Benzodioxane-benzamides as promising inhibitors of Escherichia coli FtsZ

Benzodioxane–Benzamides as FtsZ Inhibitors: Effects of Linker’s Functionalization on Gram-Positive Antimicrobial Activity

“…This modification introduces a second stereogenic center, prompting us to isolate and individually evaluate the erythro and threo isomers. As reported in our recent work focused on E. coli as a target, FZ116 (Figure 3) resulted in very strong in vitro inhibition of E. coli FtsZ and inhibition of cell division in efflux-pump-defective E. coli [15]. Stokes and co-workers also observed how the introduction of a methyl group in the same position resulted in the enhancement of the antimicrobial activity vs. S. aureus without positively affecting the solubility [17].…”

“…First, the development of the differentially substituted FZ116, FZ117, FZ118 and FZ119, the tetrahydro naphthodioxane compounds, allowed us to obtain promising derivatives with antimicrobial activities against both S. aureus and B. subtilis. This consideration, together with the recent results with efflux-deficient E. coli strains [15], strongly pave the way to FtsZ inhibitors able to possess a wide spectrum of action not restricted to exclusively gram-positive or gram-negative strains.…”

“…The syntheses of derivatives FZ118 and FZ119 followed a complete novel synthetic strategy, as reported in Scheme 4. After having applied an in house previously described synthetic strategy [23] and having achieved the 5,6,7,8-tetrahydronaphthalen-2,3-diol, this was reacted with methyl 3,4-dibromo-2-methylbutanoate (17), which was obtained through deconjugative transposition (15), bromination ( 16), and esterification of the commercially available tiglic acid. The nature of the derivative obtained allowed for the sepa- through deconjugative transposition (15), bromination (16), and esterification of the commercially available tiglic acid.…”

“…After having applied an in house previously described synthetic strategy [23] and having achieved the 5,6,7,8-tetrahydronaphthalen-2,3-diol, this was reacted with methyl 3,4-dibromo-2-methylbutanoate (17), which was obtained through deconjugative transposition (15), bromination ( 16), and esterification of the commercially available tiglic acid. The nature of the derivative obtained allowed for the sepa- through deconjugative transposition (15), bromination (16), and esterification of the commercially available tiglic acid. The nature of the derivative obtained allowed for the separation of the two isomers using flash chromatography and the definition of the erythro from the threo isomer through comparison of 1 H-NMR spectra.…”

“…They also showed MICs under 0.1 μg/mL vs. B. subtilis, and their activity is accompanied by low to no cytotoxicity towards human MRC-5 cells [14]. In addition, we recently demonstrated how both of these compounds are able to interact with E. coli FtsZ and to interfere with its essential properties, therefore exerting antimicrobial activity on efflux-pump-defective E. coli strains, such as N43 (ΔacrAB) and ΔtolC [15]. These optimal microbiological profiles make these compounds very intriguing as potential antibiotics.…”