Ligand and structure-based approaches for the exploration of structure-activity relationships of fusidic acid derivatives as antibacterial agents.

Fusidic acid () has been widely applied in the clinical prevention and treatment of bacterial infections. Nonetheless, its clinical application has been limited due to its narrow antimicrobial spectrum and some side effects. Therefore, it is necessary to explore the structure-activity relationships of derivatives as antibacterial agents to develop novel ones possessing a broad antimicrobial spectrum. First, a pharmacophore model was established on the nineteen derivatives with remarkable antibacterial activities reported in previous studies. The common structural characteristics of the pharmacophore emerging from the derivatives were determined as those of six hydrophobic centers, two atom centers of the hydrogen bond acceptor, and a negative electron center around the C-21 field. Then, seven derivatives have been designed according to the reported structure-activity relationships and the pharmacophore characteristics. The designed derivatives were mapped on the pharmacophore model, and the Qfit values of all derivatives were over 50 and possessed the highest value of 82.66. The molecular docking studies of the partial target compounds were conducted with the elongation factor G (EF-G) of . Furthermore, the designed derivatives have been prepared and their antibacterial activities were evaluated by the inhibition zone test and the minimum inhibitory concentration (MIC) test. The derivative with a chlorine group as the substituent group at C-25 of displayed the best antibacterial property with an MIC of 3.125 µM. Subsequently, 3D-QSAR was carried on all the derivatives by using the CoMSIA mode of SYBYL-X 2.0. Hence, a computer-aided drug design model was developed for , which can be further used to optimize derivatives as highly potent antibacterial agents.