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, antibacterial activity does not correlate with IMPDH inhibition. In addition, the presence of guanine does not affect the antibacterial activity of most compounds, nor does the deletion of These observations suggest that antibacterial activity derives from inhibition of another target(s). Moreover, D compounds display antibacterial activity only against, suggesting the presence of a unique target or uptake mechanism. A Δ mutant resistant to compound D73 contained a missense mutation (Gly45Cys) in , which encodes a subunit of bacterial complex I. Overexpression of the mutant conferred resistance to D73 in both wild-type and Δ strains. This strain was not resistant to Q compounds, suggesting that a different off-target mechanism operates for these compounds. Several Q compounds are also effective against , in which a second target has also been implicated, in addition to IMPDH. The fortuitous presence of multiple targets with overlapping structure-activity relationships presents an intriguing opportunity for the development of robust antibiotics that may avoid the emergence of resistance.

Expanding Benzoxazole-Based Inosine 5′-Monophosphate Dehydrogenase (IMPDH) Inhibitor Structure–Activity As Potential Antituberculosis Agents

“…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).…”

“…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.…”

Synthesis and Investigation of Phthalazinones as Antitubercular Agents

“…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) …”

Antibacterial Therapy of Tularemia: Current Status and Prospects

“… 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].…”