulation of DNA topology and DNA replication, opens a possibility of dual targeting of both enzymes. Its biological role, possibility of dual targeting and the fact that it is only present in prokaryotes make DNA gyrase an interesting target for development of new antibacterial agents. Within this master’s thesis we synthesized ethylurea derivatives of 2-aminothiazole as potential inhibitors of DNA gyrase. Since it is proven that ethylurea moiety can form key interactions with Asp73 and a bound water molecule we have introduced different substituents to improve physical and chemical properties of designed compounds. We originated from three starting compounds and as a result we have synthesized three different series of potential inhibitors with 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole, benzo[1,2-d]thiazole and thiazole as a central rings. The best inhibitory activity displayed pyrrolamide 6 (IC50 = 1,4 μM) of which, in spite of forming one hydrogen bond less than ethylurea moiety, it is pyrrolamide moiety that anchors the inhibitor in ATP binding site of DNA gyrase. The main reason for weak inhibitory activity of series with 4,5,6,7-tetrahydrobenzo[1,2-d]thiazole and thiazole central rings was inability of forming cation-π interactions between Glu50-Arg76 salt bridge and inhibitors. Series of inhibitors with unsaturated central rings which can form such interaction have shown 90-fold more potent inhibitory activity than their saturated analogs (IC50 = 3,9 μM against 350 μM). Antibacterial testing has shown weak antibacterial activity against Gram-positive bacteria and inactivity against Gram-negative bacteria. Additional testing indicated that these compounds are efflux pump substrates, thus reducing their cytoplasmic concentrations as the main reason for weak antibacterial activity or the lack of it, and not their penetration through cell wall.
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