Alkynyl-containing phenylthiazoles: Systemically active antibacterial agents effective against methicillin-resistant Staphylococcus aureus (MRSA)

Abstract

The promising activity of phenylthiazoles against multidrug-resistant bacterial pathogens, in particular MRSA, has been hampered by their limited systemic applicability, due to their rapid metabolism by hepatic microsomal enzymes, resulting in short half-lives. Here, we investigated a series of phenylthiazoles with alkynyl side-chains that were synthesized with the objective of improving stability to hepatic metabolism, extending the utility of phenylthiazoles from topical applications to treatment of a more invasive, systemic MRSA infections. The most promising compounds inhibited the growth of clinically-relevant isolates of MRSA in vitro at concentrations as low as 0.5 μg/mL, and exerted their antibacterial effect by interfering with bacterial cell wall synthesis via inhibition of undecaprenyl diphosphate synthase and undecaprenyl diphosphate phosphatase. We also identified two phenylthiazoles that successfully eradicated MRSA inside infected macrophages. In vivo PK analysis of compound 9 revealed promising stability to hepatic metabolism with a biological half-life of ∼4.5 h. In mice, compound 9 demonstrated comparable potency to vancomycin, and at a lower dose (20 mg/kg versus 50 mg/kg), in reducing the burden of MRSA in a systemic, deep-tissue infection, using the neutropenic mouse thigh-infection model. Compound 9 thus represents a new phenylthiazole lead for the treatment of MRSA infections that warrants further development.

Investigation of auranofin and gold-containing analogues antibacterial activity against multidrug-resistant Neisseria gonorrhoeae

“…Auranofin was able to achieve a 5.0 −log 10 reduction in N. gonorrhoeae inside infected endocervical cells while ceftriaxone, on the contrary, was not significantly effective. To rule out the possibility of cell death leading to a false positive result, auranofin was assayed for its in vitro cytotoxicity against End1/E6E7 endocervical cells for 24 hours via MTS cytotoxicity assay 37 . As depicted in Supplementary Fig.…”

Identification of a Phenylthiazole Small Molecule with Dual Antifungal and Antibiofilm Activity Against Candida albicans and Candida auris

“…Compounds were synthesized and characterized as described in previous reports. The synthetic schemes for compounds 1 - 23 29,31,35,48,49 , compounds 24 - 31 28 , and compounds 32 - 85 30,34,50,51 are presented in the supplementary information file. Compounds were prepared as stock 10 mg/mL or 1 mg/mL solutions in dimethyl sulfoxide (DMSO).…”

From Phenylthiazoles to Phenylpyrazoles: Broadening the Antibacterial Spectrum toward Carbapenem-Resistant Bacteria

“…This work is built on the discovery of a lead compound, phenylthiazole, which bears an alkyl side chain on one side and a guanidine head on the other side; it possesses antimicrobial activity against Gram-positive pathogens . This initial discovery was followed by intensive structural optimization to improve its antimicrobial activity and metabolic stability. − The structural optimization focused on the nitrogenous part, the lipophilic tail, and the connection with the phenylthiazole scaffold. − Our structural optimization efforts with first generation compounds using different heterorings as a linker between the guanidine head and the main scaffold overcame its metabolic instability and improved its antibacterial activity (Figure ). ,,, Using an alkynyl lipophilic moiety blocked the metabolic soft spot, increased biological half-life, and enhanced the systemic efficiency …”