Design, Synthesis, and Biological Evaluation of Nucleoside Analogues Acting against Neisseria Gonorrhoeae

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Patel, Bhautikkumar
Jen, Freda
Jennings, Michael
Zunk, Matthew
Grant, Gary
Rudrawar, Santosh
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2019
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Barcelona, Spain

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Abstract

Antimicrobial resistant Neisseria gonorrhoeae (AMR-NG) is a concerning superbug for the global health sector in the 21st century [1]. As per the current scenario, N. gonorrhoeae has developed resistance among all the antimicrobial agents for treatment since the mid-1930s [2]. In most countries, the only remaining choice for first-line monotherapy for N. gonorrhoeae is extended-spectrum cephalosporins (ESCs), such as cefixime and the more potent ceftriaxone [2,3]. Being the last treatment option for N. gonorrhoeae, the emergence of resistance in the case of ceftriaxone treatment has necessitated a dire need for developing novel therapeutic approaches. The suggested long term strategic approach would be exploring novel targets to suppress the resistance of N. gonorrhoeae [4].

The enzyme MraY (phosphor-MurNAc-pentapeptide translocase), essential for bacterial cell wall synthesis, fulfills the mentioned requirement, as it has not been explored in a clinical context [5]. Specifically, the enzyme is involved in the lipid-linked cycle of peptidoglycan biosynthesis and is reportedly targeted by naturally-occurring nucleoside antibiotics [5,6]. Because of their completely novel mechanism of action, these MraY-inhibiting candidates are therefore speculated to become a promising, long-term resolution for drug-resistant bacterial pathogens. To explore nucleoside antibiotics as a novel class of antibacterials, we have synthesized simplified analogues of a Muraymycin class of nucleoside antibiotic, having linked it together with three pharmacophores, including uridine, 5'-amino ribose, and the diverse lipophilic side chains. The synthesized analogues of Muraymycin have shown some exciting trends which will be presented in more detail.

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2nd Molecules Medicinal Chemistry Symposium - Facing Novel Challenges in Drug Discovery (MMCS2019)

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Medicinal and biomolecular chemistry

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Patel, B; Freda, J; Jennings, M; Zunk, M; Grant, G; Rudrawar, S, Design, Synthesis, and Biological Evaluation of Nucleoside Analogues Acting against Neisseria Gonorrhoeae, 2nd Molecules Medicinal Chemistry Symposium - Facing Novel Challenges in Drug Discovery (MMCS2019), 2019