| Summary: | In the present study, we designed and synthesized thiolated <b>VK3</b> analogs (<b>VK3a–g</b>) along with an extensive antimicrobial study. After the evaluation of the antibacterial and antifungal activity against various bacterial and fungal strains, we presented an initial structure–activity relationship study on these <b>VK3</b> analogs. In particular, four thiolated <b>VK3</b> analogs exhibited superior biological potency against some Gram-positive bacterial strains, including <i>Staphylococcus aureus</i> (ATCC<sup>®</sup> 29213) and <i>Enterococcus faecalis</i> (ATCC<sup>®</sup> 29212). Next, all thiolated <b>VK3</b> analogs were evaluated for their potential of cell growth inhibition on the NCI-60 cancer cell lines panel. This screening underlined that the thiolated <b>VK3</b> analogs have no visible cytotoxicity on different cancer cell lines. The selected two thiolated <b>VK3</b> analogs (<b>VK3a</b> and <b>VK3b</b>), having minimal hemolytic activity, which also have the lowest MIC values on <i>S. aureus</i> and <i>E. faecalis</i>, were further evaluated for their inhibition capacities on biofilm formation after evaluating their potential in vitro antimicrobial activity against each of the 20 clinically obtained resistant strains of <i>Staphylococcus aureus</i>. <b>VK3b</b> showed excellent antimicrobial activity against clinically resistant <i>S. aureus</i> isolates. Furthermore, the tested molecules showed nearly two log<sub>10</sub> reduction in the viable cell count at six hours according to the time kill curve studies. Although these molecules decreased biofilm attachment about 50%, when sub-MIC concentrations were used these molecules increased the percentage of biofilm formation. The molecular docking of <b>VK3a</b> and <b>VK3b</b> in <i>S. aureus</i> thymidylate kinase was conducted in order to predict their molecular interactions. <b>VK3a</b> and <b>VK3b</b> exhibited excellent lead-likeness properties and pharmacokinetic profiles that qualify them for further optimization and development. In conclusion, since investigating efficient novel antimicrobial molecules is quite difficult, these studies are of high importance, especially in the present era of antimicrobial resistance.
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