Novel chiral phthalimides: Antimicrobial evaluation and docking study against Acinetobacter baumannii's OmpA protein

Antibiotics have been a vital component in the fight against microbial diseases for over 75 years, saving countless lives. However, the global rise of multi-drug-resistance (MDR) bacterial infections is pushing us closer to a post-antibiotic era where common infections may once again become lethal. To combat MDR Acinetobacter baumannii, we investigated chiral phthalimides and used molecular docking to identify potential targets. Outer membrane protein A (OmpA) is crucial for A. baumannii resistant to antibiotics, making it a pathogen of great concern due to its high mortality rate and limited treatment options. In this study, we evaluated three distinct compounds against the OmpA protein: FIA (2-(1,3-dioxoindolin-2yl)-3-phenylpropanoic acid), FIC (2-(1,3-dioxoindolin-2yl)-4-(methylthio) butanoic acid), and FII (3-(1,3-dioxoindolin-2yl)-3-phenylpropanoic acid). Molecular docking results showed that these three compounds exhibited strong interactions with the OmpA protein. Molecular dynamics (MD) simulation analysis further confirmed the stability and binding efficacy of these compounds with OmpA. Their antimicrobial activities were assessed using the agar well diffusion method, revealing that FIA had an optimal zone of inhibition of 24 mm. Additionally, the minimum inhibitory concentrations (MIC) of these compounds were determined, demonstrating their bactericidal properties against A. baumannii, with MICs of 11 μg/μL for FIA, 46 μg/μL for FIC, and 375 μg/μL for FII. In vitro cytotoxicity data indicated that none of the three compounds were hemolytic when exposed to human red blood cells. This finding is particularly significant as it highlights the superior efficacy of FIA against A. baumannii compared to the other compounds. With thorough pharmacokinetic validations, these chiral phthalimides are promising alternative therapeutic options for treating infections caused by A. baumannii, offering new hope in the face of rising antibiotic resistance. •The study provides new insights into development of alternative antibacterial drug against resistant A. baumannii.•The interaction of FIA, FIC, and FII with the OmpA protein have also been confirmed through molecular docking analysis.•All three compounds showed strong interaction with the OmpA protein.•FIA exhibited superior efficacy against A. baumannii compared to the FIC and FII.•In vitro cytotoxicity tests revealed that none of the compounds were hemolytic to human erythrocytes.