Design synthesis, characterization, molecular docking and antimicrobial evaluation of novel heterocycles with acrylonitrile and anthracene moieties.

The synthon 3-(anthracen-9-yl)-2-cyanoacryloyl chloride 4 was produced and exploited in the creation of a wide variety of highly reactive heterocyclic compounds, by its interaction with diverse nitrogen nucleophiles. Using spectral and elemental analysis, the structures of each synthesized heterocycles were fully investigated. Ten of the thirteen novel heterocycles showed encouraging efficacy against antibiotic-resistant bacteria (MRSA). Among these, compounds 6, 7, 10, 13b, and 14 demonstrated the highest antibacterial activity, showing inhibition zones near 4 cm. However, molecular docking studies revealed varied binding affinities for Penicillin-Binding Protein 2a (PBP2a), a crucial target in MRSA resistance. Some compounds, such as 7, 10, and 14, displayed higher binding affinities and interaction stability within the PBP2a active site compared to the co-crystallized quinazolinone ligand. In contrast, compounds 6 and 13b exhibited lower docking scores but still showed substantial antimicrobial activity, with 6 showing the lowest MIC (9.7 μg/100 μL) and MBC (78.125 μg/100 μL) values. The docking analysis revealed key interactions, including hydrogen bonding and π-stacking, particularly with residues like Lys 273, Lys 316, and Arg 298, which were identified as interacting with the co-crystallized ligand within the crystal structure of PBP2a. These residues are essential for the enzymatic activity of PBP2a. These findings suggest that the synthesized compounds could serve as promising anti-MRSA agents, highlighting the importance of integrating molecular docking with biological assays to identify effective therapeutic candidates.