In vitro and in silico antibacterial evaluation of nitrocatechol chalcone and pyrazoline derivatives

Abstract

The aim of this study was to determine the in vitro antibacterial activity of nitrocatechol chalcone and pyrazoline derivatives previously synthesised by our research group against Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii and Klebsiella aerogenes, and to create and validate a pharmacophore model using this data. The enrichment factor (EF10%) and the area under the receiver operating characteristic (ROC-AUC) curve were used to validate the pharmacophore model. Using the validated pharmacophore model novel derivatives were designed and synthesised, whereafter the in vitro antibacterial activity of these derivatives was also determined against the susceptible bacteria. After the initial screening, the derivatives only had activity against S.aureus, with compound 2a, 2b and 1b (1–2 µg/ml) having comparable activity to tetracycline (2 µg/ml). A common feature pharmacophore model (max. fit: 4, rank score: 84.02) was able to accurately identify active nitrocatechol chalcones and pyrazoline derivatives within a decoy test set. The best performing pharmacophore model, i.e., hypothesis 9 (EF10%: 6.7, ROC-AUC: 0.85 ± 0.00) indicated that four hydrogen bond acceptors are important for antibacterial activity. This model was used to guide the design and synthesis of novel nitrocatechol chalcone and pyrazoline derivatives of which the in vitro antibacterial activity against both the susceptible and resistant S. aureus strains were determined. The most active compounds were 3i (0.5 µg/ml) and 3c (0.5 µg/ml) against the susceptible and resistant strain respectively, which were more active than tetracycline.