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

Journal of Medicinal Chemistry
Ali HammadAbdelrahman S Mayhoub

Abstract

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 23, was more potent than vancomycin against multidrug-resistant Gram-positive clinical isolates, including vancomycin- and linezolid-resistant methicillin-resistant Staphylococcus aureus (MRSA), with a minimum inhibitory concentration (MIC) value as low as 0.5 μg/mL. Moreover, compound 23 was superior to imipenem and meropenem against highly pathogenic carbapenem-resistant strains, such as Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli. In addition to the notable biofilm inhibition activity, compound 23 outperformed both vancomycin and kanamycin in reducing the intracellular burden of both Gram-positive and Gram-negative pathogenic bacteria. Compound 23 cleared 90% of intracellular MRSA and 98% of Salmonella enteritidis 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.

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Citations

Oct 24, 2020·Nanoscale·Ana V Morales-de-EchegarayAlexander Wei
Jan 5, 2021·European Journal of Medicinal Chemistry·Rameshwari VermaKanchugarakoppal S Rangappa
Mar 7, 2021·International Journal of Molecular Sciences·George A NaclerioHerman O Sintim
Sep 23, 2020·Journal of Medicinal Chemistry·George A NaclerioHerman O Sintim
Aug 14, 2020·Journal of Medicinal Chemistry·Jatinder KaurDaniel P Flaherty
Oct 13, 2021·Biomaterials Science·Gulcihan Guzel KayaRamón Martínez-Máñez

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