Abstract
The marine natural product, marinopyrrole A (1), was previously shown to have significant antibiotic activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). Although compound (1) exhibits a significant reduction in MRSA activity in the presence of human serum, we have identified key modifications that partially restore activity. We previously reported our discovery of a chloro-derivative of marinopyrrole A (1a) featuring a 2–4 fold improved minimum inhibitory concentration (MIC) against MRSA, significantly less susceptibility to serum inhibition and rapid and concentration-dependent killing of MRSA. Here, we report a novel fluoro-derivative of marinopyrrole A (1e) showing an improved profile of potency, less susceptibility to serum inhibition, as well as rapid and concentration-dependent killing of MRSA.
Highlights
Since we reported the synthesis of novel non-symmetrical marinopyrrole derivatives retaining their potent activity against methicillin-resistant Staphylococcus aureus (MRSA), yet less susceptible to human serum inhibition [1], several research publications on the topic of marinopyrroles have appeared [2,3,4,5,6,7]
Derivatives bear the same substituents and patterns on both phenyl Rings A and B attached to the carbonyl groups, while “non-symmetrical” marinopyrroles are those with different substituents for
As we envisaged that the “non-symmetrical” marinopyrrole derivatives should have different and possibly more favorable biological activity than their symmetrical counterparts, in particular, the molecules with diverse functional groups decorated on this unique
Summary
Since we reported the synthesis of novel non-symmetrical marinopyrrole derivatives retaining their potent activity against methicillin-resistant Staphylococcus aureus (MRSA), yet less susceptible to human serum inhibition [1], several research publications on the topic of marinopyrroles have appeared [2,3,4,5,6,7]. There are several late-stage products in development, including tedizolid, dalbavancin, oritavancin and ceptobiprole These antibiotics may add to the arsenal for combating MRSA resistance, bacteria inevitably develop resistance to all antibacterial agents that are introduced to the clinic [28]. Novel antibiotic agents of new structural classes and further advances in discovery research are urgently needed to overcome the problem of MRSA resistance. We report our design and synthesis of novel marinopyrrole derivatives with excellent antibiotic activity against MRSA, but only limited serum inactivation
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