Design, Synthesis, and Structure−Activity Relationships of Benzophenone-Based Tetraamides as Novel Antibacterial Agents

Abstract

The increase in the incidence of both hospital- and community-acquired antibiotic-resistant infections is a major concern to the healthcare community. There have been only two new classes of antibiotics approved by the FDA over the past 40 years, and clearly there is a growing need for additional antimicrobial agents. In this paper, we present our work on the discovery of a class of benzophenone containing compounds that possess good activity against MRSA, VISA, VRSA, and VRE and moderate activity against E. coli. These compounds display MIC values in the 0.5-2.0 mg/L range and are not cytotoxic against mammalian cells. Extensive structure-activity relationship studies revealed that the benzophenone was absolutely essential for antibacterial activity as was the presence of a cationic group. Although these agents display DNA binding activity, we observed that these compounds do not inhibit any macromolecular synthesis reliant upon DNA nor do they inhibit lipid or cell wall biosynthesis. Instead, we found that these agents cause membrane depolarization, indicating that the bacterial membrane was the primary site of action for these agents. Our studies suggest that caution should be taken in assigning the mechanism of action for DNA binding antibiotics.

Chemical modifications of a natural xanthone and antimicrobial activity against multidrug resistant Staphylococcus aureus and cytotoxicity against human tumor cell lines

“…Some natural xanthones are described as important anti-staphylococcal agents, including for resistant strains, having MIC values ranging from 8 until 1.95 µg/mL. 10,[33][34][35] Thus, some of the semi synthetic ω-aminoalkoxylxanthones presented herein are potential antimicrobials and can be considered relevant specially taking into account the growing problem of resistant S. aureus strains. 1 Studies have reported the synthesis and cytotoxic activity of bromoalkoxyxanthones 30 and xanthones with nitrogenated side chains 27,28 including arylhydrazones, 36 with promising results, showing IC 50 values between 2 and 30 µM.…”

Synthesis and structure–activity relationship of amidine derivatives of 3,4-ethylenedioxythiophene as novel antibacterial agents

“…Literature evidence for benzophenone-based tetraamide compounds also showed that positive charge is a necessary requirement for selective interaction with bacterial over mammalian membranes [11]. Thus, cationic compounds are strongly attracted by electrostatic interactions to bacterial over mammalian membranes, and this characteristic is used in drug design in order to increase selectivity of antibacterial agents.…”

“…The present report describes the synthesis of nine new amidine derivatives (9)(10)(11)(12)(13)(14)(15)(16)(17) and evaluation of antibacterial activity of 27 amidine derivatives from 3,4-ethylenedioxythiophene class (including 18 previously synthesized analogues). The structure-activity relationship of their antibacterial potencies and DNA binding affinities is examined.…”

Differentiation of Regioisomeric Aromatic Ketocarboxylic Acids by Positive Mode Atmospheric Pressure Chemical Ionization Collision-Activated Dissociation Tandem Mass Spectrometry in a Linear Quadrupole Ion Trap Mass Spectrometer

“…CAD-based MS n techniques have been applied to the characterization of unknown substances in many fields, including the pharmaceutical industry [19,20], and research on chemical warfare agents [21], proteins [22], volatile organic compounds [23], airborne oxidants [24], bacteria, DNA [25,26], and microextracted water samples [27]. Hydrogen/deuterium (H/D) exchange experiments [28][29][30] and molecular orbital calculations [31,32] have facilitated the differentiation of isomeric compounds.…”