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

• Published in: European journal of medicinal chemistry Vol. 120; pp. 227 - 243
• Main Authors: Straniero, Valentina, Pallavicini, Marco, Chiodini, Giuseppe, Zanotto, Carlo, Volontè, Luca, Radaelli, Antonia, Bolchi, Cristiano, Fumagalli, Laura, Sanguinetti, Maurizio, Menchinelli, Giulia, Delogu, Giovanni, Battah, Basem, De Giuli Morghen, Carlo, Valoti, Ermanno
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 14-09-2016
• Subjects: 2,6-Difluorobenzamide; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial activity; Benzamides - chemistry; Benzamides - pharmacology; Benzene Derivatives; Benzodioxane; Cell Division - drug effects; FtsZ; Hydrophobic and Hydrophilic Interactions; Methicillin resistance; Methicillin-Resistant Staphylococcus aureus - cytology; Methicillin-Resistant Staphylococcus aureus - drug effects; Mycobacterium tuberculosis; Staphylococcus aureus; Structure-Activity Relationship; 2,6-Difluorobenzamide; FtsZ; Mycobacterium tuberculosis; Antibacterial activity; Methicillin resistance; Staphylococcus aureus; Benzodioxane
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.03.068

Lipophilic substituents at benzodioxane C (7) of 3-(benzodioxan-2-ylmethoxy)-2,6-difluorobenzamide improve the antibacterial activity against methicillin-resistant Staphylococcus aureus strains to MIC values in the range of 0.2–2.5 μg/mL, whereas hydrophilic substituents at the same position and modifications at the benzodioxane substructure, excepting for replacement with 2-cromanyl, are deleterious. Some of the lead compounds also exhibit good activity against Mtb. Parallel SARs to those of 3-(2-benzothiazol-2-ylmethoxy)-2,6-difluorobenzamide, well known FtsZ inhibitor, and cells alterations typical of FtsZ inhibition indicate such a protein as the target of these potent antibacterial benzodioxane-benzamides.
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•The antibacterial 3-(1,4-benzodioxan-2-yl)-2,6-difluorobenzamide was modified.•Lipophilic substituents at benzodioxane C(7) increase activity to <1 μg/mL MIC.•Hydrophilic substituents at C(7) and CH2 in place of O(1) are deleterious.•Mtb and methicillin resistant Sa are highly sensitive to the class lead compounds.•Cell alterations from FtsZ inhibition and SARs were found as for analogue FtsZ inhibitors.