In silico evaluation of the influence of N-alkylation and halogenation on isatin Schiff bases as potential inhibitors of bacterial DNA gyrase
Abstract
Isatin Schiff bases are multifunctional pharmacophores with reported antimicrobial relevance, and structural modifications such as halogenation and N-alkylation may influence their interaction with bacterial targets. In this docking-based study, a focused series of 20 3-[(pyridin-3-yl)imino]-1H-indole-2-one derivatives was designed to explore how halogen substitution and N-chloroalkylation affect the predicted binding of the isatin scaffold to the ATP-binding domain of Staphylococcus aureus DNA gyrase subunit B (PDB ID: 5CPH). The ligand set included non-alkylated analogs and N-(2-chloroethyl), N-(3-chloropropyl), and N-(3-chloroisobutyl) derivatives bearing fluorine, chlorine, bromine, or iodine substituents. Molecular docking predicted binding free energies ranging from –6.51 to –8.61 kcal/mol. Fluorination was most favorable in the non-alkylated series, whereas bromine and iodine became more beneficial in the presence of bulkier N-chloroalkyl substituents. The best-scoring compounds were stabilized mainly by hydrophobic and π-related contacts with Ile51, Ile86, Ile102, Ile175, and Leu103, together with hydrogen-bonding or water-mediated interactions involving Asp81, Asn54, Ser55, and Arg84. These results suggest that the effect of halogenation is context-dependent and influenced by the size and flexibility of the N-substituent. The study provides a preliminary docking-based structure–activity relationship (SAR) model for prioritizing isatin Schiff bases for further…
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