Evaluation of Pipemidic Acid Derivatives for Potential Antimicrobial Activity Application: In silico Studies on Bioactivity

Background: Pipemidic acid is a broad-spectrum quinolone antibacterial agent for the treatment of chronic urinary tract infections against both gram-positive and gram-negative bacteria. Both quinolone and fluoroquinolone antibiotics have been useful in combating bacterial infections. However, patients suffer severe side effects when they stop taking the medication. The piperazinyl region of pipemidic acid is highly responsible for the side effects. Objective: The objective of this study is to design new compounds in which the piperazinyl region is masked by way of conjugation to benzoic acid derivatives. Methods: In silico studies were conducted using AutoDockTools software for ligand-protein docking. The docking scores were compared to the parent pipemidic acid docked to Bacterial DNA (deoxyribonucleic acid) gyrase and GABA (gamma-Aminobutyric acid) receptor from the PDB (Protein Data Bank) database. Sites of metabolism, biological activity, quantum chemical descriptors, and ADME (absorption, distribution, metabolism, and excretion) property predictions for each designed ligand were also evaluated. Results: The docking studies and biological activity predictions showed good anti-infective properties (ligand PAR03) whilst also suggesting a reduction in GABA receptor agonist activity. The performance of PAR03 correlates with its electronic properties showing electrophilic character (can generate Reactive Electrophilic Species (RES)). Conclusion: The results from this study indicate that modification of the piperazinyl region of pipemidic acid can be an effective way to improve the drug potency whilst also ensuring reduction of the associated side effects.