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

The narrow antibacterial spectrum of phenylthiazole antibiotics was expanded by replacing central thiazole with a pyrazole ring while maintaining its other pharmacophoric features. The most promising derivative, compound , was more potent than vancomycin against multidrug-resistant Gram-positive clinical isolates, including vancomycin- and linezolid-resistant methicillin-resistant MRSA), with a minimum inhibitory concentration (MIC) value as low as 0.5 μg/mL. Moreover, compound was superior to imipenem and meropenem against highly pathogenic carbapenem-resistant strains, such as , and . In addition to the notable biofilm inhibition activity, compound outperformed both vancomycin and kanamycin in reducing the intracellular burden of both Gram-positive and Gram-negative pathogenic bacteria. Compound cleared 90% of intracellular MRSA and 98% of at 2× the MIC. Moreover, preliminary pharmacokinetic investigations indicated that this class of novel antibacterial compounds is highly metabolically stable with a biological half-life of 10.5 h, suggesting a once-daily dosing regimen.