Non-transpeptidase binding arylthioether β-lactams active against Mycobacterium tuberculosis and Moraxella catarrhalis

Abstract

The prevalence of drug resistance in both clinical and community settings as a consequence of alterations of biosynthetic pathways, enzymes or cell wall architecture is a persistent threat to human health. We have designed, synthesized, and tested a novel class of non-transpeptidase, β-lactamase resistant monocyclic β-lactams that carry an arylthio group at C4. These thioethers exhibit inhibitory and cidal activity against serine β-lactamase producing Mycobacterium tuberculosis wild type strain (Mtb) and multiple (n=8) β-lactamase producing Moraxella catarrhalis clinical isolates.

Acid-catalyzed reaction of 1-(2,2-dimethoxyethyl)ureas with phenols as an effective approach to diarylethanes and dibenzoxanthenes

“…General. 1 H NMR spectra were recorded on Bruker MSL 400 spectrometer (working frequency 400.13 MHz) in CDCl3 and (CD3)2SO relative to the residual solvent protons. 13 C NMR spectra were recorded on Bruker Avance 600 spectrometer (working frequency 150.90 MHz).…”

“…Diarylethanes containing urea fragments are known for their pharmacological activity. According to the literature, these compounds exhibit antibacterial activity, [1][2][3] may act as inhibitors of lysine-specific histone demethylase 1 (LSD1) 4 and antagonists of muscarinic acetylcholine 5 and chemokine type 3 receptors (CCR3) 6 . Additionally, some of them can be used in malaria 7 and sclerosis 8 treatment (Figure 1, A).…”

Addressing Antimicrobial Resistance through New Medicinal and Synthetic Chemistry Strategies

“…6 ) that carry an arylthio group at C4 have been also reported. 161,162 These N -unsubstituted lactams exhibit inhibitory and cidal activity against serine β-lactamase producing wild-type strain Mtb and multiple β-lactamase producing Moraxella catarrhalis clinical isolates. 162 These examples of nontraditional β-lactams, none of which possess an ionizable group at the lactam nitrogen, confirm that natural products inspire the design and preparation of new synthetically accessible structures in addition to strategies.…”

“…161,162 These N -unsubstituted lactams exhibit inhibitory and cidal activity against serine β-lactamase producing wild-type strain Mtb and multiple β-lactamase producing Moraxella catarrhalis clinical isolates. 162 These examples of nontraditional β-lactams, none of which possess an ionizable group at the lactam nitrogen, confirm that natural products inspire the design and preparation of new synthetically accessible structures in addition to strategies. 163 It has been demonstrated that a given function can be achieved with many different structures, as a “design-for-function strategy becomes a powerful tool for creating totally new targets inspired by natural product leads or by abiological needs.” 163 β-lactam antibiotic structures are one illustration of our understanding that while preserving/improving a function/activity, chemists can move from the natural realm to the design of structures, often from complex to very simplified ones.…”

Antibacterial and β‐Lactamase Inhibitory Activity of Monocyclic β‐Lactams

“…Some of them act as inhibitors of enzymes such as β‐lactamases, thereby countering specific bacterial resistance mechanisms, or serine proteases, human leukocyte elastases, tryptases, thrombins, chymases, and so on. In addition, β‐lactam‐containing cholesterol absorption inhibitors and vasopressin V1a antagonists have been reported, as well as anticancer, antitubercular, anti‐HIV, antidiabetic, anti‐inflammatory, and antiparkinsonian agents. The various pharmacological activities of monocyclic β‐lactams have extensively been reviewed recently by Mehta et al .…”