A new series of phenylthiazoles with t-butyl lipophilic component was synthesized and their antibacterial activity against a panel of multidrug-resistant bacterial pathogens was evaluated. Five compounds demonstrated promising antibacterial activity against methicillin-resistant staphylococcal strains and several vancomycin-resistant staphylococcal and enterococcal species. Additionally, three derivatives 19, 23 and 26 exhibited rapid bactericidal activity, and remarkable ability to disrupt mature biofilm produced by MRSA USA300. More importantly, a resistant mutant to 19 couldn't be isolated after subjecting MRSA to sub-lethal doses for 14 days. Lastly, this new series of phenylthiazoles possesses an advantageous attribute over the first-generation compounds in their stability to hepatic metabolism, with a biological half-life of more than 9 h.
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.
Phenylthiazoles were reported previously as a new scaffold with antibacterial activity against an array of multidrug-resistant staphylococci. However, their promising antibacterial activity was hampered in large part by their short half-life due to excessive hepatic clearance. Close inspection of the structure-activity-relationships (SARs) of the phenylthiazoles revealed two important structural features necessary for antibacterial activity (a nitrogenous and a lipophilic component). Incorporating the nitrogenous part within a pyrimidine ring resulted in analogues with a prolonged half-life, while the biphenyl moiety revealed the most potent analogue 1b. In this study, advantageous moieties have been combined to generate a new hybrid scaffold of 5-pyrimidinylbiphenylthiazole with the objective of enhancing both anti-MRSA activity and drug-like properties. Among the 37 tested biphenylthiazoles, piperazinyl-containing derivatives 10, 30, and 36 were the most potent analogues with MIC values as low as 0.39 μg/mL. Additionally, 36 exhibited significant improvement in stability to hepatic metabolism.
A new series of oxadiazolylbiphenylthiazoles was prepared with the objective of improving the limited solubility of first-generation derivatives while maintaining antibacterial activity against drug-resistant Staphylococcus aureus. Studying the structure-activity relationship at the cationic part provided the piperazine-1-carboximidamide derivative 27 with a MIC (MRSA) value of 1.1 μg/mL, bactericidal mode of action, and a 50-fold improvement in aqueous solubility. Additionally, 27 exhibited a wider safety margin against mammalian cells, and most importantly, a significant improvement in oral bioavailability.
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