Guaiacol–chalcone and nitroguaiacol–chalcone derivatives: In vitro and in silico antibacterial evaluation

• Novel antibiotics are urgently needed to combat antimicrobial resistance. • Guaiacol–chalcone and nitroguaiacol–chalcone derivatives had in vitro antibacterial activity. • A nitroguaiacol–chalcone derivative had a synergistic effect combined with chloramphenicol. • Synergism suggest the nitroguaiacol–chalcone also target bacterial protein synthesis. • A ring aromatic, a hydrophobic moiety and two hydrogen bond acceptors are important for activity. This study aimed to design and synthesise novel guaiacol–chalcone and nitroguaiacol–chalcone derivatives and determine their in vitro antibacterial activity against five pathogens viz. Staphylococcus aureus, Klebsiella pneumoniae , Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella aerogenes. The checkerboard assay was used to explore potential synergism with existing antibiotics to shed light on a possible antibacterial mechanism of action. A pharmacophore model was constructed to identify key chemical entities the derivatives had which are necessary for activity. The pharmacophore model was validated utilising the enrichment factor (EF 10 % ) and the area under the receiver operating characteristic (ROC-AUC) curve metrics. The most active derivative was nitroguaiacol–chalcone derivative 2c (8 µg/ml), with activity against susceptible and methicillin-resistant strains of S. aureus . The checkerboard assay showed that one nitroguaiacol–chalcone derivative ( 2a ) had a synergistic effect when combined with chloramphenicol (FICI min : 0.45 ± 0.09), implying its antibacterial mechanism of action might also target bacterial protein synthesis. Active guaiacol–chalcone and nitroguaiacol–chalcone derivatives were accurately identified by the common feature pharmacophore model (max. fit: 4, rank score: 52.34). The leading pharmacophore model, i.e ., hypothesis 1 (EF 10 % : 8, ROC-AUC: 0.95 ± 0.02) indicated that four features are important for antibacterial activity i.e ., a ring aromatic, a hydrophobic moiety and two hydrogen bond acceptors.