Design, Synthesis and Biological Evaluation of N-Sulfonylphenyl glyoxamide-Based Antimicrobial Peptide Mimics as Novel Antimicrobial Agents

Publication Type:
Journal Article
ChemistrySelect, 2017, 2 (12), pp. 3452 - 3461
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© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Antibiotic resistance is a major global health concern. There is an urgent need for the development of novel antimicrobials. Recently, phenylglyoxamide-based small molecular antimicrobial peptide mimics have been identified as potential new leads to treat bacterial infections. Here, we describe the synthesis of novel phenylglyoxamide derivatives via the ring-opening reaction of N-sulfonylisatins with primary amines, followed by conversion into hydrochloride, quaternary ammonium iodide or gunidinium salts. The antibacterial activity of the compounds against Staphylococcus aureus was evaluated by in vitro assays. Structure-activity relationship studies revealed that 5-bromo-substituent at the phenyl ring, octyl group appended to the ortho sulfonamide group or guanidine hydrochloride salt as the terminal group significantly contributed to potency. The most potent compound, the gunidinium salt 35 d, exhibited a minimum inhibitory concentration value of 12 μM and a therapeutic index of 15. It also demonstrated its potential to act as antimicrobial pore-forming agent. Overall, the results identified 35 d as a new lead antimicrobial compound.
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