Promising Antibacterial and Antifungal Agents Based on Thiolated Vitamin K3 Analogs: Synthesis, Bioevaluation, Molecular Docking

In the present study, we designed and synthesized thiolated analogs ( ) 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 analogs. In particular, four thiolated analogs exhibited superior biological potency against some Gram-positive bacterial strains, including (ATCC 29213) and (ATCC 29212). Next, all thiolated analogs were evaluated for their potential of cell growth inhibition on the NCI-60 cancer cell lines panel. This screening underlined that the thiolated analogs have no visible cytotoxicity on different cancer cell lines. The selected two thiolated analogs ( and ), having minimal hemolytic activity, which also have the lowest MIC values on and , 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 . showed excellent antimicrobial activity against clinically resistant isolates. Furthermore, the tested molecules showed nearly two log 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 and in thymidylate kinase was conducted in order to predict their molecular interactions. and 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.