Structure-Based Computational Screening of N۱-(۱-(۱H-Benzo[d]imidazol-۲-yl)ethyl)benzene-۱,۴-diamine Derivatives as Antibacterial Agents Against Streptococcus pneumoniae

The increasing prevalence of antibiotic-resistant Streptococcus pneumoniae highlights the urgent need for new antibacterial scaffolds with improved efficacy and favorable pharmacokinetic profiles. In this study, a series of N۱-(۱-(۱H-benzo[d]imidazol-۲-yl)ethyl)benzene-۱,۴-diamine derivatives (RS۱–RS۳۰) were rationally designed and synthesized by varying the benzimidazole R₁ substituent (H or CH₃) and terminal aryl (—Ar) moieties of the compounds. Molecular docking studies were performed against the S. pneumoniae target protein (PDB ID: ۵ZQ۰), revealing that most of the synthesized compounds exhibited stronger binding affinities (−۷.۵ to −۹.۹ kcal/mol) than the native ligand (−۷.۹ kcal/mol). Notably, compounds RS۲۴ (−۹.۹ kcal/mol), RS۹ (−۹.۷ kcal/mol), RS۲ (−۹.۶ kcal/mol), RS۱ (−۹.۵ kcal/mol), RS۱۶ (−۹.۵ kcal/mol), and RS۱۷ (−۹.۵ kcal/mol) demonstrated highly stable interaction profiles through salt bridge formation, hydrogen bonding, and hydrophobic interactions with the key residues GLU۳۳۳, PHE۲۸۱, LYS۳۸۵, and TYR۳۱۲. Comprehensive in silico ADMET analysis indicated that the synthesized derivatives possessed improved physicochemical properties, including optimized molecular weights (۳۴۰–۴۴۴ Da), reduced TPSA values (۵۳–۱۱۳ Ų), and favorable lipophilicity (logP ~۳.۰–۵.۲) compared with the native ligand (TPSA ۱۸۲.۶۳ Ų). Most compounds showed enhanced predicted absorption (high F۵۰% values up to ~۰.۹۸), acceptable distribution behavior, manageable CYP interaction profiles, and reduced toxicity risk. Collectively, these findings suggest that the synthesized benzimidazole derivatives are promising lead candidates for further experimental validation as antibacterial agents against S. pneumoniae.

کلیدواژه ها:

Benzimidazole scaffold ، Pneumococcal infection ، Structure&ndash ، activity relationship ، Molecular Modeling ، Pharmacokinetic prediction ، Lead optimization