Antibacterial Potential: Design, Synthesis, Characterization of New Isatin Derivatives with Sulfonamide Moiety
TL;DR
The results indicate that although B1 showed better docking affinity, B2 was more effective experimentally, highlighting the importance of combining in silico and in vitro analyses in evaluating new Isatin derivatives as potential antibacterial agents.
Abstract
Background: Klebsiella pneumoniae is a clinically significant, multidrug-resistant (MDR) pathogen in humans and a major contributor to hospital-acquired infections, leading to increased morbidity and mortality due to limited treatment options. Molecular Operating Environment (MOE) software was used for molecular docking studies to identify the most promising compounds based on the highest S-scores prior to synthesis. New Isatin derivatives were synthesized through the reaction of (Z)-ethyl 4-(5-fluoro-2-oxoindolin-3-ylideneamino) benzoate (A1) and (Z)-ethyl 4-(5-methyl-2-oxoindolin-3-ylideneamino) benzoate (A2) with sulfadiazine. Spectroscopic techniques, including FT-IR and ¹H-NMR, were employed to confirm the successful synthesis of these derivatives. The antibacterial activity of the compounds was evaluated in vitro by measuring the inhibition zones and comparing them with those produced by the standard antibiotic disc, amikacin. Among the synthesized derivatives, B2 exhibited the highest docking score (-8.395) against the protein (PDB code: 8QK2, chain A), compared to B1, which S score -7.954. Therefore, compound B2 shows the most promising potential for antimicrobial activity. Aim: This study aimed to design, synthesize, characterize, and evaluate the antibacterial potential of new isatin derivatives incorporating a sulfonamide moiety, using molecular docking and in vitro assays against K. pneumoniae. Methodology: Molecular docking was performed using MOE 2015.10 software to identify the most promising ligand–receptor interactions with the target protein (PDB: 8QK2, chain A). Two Schiff base intermediates (A1–A2) were synthesized from substituted isatin and ethyl-4-aminobenzoate, followed by reaction with sulfadiazine to obtain final derivatives (B1–B2). Structural characterization was conducted using FT-IR spectroscopy, ¹H-NMR, melting point determination, and TLC. Antibacterial activity was assessed using the agar well diffusion method, and inhibition zones were compared with the standard antibiotic amikacin. Results: Molecular docking of the synthesized Isatin derivatives with the protein (PDB: 8QK2, chain A) using MOE 2015.10 showed that derivative B1 had the highest docking score (-8.395), while B2 scored -7.954, with both interacting at key amino acids Phe141, Trp46, Arg80, and Asn79. The derivatives were synthesized via a Schiff base reaction with benzocaine, followed by reaction with sulfadiazine, and characterized by FT-IR, which confirmed C=N imine and C=O amide groups, and ¹H-NMR, which revealed signals for amide NH, Isatin NH, NH-SO₂, aromatic protons, and substituents (-F in B1, -CH₃ in B2). Biological evaluation showed that B2 exhibited stronger antibacterial activity than B1, especially at higher concentration (0.06), reaching inhibition zones up to 35 mm, while B1 had moderate activity. These results indicate that although B1 showed better docking affinity, B2 was more effective experimentally, highlighting the importance of combining in silico and in vitro analyses in evaluating new Isatin derivatives as potential antibacterial agents. Conclusion: The integration of sulfonamide moieties with isatin-based structures significantly enhanced antibacterial activity.