High-valued pyrazinoindole analogues: Synthesis, antibacterial activity, structure activity relationship and molecular dynamics analyses

Abstract

The constant emergence of drug-resistant strains of bacteria places a sustained burden on mankind as most antibiotics commonly used for treating bacterial infections are no longer efficient. This poses an urgent need for a new and effective class of antibacterial agents. Nitrogen-containing heterocycles have been found to have the most comprehensive spectrum of biological activities. Herein, we propose the route to access pyrazinoindole derivatives and evaluated them for in-vitro antibacterial activity. Synthesized analogs were tested for their antimicrobial activity against two gram-negative and two gram-positive bacteria. The range of minimum inhibitory concentration (MIC) was found in between 3.75 and 60 µg/mL where gentamycin was used as a standard drug. The structure-activity relationship studies also depicted the correlation of the electronic parameters with the antibacterial activity of the target compounds. Our findings were further confirmed using in-silico assays and favourable results were obtained in accordance with experimental outcomes. We mechanistically revealed that pyrazinoindole based compound 4g has strong non-covalent interactions by using H-bonds and hydrophobic interactions through molecular dynamics simulation studies, making it potential antibacterial compound. Further, results were strengthen by energy landscape which showed the stable binding of compound 4g, with free energy ΔPB and ΔGB computed to −20.02 kcal/mol and −19.53 kcal/mol, through MM/PB (GB) surface area analysis. In conclusion, this study reports the potential pyrazinoindole based antibacterial compound with possible mechanism by altering the regulatory enzyme of bacteria.

Keywords

• Pyrazinoindole
• Stereospecific
• Antibacterial activity
• Molecular dynamic simulation analysis
• Structure activity relation