Abstract
Abstract
Background and Purpose
This study has two objectives, first to identify new antimicrobial targets to counteract antimicrobial resistance and second to develop low-molecular-weight chalcone-derived heterocycles that specifically target the Di-Acetyl-Lys-D-Ala-D-Ala complex to address the pharmacokinetic challenges, notably inadequate oral bioavailability.
Experimental Approach Chalcone derivatives (Ia-f) were synthesized and cyclized to give 1,2-pyrazolines (IIa-f) and 1,5-benzodiazepines (IIIa-f) and characterized spectroscopically. Molecular docking with SpNOX (8QQ1), SAP2 (1EAG) and the vancomycin–D-Ala–D-Ala complex (1FVM). Pharmacokinetic predictions were performed using SwissADME. The antimicrobial activity was evaluated against four bacterial strains and Candida albicans. Statistical analyses and structure-activity relationship (SAR) evaluations were performed.
Findings/Results
Compounds IIIb showed a highest binding affinity to SpNOX and a better antibacterial potential. IIIf showed the best docking results against SAP2. The compound IIb showed the highest interaction with the vancomycin–D-Ala–D-Ala complex and increased activity against Gram-positive bacteria while the compound IIe showed notable antifungal activity against C. albicans. All compounds satisfied Lipinski's Rule of Five, and the 1,5-benzodiazepine series had more favorable predicted pharmacokinetic properties. Scaffold type, concentration and their interaction had significant effects on antimicrobial activity (P < 0.0001) and SAR analysis revealed the importance of scaffold structure and aromatic substitution.
Conclusion and Implications
The integrated approach enabled the identification of IIb, IIIb, IIe and IIIf compounds as candidates. These results confirmed the utility of SpNOX and SAP2 as alternate targets and validated the vancomycin-recognition approach. This study shows the first application of the SpNOX dehydrogenase domain for docking of these scaffolds.
