Alkanoyl imidazoles from a marine-derived Nocardiopsis species: anomalous NMR behavior and antibacterial activity conferred by N-alkylation

Abstract

Bacterial infections remain a major global health challenge. Marine-derived micro-organisms represent a promising source for the development of anti-infective agents. Structural modification and diversification based on natural products serve as important and effective strategies for the discovery of lead compounds. In this study, we identified four alkanoyl imidazole alkaloids, bulbimidazoles A–D (1–4), from a marine-derived Nocardiopsis strain, with compound 4 being newly reported. During structural characterization, we observed anomalous behavior in the ¹³C nuclear magnetic resonance (NMR) spectra of these compounds in the form of absent signals corresponding to the three carbons of the imidazole ring and the carbonyl of the acyl side chain. A similar phenomenon was noted in various other compounds containing the imidazole moiety. This observation can be ascribed to the aromaticity and internal double-bond resonance of the imidazole ring. Salt formation of the imidazole derivatives was found to effectively restore the carbon signals, which facilitates structural identification. In addition, N-alkylation of the imidazole ring was shown to normalize NMR signals by locking the double-bond arrangement. A subset of the alkyl-modified derivatives of bulbimidazole B (2) displayed antibacterial activity with varying levels of potency. Notably, derivatives functionalized with n-pentyl, phenethyl, or 2-thienylethyl groups exhibited potent activity against both Staphylococcus aureus and methicillin-resistant S. aureus (MRSA). Mechanistic studies focused on the 2-thienylethyl-modified analog (A38) revealed that its antibacterial function is mediated through disruption of the bacterial cell membrane.

Keywords

Alkanoyl imidazoles / Marine-derived actinomycetes / Structural modification / Antibacterial activity / Nuclear magnetic resonance

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The Author(s), under exclusive licence to Ocean University of China