Synthesis and Biological Activity of Cyanoethyl Derivatives of Fusidic Acid

et al. 2022

Antibiotics

Fusidic acid (FA), a narrow-spectrum antibiotics, is highly sensitive to various Gram-positive cocci associated with skin infections. It has outstanding antibacterial effects against certain Gram-positive bacteria whilst no cross-resistance with other antibiotics. Two series of FA derivatives were synthesized and their antibacterial activities were tested. A new aromatic side-chain analog, FA-15 exhibited good antibacterial activity with MIC values in the range of 0.781–1.563 µM against three strains of Staphylococcus spp. Furthermore, through the assessment by the kinetic assay, similar characteristics of bacteriostasis by FA and its aromatic derivatives were observed. In addition, anti-inflammatory activities of FA and its aromatic derivatives were evaluated by using a 12-O-tetradecanoylphorbol-13-acetate (TPA) induced mouse ear edema model. The results also indicated that FA and its aromatic derivatives effectively reduced TPA-induced ear edema in a dose-dependent manner. Following, multiform computerized simulation, including homology modeling, molecular docking, molecular dynamic simulation and QSAR was conducted to clarify the mechanism and regularity of activities. Overall, the present work gave vital clues about structural modifications and has profound significance in deeply scouting for bioactive potentials of FA and its derivatives.

Section: Resultssupporting

confidence: 85%

Synthesis and Biological Evaluation of Novel Fusidic Acid Derivatives as Two-in-One Agent with Potent Antibacterial and Anti-Inflammatory Activity

Cao

et al. 2022

Antibiotics

“…In 2018, Salimova et al synthesized some cyanoethyl derivatives of FA, which were screened primarily in vitro. Modification of FA with cyanoethyl fragments did not increase the activity, which is consistent with the previously summarized SAR (Salimova et al, 2018). Lu et al have designed and synthesized 14 derivatives that blocked the metabolic sites (3-OH and 21-COOH) of FA, six of which had good antibacterial activity, MIC values of compounds 5 and 6 were less than 0.25 μg/ ml; however, this result was contrary to previously SAR studies of the 21-COOH, as summarized by Daehne et al Pharmacokinetic experiments were also performed, compounds 5 and 6 released FA in vivo, and their half-life was longer than that of FA.…”

Section: Anti-gram-positive Bacterial Activitysupporting

confidence: 91%

Bioactivities and Structure–Activity Relationships of Fusidic Acid Derivatives: A Review

Long

et al. 2021

Front. Pharmacol.

Fusidic acid (FA) is a natural tetracyclic triterpene isolated from fungi, which is clinically used for systemic and local staphylococcal infections, including methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci infections. FA and its derivatives have been shown to possess a wide range of pharmacological activities, including antibacterial, antimalarial, antituberculosis, anticancer, tumor multidrug resistance reversal, anti-inflammation, antifungal, and antiviral activity in vivo and in vitro. The semisynthesis, structural modification and biological activities of FA derivatives have been extensively studied in recent years. This review summarized the biological activities and structure–activity relationship (SAR) of FA in the last two decades. This summary can prove useful information for drug exploration of FA derivatives.

“…Based on a set of FA derivatives with remarkable antibacterial activity reported in previous studies (Godtfredsen et al, 1966;Riber et al, 2006;Lv et al, 2017;Kong et al, 2018;Salimova et al, 2018;Singh et al, 2020), a pharmacophore model was established to gain an insight into the necessary features for designing antibacterial agents. A total of 19 FA derivatives selected from the literature reports were aligned by using the GALAHAD module of SYBYL-X 2.0.…”

Section: Establishment Of a Pharmacophore Modelmentioning

confidence: 99%

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

Zheng

et al. 2023

Front. Chem.

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.