Antibacterial activity of griseofulvin analogs as example of drug repurposing

Abstract Griseofulvin is a well-known antifungal drug launched in 1962 by Merck & Co. for treatment of dermatophyte infections. However, according to the predictions using Way2Drug computational drug repurposing platform, it may have antibacterial activity. Since no faultless confirmation of this prediction was found in the published literature, we estimated in silico antibacterial activity for 42 griseofulvin derivatives synthesized earlier. Antibacterial activity was predicted for 33 from 42 molecules, which lead to the conclusion that this activity might be considered as typical for the appropriate chemical series. Therefore, the experimental testing of antibacterial activity was performed on a panel of gram-positive and gram-negative microorganisms. The antibacterial activity was evaluated using the microdilution method detecting the minimal inhibitory (MIC) and minimal bactericidal (MBC) concentrations. The tested compounds exhibited the potent antibacterial activity against all the studied bacteria, with MIC and MBC ranging from 0.0037-0.04 mg/ml and 0.01-0.16 mg/ml, respectively. Their activity exceeded 2.5 to 12 times those of the ampicillin and 2 to 8 times those of the streptomycin, which were used as the reference drugs. Similarity analysis for all 42 compounds with the about 470 thousand drug-like compounds indexed by Clarivate Analytics Integrity database confirmed the significant novelty of the antibacterial activity for the compounds from this chemical class. Therefore, our study demonstrated that by computer-aided prediction of biological activity spectra for a particular chemical series it is possible to identify typical biological activities, which may be used for discovery of new applications for those molecules, e.g., drug repurposing.