Antibacterial Effect, ADMET Properties, and Molecular Docking of Morpholine Derivatives with Varying Alkyl Chain Length Against Methicillin Resistant Staphylococcus aureus (MRSA) Isolates

Abstract

AbstractIn this work, we synthesized a series of nine tetraalkylammonium salts derived from N‐methyl morpholine and assessed their antibacterial efficacy against Methicillin‐Resistant Staphylococcus aureus (MRSA). The investigated morpholinium cations differ by the length of one linear alkyl chain, which ranges from 1 to 18 carbon atoms. We found that compounds with alkyl chains in the n‐C12H25‐(n‐dodecyl) to C16H33‐(n‐hexadecyl) display the highest bactericidal effects, exhibiting Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) values of 3.9 μg/mL – surpassing the effectiveness of the commercial drug Linezolid. Conversely, compounds with shorter chains (<5 carbon atoms) are inactive against MRSA, establishing a clear structure‐activity relationship. Assays on A. salina reveal that short‐alkyl‐chain morpholinium derivatives, inactive against MRSA), are moderately toxic, while the strongest bactericides of our set demonstrate high or extreme toxicity to A. salina. Our findings underscore the potential of morpholine derivatives as a means to control Methicillin‐Resistant Staphylococcus aureus and pinpoint the need to develop safe applications for these compounds given their potential toxicity.