Identification of CH2-linked quinolone-aminopyrimidine hybrids as potent anti-MRSA agents: Low resistance potential and lack of cross-resistance with fluoroquinolone antibiotics.
Eur J Med Chem
; 271: 116399, 2024 May 05.
Article
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| MEDLINE
| ID: mdl-38640868
ABSTRACT
The structural optimization of B14, an antibacterial agent we previously obtained, has led to the discovery of a new class of CH2-linked quinolone-aminopyrimidine hybrids with potent anti-MRSA activities. Surprisingly, the hybrids lacking a C-6 fluoro atom at the quinolone nucleus showed equal or even stronger anti-MRSA activities than their corresponding 6-fluoro counterparts, despite the well-established structure-activity relationships (SARs) indicating that the 6-fluoro substituent enhances the antibacterial activity in conventional fluoroquinolone antibiotics. Moreover, these new hybrids, albeit structurally related to conventional fluoroquinolones, showed no cross-resistance with fluoroquinolone drugs. The most active compound, 15m, exhibited excellent activities with a MIC value of 0.39 µg/mL against both fluoroquinolone-sensitive strain USA500 and -resistant MRSA isolate Mu50. Further resistance development studies indicated MRSA is unlikely to acquire resistance against 15m. Moreover, 15m displayed favorable in vivo half-life and safety profiles. These findings suggest a rationale for further evolution of quinolone antibiotics with a high barrier to resistance.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Pirimidinas
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Pruebas de Sensibilidad Microbiana
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Quinolonas
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Fluoroquinolonas
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Staphylococcus aureus Resistente a Meticilina
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Antibacterianos
Límite:
Animals
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Humans
Idioma:
En
Revista:
Eur J Med Chem
Año:
2024
Tipo del documento:
Article
País de afiliación:
China