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.
U ovom istraživanju analizirano je dvanaest novosintetiziranih N-(supstituiranih fenil)-2-kloroacetamida radi determinacije njihova antimikrobnog potencijala u korelaciji s kvantitativnom analizom aktivnosti spojeva i njihove molekularne strukture (QSAR analiza). QSAR analiza omogućena je primjenom predikcijskih modela (Molinspiration, SwissADME, PreADMET i PkcSM) te je verificirana potvrđenom antimikrobnom aktivnošću sintetiziranih spojeva prema bakterijama Escherichia coli, Staphylococcus aureus, na meticilin otporan S. aureus (MRSA) i prema gljivici Candida albicans. Novosintetizirani spojevi zadovoljavaju sve predikcijske modele za značajnu potencijalnu biološku aktivnost prema kriterijima Lipinskog, Vebera i Egana. Na osnovi određene antimikrobne aktivnosti spojeva, svi kloroacetamidi pokazali su učinkovitost prema sojevima gram-pozitivnih bakterija S. aureus i MRSA, neznatno manju učinkovitost prema gram-negativnoj E. coli i umjerenu učinkovitost prema gljivici C. albicans. Naše je istraživanje potvrdilo potencijal biološke aktivnosti kloroacetamida, koji je bilo uvjetovan intenzitetom manifestirane aktivnosti u zavisnosti od pozicije supstituenata vezanih za fenilni prsten, što je i razlog značajnije učinkovitosti pojedinih spojeva prema gram-negativnima u odnosu na gram-pozitivne bakterije ili gljivicu C. albicans. Budući da imaju halogenirani p-supstituirani fenilni prsten, N-(4-klorofenil), N-(4-fluorofenil) i N-(3-bromofenil) kloroacetamidi bili su među najaktivnijima zahvaljujući visokoj lipofilnosti, koja im omogućava da brzo prolaze kroz fosfolipidni dvosloj stanične membrane. Ovi spojevi najviše obećavaju u daljim ispitivanjima, naročito protiv gram-pozitivnih bakterija i patogenih gljivica.
Keywords: N-substituted amides; antimicrobial potential; quantitative analysis of chemical structure and activity relationship.
© 2021 Aleksandra Bogdanović et al., published by Sciendo.