From Phenylthiazoles to Phenylpyrazoles: Broadening the Antibacterial Spectrum toward Carbapenem-Resistant Bacteria.
Hammad A, Abutaleb NS, Elsebaei MM, Norvil AB, Alswah M, Ali AO, Abdel-Aleem JA, Alattar A, Bayoumi SA, Gowher H, Seleem MN, Mayhoub AS.
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 <b>23</b>, was more potent than vancomycin against multidrug-resistant Gram-positive clinical isolates, including vancomycin- and linezolid-resistant methicillin-resistant <i>Staphylococcus aureus (</i>MRSA), with a minimum inhibitory concentration (MIC) value as low as 0.5 μg/mL. Moreover, compound <b>23</b> was superior to imipenem and meropenem against highly pathogenic carbapenem-resistant strains, such as <i>Acinetobacter baumannii</i>, <i>Klebsiella pneumoniae,</i> and <i>Escherichia coli</i>. In addition to the notable biofilm inhibition activity, compound <b>23</b> outperformed both vancomycin and kanamycin in reducing the intracellular burden of both Gram-positive and Gram-negative pathogenic bacteria. Compound <b>23</b> cleared 90% of intracellular MRSA and 98% of <i>Salmonella enteritidis</i> 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.