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

Abstract

Introduction: Fusidic acid (FA) 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. Purpose: Therefore, it is necessary to explore the structure-activity relationships of FA derivatives as antibacterial agents to develop novel ones possessing a broad antimicrobial spectrum. Methods and result: First, a pharmacophore model was established on the nineteen FA derivatives with remarkable antibacterial activities reported in previous studies. The common structural characteristics of the pharmacophore emerging from the FA 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 FA derivatives have been designed according to the reported structure-activity relationships and the pharmacophore characteristics. The designed FA derivatives were mapped on the pharmacophore model, and the Qfit values of all FA derivatives were over 50 and FA-8 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 S. aureus. Furthermore, the designed FA derivatives have been prepared and their antibacterial activities were evaluated by the inhibition zone test and the minimum inhibitory concentration (MIC) test. The derivative FA-7 with a chlorine group as the substituent group at C-25 of FA 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. Conclusion: Hence, a computer-aided drug design model was developed for FA, which can be further used to optimize FA derivatives as highly potent antibacterial agents.

Keywords: antibacterial; derivatives; fusidic acid; pharmacophore model; structure–activity relationships.

FIGURE 1

Map of a common feature pharmacophore model. AA, the atom center of the hydrogen bond acceptor; HY, hydrophobic group; and NC, negative center.

FIGURE 2

Binding mode of four derivatives in the S. aureus EF-G pocket: (A) FA-8; (B) FA-9; (C) FA-20; and (D) FA-22. The relevant ligand molecules were colored by magenta, and the vital amino acid was colored by cyan. The red color dash indicated the salt bridge force; the yellow color dash indicated the hydrogen bond; and the green color indicated the halogen bond interaction.

SCHEME 1

Synthetic route of FA-6∼9. Reagents and conditions: (A) DMF, Et₃N (1.3 eq.), 30 min; (B) tBuCO₂CH₂Cl, overnight, 50°C; (C) O₃, NMO (1 eq.), DCM, 0°C; (D) Wittig’s reaction; (E) K₂CO₃ (2 eq.), methanol, r. t., 1 h; (F) K₂CO₃ (2 eq.), methanol, r. t., overnight; (G) 2 N NaOH (5 eq.), ethanol, refluxed, overnight; and (H) K₂CO₃ (2 eq.), methanol, r. t., overnight.

SCHEME 2

Synthetic route of FA-17∼22 and FA-24. Reagents and conditions: (A) DMF, Et₃N (1.3 seq.), 30 min; (B) tBuCO₂CH₂Cl, overnight, 50°C; (C) pyridine (2 eq.), methane sulfonyl chloride (5 eq.), DCM, overnight; (D) tetrabutylammonium chloride/bromide/iodide/nitrite/sodium azide (2 eq.), THF, reflux, overnight; (E) K₂CO₃ (2 eq.), methanol, r. t., 1 h; (F) 2,6-lutidine, 130°C, 2 h.

FIGURE 3

(A) Relationship between the experimental and predicted antibacterial activities by the QSAR model, pMIC = -lg MIC, showing R ² = 0.921; (B) flexible alignment of derivatives shown in the stick model; (C) steric fields, green favorable and yellow disfavored; (D) Phase electrostatic fields, blue favorable and red disfavored; (E) hydrophobic fields, yellow favorable and white disfavored; and (F) H-bond acceptor fields, magenta favorable and red disfavored.