*2.1. Drug Design Strategy*

2.1.1. Structure-Based Similarity Analysis

Based on our previous research on *N*-{4-[(4-chlorophenyl)sulfonyl]benzoyl}-*L*-valine derivatives as antimicrobial and antibiofilm agents, we made modifications in the structures of the target molecules by replacing the chlorine atom with the more lipophilic bromine atom. The objective of this study was to increase the lipophilic character of the newly synthesized compounds while maintaining the substituent's electronic effects. The proposed structures **5**–**8** were virtually explored on the ChEMBL database to demonstrate their original character and to assess their antimicrobial potential using similar compounds.

The search for similar compounds of *N*-acyl-*L*-valine **5** and α-acylamino ketones **7a** and **7b** returned 34 results and no similar structure for 4*H*-1,3-oxazol-5-one **6** and 1,3-oxazoles **8a** and **8b**, highlighting the originality of the proposed structures. No antimicrobial results were found for the 34 structurally similar compounds recorded in ChEMBL.

The substructure search based on the common 1-bromo-4-(phenylsulfonyl)benzene scaffold returned 32 compounds with 237 registered minimal inhibitory concentration (MIC) values, ranging from 2.5 up to 1024 μg/mL. All 32 compounds share an R-{4-[(4 bromophenyl)sulfonyl]phenyl} structure (Figure 2). The wide range of the MIC values indicates that the nature of the R group is very important for the potency of the antimicrobial effect. The lipophilic character of the compounds, expressed by the clogP value, seems to confirm the hypothesis of a better antimicrobial effect for most tested bacterial strains (Figure 2). The newly designed bromo derivatives have clogP values above the average of their similar compounds, indicating a potentially improved antimicrobial effect.

**Figure 2.** MIC values for the compounds resulted after the substructure search based on the 1-bromo-4-(phenylsulfonyl)benzene scaffold. NaN presents the new compounds **5**, **6**, **7a**,**b**, and **8a**,**b**.
