Marinopyrrole Derivatives as Potential Antibiotic Agents against Methicillin-Resistant Staphylococcus aureus (III)

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.

A twist of nature – the significance of atropisomers in biological systems

“…Various manipulations to 28 and some of its synthetic precursors have allowed access to multiple analogues for SAR studies. 64,65,69,70 The first, and thus far only, synthesis of marinopyrrole B (29) was reported in 2013 by Cheng et al (not shown), whereby the bipyrrole core in this case was instead generated through alkylation of a trihalogenated pyrrole, which underwent further manipulations to complete a Paal-Knorr construction of the second pyrrole ring, a precursor which allowed for the generation of rac-29. 71 Scheme 5: Convergent total synthesis of racemic marinopyrrole A (28).…”

Marinopyrroles: Unique Drug Discoveries Based on Marine Natural Products

“…This suggests the binding sites contain both hydrogen bond donors and acceptors. Similar to the effects of chlorine‐substituted marinopyrroles, fluorine substitutions in ring B profoundly contribute the antibacterial activity . Compound 72 with 5‐fluorine substitution exhibited the same potency with two‐ to four‐fold improvement in antibacterial activity over the parent compound (±)‐ 23 .…”

“…Several marinopyrrole derivatives have been synthesized for their potential antibiotic and anticancer activity since the first report of marinopyrroles in 2008 . They include the derivatives from Hughes et al., Nicolaou et al., Cheng et al., Cheng et al., and Li et al . Since the first total synthesis of marinopyrrole A was published in 2010, 13 patents have been filed with the United States and Patent Cooperation Treaty and published by Li‐Qin et al.…”

“…). Symmetrical derivatives have equal substituents with the same substitution pattern on both phenyl rings A and B attached to the carbonyl group, while asymmetrical or nonsymmetrical marinopyrroles have different substituents on rings A and B …”

“…Li et al. designed and synthesized a series of asymmetrical marinopyrroles whose anti‐MRSA activities were evaluated in collaboration with the Nizet et al . As envisaged by the designer, asymmetrical marinopyrroles may demonstrate biological activity distinct from its symmetrical counterparts.…”