Design, Synthesis, and in Silico Evaluation of 1,5‐Disubstituted 1,2,3‐Triazoles as Potent Antibacterial Agents—Click‐Coupling Reaction, Molecular Docking, and Pharmacokinetic Analysis

ABSTRACT In the present study, the two‐step synthesis of new 1,5‐disubstituted 1,2,3‐triazoles via CuI‐catalyzed click reaction, followed by Pd‐catalyzed Sonogashira or Suzuki coupling, is described. The newly synthesized compounds 3b, 3c, 3e‐3 h, 5b, and 5c, as well as 7a–7c, were studied for their pharmacokinetic properties and antibacterial activity using detailed in silico methods, which included molecular docking and pkCSM ADMET calculations. Docking against protein 1KZN showed good binding energies for several derivatives, up to –7.85 kcal/mol, matching or better than the standard rifampicin at –6.99 kcal/mol. pkCSM analysis predicted good oral absorption and low toxicity. Strikingly, the antibacterial bioactivity screening confirmed this observation: most derivatives displayed large inhibition zones against Pseudomonas aeruginosa , reaching up to ∼48 mm for 3f, and Staphylococcus aureus , reaching up to ∼45 mm for 3e, exceeding the standards of vancomycin and rifampicin at 19 mm. This straightforward concurrence between the computational and biological data underlines the potential of the identified triazoles as promising next‐generation antibacterial leads.