Design, Synthesis, and Biological Evaluation of 4-Alkyliden-beta Lactams:  New Products with Promising Antibiotic Activity Against Resistant Bacteria

Abstract

The design, synthesis, and antibacterial activity of 4-alkyliden-azetidin-2-ones as new antimicrobial agents against multidrug-resistant pathogens is reported. 4-Alkyliden-azetidin-2-ones were easily obtained using an original protocol starting from 4-acetoxy-azetidinones and diazoesters. Parent compounds were further elaborated to obtain a small library of 4-alkylidene derivatives. A molecular modeling approach using GRID descriptors based on the concept of VRS identified attractive drug candidates and contributed to the rationalization of functional group effects in QSARs. The in vitro antibacterial activity of the new agents was evaluated against 43 recent clinical isolates of antibiotic-susceptible and -resistant Gram-positive and Gram-negative pathogens by determining their minimum inhibitory concentrations (MICs). The most active compound showed MIC values ranging from 0.25 to 32 mg/L against some of the bacterial species tested. Interestingly, some compounds demonstrated similar activity against methicillin-susceptible and -resistant strains of Staphylococcus aureus suggesting possible alternative mechanisms of action of these agents, supported by citotoxicity and preliminary scanning electron microscopy studies.

Synthesis and Biological Activity of a Series of Novel N‐Substituted β‐Lactams Derived from Natural Gallic Acid

“…The following condensation reaction between hydrazides 2 and various aldehyde or ketone led to the important substrates, substituted benzoylhydrazone 3a-h. Then the various benzoylhydrazone derivatives 3a-h were treated with ketenes, generated in-situ from 2-chloroacetyl chloride in the presence of triethylamine to give desired multi-substituted monocyclic b-lactams derivatives 4a-h. All the target compounds 4a-h gave satisfactory chemical analyses. 1 H NMR, ESI-MS spectra and elemental analyses were consistent with the assigned structures. The ketene-imine heterocyclization reaction is most probably initiated by a nucleophilic attack of the imino hydrazone nitrogen to the carbonyl carbon of in-situ generated ketene leading to an intermediate, with subsequent intramolecular reaction leading to the formation of target compounds.…”

“…Their physico-chemical properties and the spectra data are as follows : N-(3-Chloro-2-oxo-4-phenylazetidin-1-yl)-3,4 N-(3-Chloro-2-(4-chlorophenyl)-4-oxoazetidin-1-yl)-3,4,5-trimethoxybenzamide (4b) This compound was obtained following the above method as white flocculus, yield 65%, m.p. 147-149°C; 1 N-(3-Chloro-2-isopropyl-4-oxoazetidin-1-yl) …”

“…[1][2][3][4] The most widely used antibiotics such as the penicillins, 5 aztreonam, cephalosporins, 6 carumonam, monobactams and nocardicins ( Fig. 1) all contain the azetidine-2-one heterocycle, which is the core structural feature in a number of broad spectrum b-lactams derivatives.…”

Ugi products containing boronate esters

“…Compounds containing a β-lactam moiety have been used extensively as antimicrobial agents [45,46]. It is hoped that the presence of both a boron group and a β-lactam moiety will provide enhanced biological activities for these novel boroncontaining dipeptide derivatives.…”

Antibiotic delivery by liposomes from prokaryotic microorganisms: Similia cum similis works better

“…[11][12] To face problems related to the use of antimicrobial agents, high doses of antibiotics or development of new drugs are continuously required. 13 In this contest, a viable strategy is to enhance the efficacy of the current antibiotic arsenal. For instance, the administration of bioactive compounds encapsulated in nanoparticles, [14][15][16][17] and liposomes, [18][19][20][21] has been indicated as a promising approach.…”