2017
DOI: 10.1128/aac.00939-17
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Benzoxazoles, Phthalazinones, and Arylurea-Based Compounds with IMP Dehydrogenase-Independent Antibacterial Activity against Francisella tularensis

Abstract: is the causative agent of tularemia and a potential biowarfare agent. The virulence of is decreased by deletion of, the gene encoding IMP dehydrogenase (IMPDH), suggesting that this enzyme is a target for antibacterial design. Here we report that growth is blocked by inhibitors of bacterial IMPDHs. Seventeen compounds from two different frameworks, designated the D and Q series, display antibacterial activities with MICs of<1 μM. These compounds are also active against intracellular infections. Surprisingly, a… Show more

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Cited by 11 publications
(10 citation statements)
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References 60 publications
(65 reference statements)
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“…These inhibitors exploit the highly diverged cofactor binding site, which explains their selectivity for bacterial over eukaryotic orthologs of IMPDH 9, 17 . Individual members of the A , D , P and Q -series display antibacterial activity against Mtb as well as other pathogens 9, 41, 42 . The best Q compound, 3 (Figure 1A), was a potent inhibitor of Mtb IMPDH2 ( K i,app = 14 nM) and displayed moderate antibacterial activity (MIC = 6.3 and 11 μM in minimal GAST/Fe and rich 7H9/ADC/Tween media, respectively).…”
Section: Introductionmentioning
confidence: 99%
See 1 more Smart Citation
“…These inhibitors exploit the highly diverged cofactor binding site, which explains their selectivity for bacterial over eukaryotic orthologs of IMPDH 9, 17 . Individual members of the A , D , P and Q -series display antibacterial activity against Mtb as well as other pathogens 9, 41, 42 . The best Q compound, 3 (Figure 1A), was a potent inhibitor of Mtb IMPDH2 ( K i,app = 14 nM) and displayed moderate antibacterial activity (MIC = 6.3 and 11 μM in minimal GAST/Fe and rich 7H9/ADC/Tween media, respectively).…”
Section: Introductionmentioning
confidence: 99%
“…We have developed triazole ( A series), benzimidazole ( C series), phthalazinone ( D series), 4-oxo-[1]­benzopyrano­[4,3- c ]­pyrazole ( N series), urea ( P series), and benzoxazole ( Q series) inhibitors of prokaryotic IMPDHs, including Mtb IMPDH2. , These inhibitors exploit the highly diverged cofactor binding site, which explains their selectivity for bacterial over eukaryotic orthologs of IMPDH. , Individual members of the A , D , P , and Q series display antibacterial activity against Mtb as well as other pathogens. ,, The best Q compound, 3 (Figure A), was a potent inhibitor of Mtb IMPDH2 ( K i,app = 14 nM) and displayed moderate antibacterial activity (MIC = 6.3 and 11 μM in minimal GAST/Fe and rich 7H9/ADC/Tween media, respectively). The values of MIC increased three- to seven-fold in the presence of guanine, suggesting that antibacterial activity resulted from the on-target inhibition of Mtb IMPDH2.…”
Section: Introductionmentioning
confidence: 99%
“…For example, the clinically used anti‐cancer drug oliparib ( 1 , Figure ) inhibits the poly(ADP‐ribose)polymerase, while azelastine ( 2 ) is an antihistamine preferentially taken up by lung and alveolar macrophages . Anti‐bacterial phthalazinones include amide 3 , which inhibits Francisella tularensis , a potential bioterrorism agent, with a minimum bactericidal concentration (MBC) of 0.94 μ m , and oxadiazole 4 , which is anti‐bacterial against Escherichia coli and Salmonella typhi . Although the mode of action of anti‐bacterial phthalazinones has not been studied, we reasoned that phthalazinones might exhibit anti‐tubercular activity due to their ability to mimic the benzoquinone moiety in menaquinone (MK), a key intermediate in the mycobacterial respiratory chain of Mycobacterium tuberculosis , the causative agent of tuberculosis (TB) …”
Section: Introductionmentioning
confidence: 99%
“… êà÷åñòâå ïîòåíöèàëüíûõ íîâûõ àëüòåðíàòèâíûõ ïðåïàðàòîâ äëÿ ëå÷åíèÿ òóëÿðåìèè ïðåäëîaeåíû íîâûå ñèíòåòè÷åñêèå áèñ-èíäîëüíûå ñîåäèíåíèÿ [29], áåíçîêñàçîëû, ôòàëàçèíîíû è ñîåäèíåíèÿ íà îñíîâå àðèëìî÷åâèíû [30].…”
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