Abstract
In this study we screened twelve newly synthesised N-(substituted phenyl)-2-chloroacetamides for antimicrobial potential relying on quantitative structure-activity relationship (QSAR) analysis based on the available cheminformatics prediction models (Molinspiration, SwissADME, PreADMET, and PkcSM) and verified it through standard antimicrobial testing against Escherichia coli, Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), and Candida albicans. Our compounds met all the screening criteria of Lipinski’s rule of five (Ro5) as well as Veber’s and Egan’s methods for predicting biological activity. In antimicrobial activity tests, all chloroacetamides were effective against Gram-positive S. aureus and MRSA, less effective against the Gram-negative E. coli, and moderately effective against the yeast C. albicans. Our study confirmed that the biological activity of chloroacetamides varied with the position of substituents bound to the phenyl ring, which explains why some molecules were more effective against Gram-negative than Gram-positive bacteria or C. albicans. Bearing the halogenated p-substituted phenyl ring, N-(4-chlorophenyl), N-(4-fluorophenyl), and N-(3-bromophenyl) chloroacetamides were among the most active thanks to high lipophilicity, which allows them to pass rapidly through the phospholipid bilayer of the cell membrane. They are the most promising compounds for further investigation, particularly against Gram-positive bacteria and pathogenic yeasts.
Highlights
In this study we screened twelve newly synthesised N-(substituted phenyl)-2-chloroacetamides for antimicrobial potential relying on quantitative structure-activity relationship (QSAR) analysis based on the available cheminformatics prediction models (Molinspiration, SwissADME, PreADMET, and PkcSM) and verified it through standard antimicrobial testing against Escherichia coli, Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), and Candida albicans
N-(substituted phenyl)-2-chloroacetamides – namely N-phenyl chloroacetamide (SP1), N-(4-methylphenyl) chloroacetamide (SP2), N-(4-metoxylphenyl) chloroacetamide (SP3), N-(4-chlorophenyl) chloroacetamide (SP4), N-(4-bromophenyl) chloroacetamide (SP5), N-(4fluorophenyl) chloroacetamide (SP6), N-(4-iodophenyl) chloroacetamide (SP7), N-(4-acetylphenyl) chloroacetamide (SP8), N-(4-hydroxyphenyl) chloroacetamide (SP9), N-(4cyanophenyl) chloroacetamide (SP10), N-(3-cyanophenyl) chloroacetamide (SP11), and N-(3-bromophenyl) chloroacetamide (SP12) – were synthesised following the method described in our earlier article [19]
Its name stems from the following cheminformatics filters: molecular weight (MW)≤500 g/mol, number of hydrogen bond donor (HBD)≤5, number of hydrogen bond acceptor (HBA)≤10, and logP≤5), whose aim is to filter out compounds that do not satisfy the most common oral absorption parameters
Summary
In this study we screened twelve newly synthesised N-(substituted phenyl)-2-chloroacetamides for antimicrobial potential relying on quantitative structure-activity relationship (QSAR) analysis based on the available cheminformatics prediction models (Molinspiration, SwissADME, PreADMET, and PkcSM) and verified it through standard antimicrobial testing against Escherichia coli, Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), and Candida albicans. Bearing the halogenated p-substituted phenyl ring, N-(4-chlorophenyl), N-(4-fluorophenyl), and N-(3-bromophenyl) chloroacetamides were among the most active thanks to high lipophilicity, which allows them to pass rapidly through the phospholipid bilayer of the cell membrane They are the most promising compounds for further investigation, against Gram-positive bacteria and pathogenic yeasts. The growing spread and resistance of various pathogens call for developing new promising antimicrobial agents One such group of agents that have received attention due to a wide variety of biological activities (such as analgesic, antipyretic, antimicrobial, bactericidal, fungicidal, hypoglycaemic, and antitumor) and applications in agriculture are chloroacetamides [1,2,3,4,5,6,7,8,9,10]. The synthesised derivatives were evaluated in vitro for antimicrobial activity against some of the most common pathogens
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