3-(Benzodioxan-2-ylmethoxy)-2,6-difluorobenzamides bearing hydrophobic substituents at the 7-position of the benzodioxane nucleus potently inhibit methicillin-resistant Sa and Mtb cell division

Straniero, Valentina; Pallavicini, Marco; Chiodini, Giuseppe; Zanotto, Carlo; Volontè, Luca; Radaelli, Antonia; Bolchi, Cristiano; Fumagalli, Laura; Sanguinetti, Maurizio; Menchinelli, Giulia; Delogu, Giovanni; Battah, Basem; Morghen, Carlo De Giuli; Valoti, Ermanno

doi:10.1016/j.ejmech.2016.03.068

Cited by 28 publications

(47 citation statements)

References 15 publications

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“…Mesylation (resulting in 24 ) and O‐alkylation of 2,6‐difluoro‐3‐hydroxybenzamide afforded 2 . The 7‐phenoxycarbonyl‐substituted benzodioxane 4 was synthesized from 2‐benzyloxymethyl‐1,4‐benzodioxan‐7‐carboxylic acid, detailed preparation of which was reported in our previous paper . Subsequent esterification with phenol, using EDAC⋅HCl and HOBT, afforded 28 , which underwent hydrogenolysis (resulting in 29 ), mesylation (resulting in 30 ), and condensation with 2,6‐difluoro‐3‐hydroxybenzamide, yielding derivative 4 .…”

Section: Resultsmentioning

confidence: 99%

“…The present study was conceived as a dual SAR study: the first part of the work was focused on the modification of the carboxymethyl functionality of derivative III (derivatives 1 – 12 ), whereas in the second section, the benzodioxane substructure of I was isosterically modified, as a continuation of our previous project (derivatives 13 – 16 ).…”

Section: Resultsmentioning

confidence: 99%

“…Derivatives 1 – 4 were designed and prepared, taking into consideration our previous results, in which the introduction of hindered halogens (Br or I) on the benzodioxane scaffold was well‐tolerated and resulted in potent bactericidal molecules . In 1 , the methyl ester was elongated to an ethyl ester, and the resulting MIC value and cytotoxicity, were similar to that of III (see Table ).…”

Section: Resultsmentioning

confidence: 99%

“…In the third series, we introduced several small heterocycles, as suggested in a previous study in which good results were achieved with substituents having modest to high lipophilicity. In particular, we converted the methyl ester into a cyclic imino ether, yielding oxazole derivatives 9 and 10 , linked by C(2) or C(4) of the heterocycles to the benzodioxane ring.…”

Section: Resultsmentioning

confidence: 99%

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2,6‐Difluorobenzamide Inhibitors of Bacterial Cell Division Protein FtsZ: Design, Synthesis, and Structure–Activity Relationships

et al. 2017

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A wide variety of drug‐resistant microorganisms are continuously emerging, restricting the therapeutic options for common bacterial infections. Antimicrobial agents that were originally potent are now no longer helpful, due to their weak or null activity toward these antibiotic‐resistant bacteria. In addition, none of the recently approved antibiotics affect innovative targets, resulting in a need for novel drugs with innovative antibacterial mechanisms of action. The essential cell division protein filamentous temperature‐sensitive Z (FtsZ) has emerged as a possible target, thanks to its ubiquitous expression and its homology to eukaryotic β‐tubulin. In the latest years, several compounds were shown to interact with this prokaryotic protein and selectively inhibit bacterial cell division. Recently, our research group developed interesting derivatives displaying good antibacterial activities against methicillin‐resistant Staphylococcus aureus, as well as vancomycin‐resistant Enterococcus faecalis and Mycobacterium tuberculosis. The aim of the present study was to summarize the structure–activity relationships of differently substituted heterocycles, linked by a methylenoxy bridge to the 2,6‐difluorobenzamide, and to validate FtsZ as the real target of this class of antimicrobials.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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2,6‐Difluorobenzamide Inhibitors of Bacterial Cell Division Protein FtsZ: Design, Synthesis, and Structure–Activity Relationships

et al. 2017

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“…In this context, we recently identified a copious class of FtsZ inhibitors. They potently inhibited both methicillin‐sensitive and methicillin‐resistant S. aureus and M. tuberculosis …”

Section: Introductionmentioning

confidence: 99%

Benzodioxane‐Benzamides as Antibacterial Agents: Computational and SAR Studies to Evaluate the Influence of the 7‐Substitution in FtsZ Interaction

et al. 2019

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FtsZ is a crucial prokaryotic protein involved in bacterial cell replication. It recently arose as a promising target in the search for antimicrobial agents able to fight antimicrobial resistance. In this work, going on with our structure‐activity relationship (SAR) study, we developed variously 7‐substituted 1,4‐benzodioxane compounds, linked to the 2,6‐difluorobenzamide by a methylenoxy bridge. Compounds exhibit promising antibacterial activities not only against multidrug‐resistant Staphylococcus aureus, but also on mutated Escherichia coli strains, thus enlarging their spectrum of action toward Gram‐negative bacteria as well. Computational studies elucidated, through a validated FtsZ binding protocol, the structural features of new promising derivatives as FtsZ inhibitors.

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How do reaction conditions affect the enantiopure synthesis of 2‐substituted‐1,4‐benzodioxane derivatives?

et al. 2018

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Several biologically active compounds structurally include the enantiopure 2-substituted-1,4-benzodioxane scaffold. The straightforward racemization that affects reactions involving most of the common chemical reactives is thus a crucial issue. The developing of a completely stereo-controlled synthetic route that does not affect the enantiomeric excess is consequently mandatory. It is also important to set up a reliable chiral HPLC method, able to follow the reaction, and to improve the synthetic performances. Here, we report the chiral investigation of two different synthons, we specifically evaluated the synthetic pathways that could be run in order to afford them, avoiding the racemization processes, which could normally occur in basic conditions. In addition, we developed peculiar chiral HPLC methods in order to resolve the enantiomers, define the enantiomeric excess, and fully characterize these compounds.

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3-(Benzodioxan-2-ylmethoxy)-2,6-difluorobenzamides bearing hydrophobic substituents at the 7-position of the benzodioxane nucleus potently inhibit methicillin-resistant Sa and Mtb cell division

Cited by 28 publications

References 15 publications

2,6‐Difluorobenzamide Inhibitors of Bacterial Cell Division Protein FtsZ: Design, Synthesis, and Structure–Activity Relationships

2,6‐Difluorobenzamide Inhibitors of Bacterial Cell Division Protein FtsZ: Design, Synthesis, and Structure–Activity Relationships

Benzodioxane‐Benzamides as Antibacterial Agents: Computational and SAR Studies to Evaluate the Influence of the 7‐Substitution in FtsZ Interaction

How do reaction conditions affect the enantiopure synthesis of 2‐substituted‐1,4‐benzodioxane derivatives?

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