Design and Synthesis of 4‐Alkylidene‐β‐lactams: Benzyl‐ and Phenethyl‐carbamates as Key Fragments to Switch on Antibacterial Activity

Abstract

The emergence of multidrug-resistant bacterial strains is particularly important in chronic pathologies such as cystic fibrosis (CF), in which persistent colonization and selection of resistant strains is favored by the frequent and repeated use of antibacterial agents. Staphylococcus aureus is a common pathogen in CF patients that has an associated increased multidrug resistance. In previous studies we demonstrated that the presence of a 4-alkylidene side chain directly linked to a β-lactam appeared to strengthen the potency against S. aureus, especially against methicillin-resistant S. aureus (MRSA) strains. In the present study, 21 new 4-alkylidene-β-lactams were synthesized and evaluated for antibacterial activity. We designed the new compounds to have aryl, benzyl, or phenethyl-carbamate groups on the C3 hydroxyethyl side chain. We found a correlation between biological activity and the nitrogen substituent of the carbamate group, and two phenethyl-carbamate β-lactams were shown to be valuable antibacterial agents against selected linezolid-resistant strains, with a minimum inhibitory concentrations of 2-4 mg L .

Antistaphylococcal Activities and ADME-Related Properties of Chlorinated Arylcarbamoylnaphthalenylcarbamates

“…Thus, MRSA infections continue to be a challenge in the design of new active agents. Based on long-standing interest in anti-infective agents, small molecules structurally derived from salicylanilide and its carbamates [10][11][12][13][14][15][16][17] have been designed as naphthalene analogues of salicylanilides [18][19][20][21][22], see Scheme 1. Some of these molecules were able to effectively inhibit S. aureus [13,14,19,21].…”

“…The compounds investigated in this paper were derived from recently described 1-hydroxynaphthalene-2-carboxanilides [18,20,21,31]. As carbamates or compounds with two amide groups tend to have stronger antibacterial potential [10,[14][15][16][17], a series of carbamates was prepared from the antibacterial-ineffective, and to human cells non-toxic, 1-hydroxy-N-(2,4,5-trichlorophenyl)-2-naphthamide (1), in order to increase antimicrobial efficacy. This study describes the microwave synthesis of the starting anilide 1, the subsequent preparation of carbamates, the investigation of ADME-related properties, and the antistaphylococcal activity.…”

Spiro-Lactams as Novel Antimicrobial Agents

“…Since the discovery of benzylpenicillin in 1928, β-lactams emerged as one of the most important and well-studied class of compounds in both the organic and the medicinal chemistry fields [1][2][3][4][5][6][7][8][9][10]. Although the huge impact of β-lactams on public health has been mainly associated with its antibiotic activity, several molecules containing the β-lactam core showed potential activity against other diseases, namely as cholesterol absorption inhibitors, β-lactamase inhibitors, antitumoral and antiviral agents [6,[11][12][13][14][15].…”

Exploration of (3‐benzyl‐5‐hydroxyphenyl)carbamates as new antibacterial agents against Gram‐positive bacteria

“…Carbamates, which are closely related to amides and ureas, were applied in drug design to improve metabolic stability and bioactivity . However, antibacterial agents with the carbamate unit as the pharmacophore are rarely reported . The good antibacterial activity observed in the preliminary test suggested that (3‐benzyl‐5‐hydroxyphenyl)carbamates have potential as a new kind of antibacterial agent.…”