Explorative Chemistry Delivers a Novel Lead Structure

Explorative Chemistry Delivers a Novel Lead Structure 

Generally, the outcome of the HTS was successful because for the first time small-molecule inhibitors of the enzymatic domain of catA were available. Unfortunately, the submicromolar hit series identified had in our opinion only a low potential for further optimization due to varying reasons including rather poor compound metrics. Our X-ray studies had revealed the fragmentation of one series represented by compound 7 and an unfavorable binding mode with 

By starting from 9a and applying the strategy described above, we were able to increase the activity by a factor of 100 with derivative 9b. We also identified 

As can be seen from Table 23.1, the highest inhibitory activity among the compound series 9 was observed with derivative 9c featuring a biphenyl substituent in the 6-amino acid residue. 

The introduction of an oxygen linker between the two phenyl groups (9k) led to somewhat reduced inhibitory activity. Switching to simple phenyl residues on the 6-amino acid scaffold, the ortho-tolyl derivative 9b showed a noticeable 

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