Diarylacylhydrazones: Clostridium-selective antibacterials with activity against stationary-phase cells

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• 作者：Chao Chen ; Naveen K. Dolla ; Gabriele Casadei ; John B. Bremner ; Kim Lewis ; Michael J. Kelso
• 关键词：CCCP ; carbonyl cyanide m-chlorophenylhydrazone ; CDAD ; Clostridium difficile-associated diarrhoea ; CDI ; Clostridium difficile infection ; DACC ; Data Analysis and Coordination Centre ; 2 ; 4-DNP ; 2 ; 4-dinitrophenol ; DMSO ; dimethyl sulfoxide ; FDA ; US Food and Drug Administration ; HTS ; high-throughput screening ; MBC ; minimum bactericidal concentration ; MIC ; minimum inhibitory concentration ; NCI ; National Cancer Institute ; NIH ; National Institutes of Health ; PBS ; phosphate buffered saline ; PCP ; pentachlor
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：15 January, 2014
• 年：2014
• 卷：24
• 期：2
• 页码：595-600
• 全文大小：853 K

文摘

Current antibiotics for treating m>Clostridium difficilem> infections (CDI), that is, metronidazole, vancomycin and more recently fidaxomicin, are mostly effective but treatment failure and disease relapse remain as significant clinical problems. The shortcomings of these agents are attributed to their low selectivity for m>C. difficilem> over normal gut microflora and their ineffectiveness against m>C. difficilem> spores. This Letter reports that certain diarylacylhydrazones identified during a high-throughput screening/counter-screening campaign show selective activity against two m>Clostridiumm> species (m>C. difficilem> and m>Clostridium perfringensm>) over common gut commensals. Representative examples are shown to possess activity similar to vancomycin against clinical m>C. difficilem> strains and to kill stationary-phase m>C. difficilem> cells, which are responsible for spore production. Structure-activity relationships with additional synthesised analogues suggested a protonophoric mechanism may play a role in the observed activity/selectivity and this was supported by the well-known protonophore carbonyl cyanide m>mm>-chlorophenyl hydrazone (CCCP) showing selective anti-m>Clostridiumm> effects and activity similar to diarylacylhydrazones against stationary-phase m>C. difficilem> cells. Two diarylacylhydrazones were shown to be non-toxic towards human FaDu and Hep G2 cells indicating that further studies with the class are warranted towards new drugs for CDI.