Amidine Derivatives of Avibactam: Synthesis and In Vitro β‐Lactamase Inhibition Activity

Abstract

Avibactam is a non‐β‐lactam based second generation β‐lactamase inhibitor containing diazabicyclooctane (DBO) ring as the β‐lactam mimic. We substituted C2 position of DBO scaffold by a number of amidine derivatives to form water soluble final compounds A1‐A14. The synthesized compounds were evaluated for their antibacterial and synergistic activity in combination with an antibiotic in vitro. The compounds, were tested against ten bacterial strains alone and in combination with existing antibiotic, meropenem. All compounds didn't show antibacterial activity when alone (MIC,>128 μM), however exhibited moderate to good synergistic activity in the presence of meropenem by lowering its MIC values. Compound A7 proved the most potent among other counterparts against all bacterial species with MIC from <0.29 μM to 2.34 μM, and showed comparable or improved activity to avibactam against eight bacterial strains. Compound A7 may prove a lead for next level in vivo and clinical studies.

Biological evaluation of some novel 1,3-bis substituted-2-isopropylamidines by in silico molecular dynamics and simulation studies

“…25 An amidine-based ionic liquid was reported by Lucio et al that could be used as an electrolyte in Al batteries. 26 Yang et al reported the synthesis of a set of amidine derivatives of avibactam and their use as antibacterial agents by in vitro inhibition of b-lactamase, in combination with an antibiotic. 27 Scheme 2 Reported routes for the synthesis of amidines.…”

Biological evaluation of some novel 1,3-bis substituted-2-isopropylamidines by in silico molecular dynamics and simulation studies

“…25 An amidine-based ionic liquid was reported by Lucio et al that could be used as an electrolyte in Al batteries. 26 Yang et al reported the synthesis of a set of amidine derivatives of avibactam and their use as antibacterial agents by in vitro inhibition of b-lactamase, in combination with an antibiotic. 27 Scheme 2 Reported routes for the synthesis of amidines.…”

Amidine Syntheses from Classic to Contemporary for Medicinal Lead Compounds and Natural Products

“…The optimal compound ( 3 ) compound outperformed the starting Avibactam in a large percentage out of the bacterial strains tested. [ 72 ] Here and in the previous example, the amidine provided a functional linker connecting different functional groups to the core bactam.…”

A Comprehensive Review of Recent Synthetic Strategies and Functionalization of Amidines

“…Additionally, other research groups have tested similar cyanide compounds with various amine sources using numerous reaction conditions and reagents to produce a broad range of amidine compounds. [157][158][159] Debnath et al demonstrated an efficient Cu-catalyzed strategy for the synthesis of substituted amidines via nucleophilic 1,2addition of amines 4 derivatives into various aryl nitriles 51. This catalytic reaction proceeded smoothly in the presence of CuCl, Cs 2 CO 3 , and 2,2'-bipyridine as a ligand under an oxygen (O 2 ) atmosphere in 2,2,2-trifluoroethanol (TFE) solvent at 100 • C for 15 h. Furthermore, this simple and sustainable protocol tolerates numerous functional groups, enabling the direct synthesis of substituted amidine derivatives 69 in yields up to 93%, as shown in Scheme 34 [160].…”

“…Additionally, other research groups have tested similar cyanide compounds with various amine sources using numerous reaction conditions and reagents to produce a broad range of amidine compounds. [157–159]…”

Biological evaluation of some novel 1,3-bis substituted-2-isopropylamidines by in silico molecular dynamics and simulation studies

“…25 An amidine-based ionic liquid was reported by Lucio et al that could be used as an electrolyte in Al batteries. 26 Yang et al reported the synthesis of a set of amidine derivatives of avibactam and their use as antibacterial agents by in vitro inhibition of b-lactamase, in combination with an antibiotic. 27 Scheme 2 Reported routes for the synthesis of amidines.…”

Amidine Syntheses from Classic to Contemporary for Medicinal Lead Compounds and Natural Products

“…The optimal compound ( 3 ) compound outperformed the starting Avibactam in a large percentage out of the bacterial strains tested. [ 72 ] Here and in the previous example, the amidine provided a functional linker connecting different functional groups to the core bactam.…”

A Comprehensive Review of Recent Synthetic Strategies and Functionalization of Amidines

“…Additionally, other research groups have tested similar cyanide compounds with various amine sources using numerous reaction conditions and reagents to produce a broad range of amidine compounds. [157][158][159] Debnath et al demonstrated an efficient Cu-catalyzed strategy for the synthesis of substituted amidines via nucleophilic 1,2addition of amines 4 derivatives into various aryl nitriles 51. This catalytic reaction proceeded smoothly in the presence of CuCl, Cs 2 CO 3 , and 2,2'-bipyridine as a ligand under an oxygen (O 2 ) atmosphere in 2,2,2-trifluoroethanol (TFE) solvent at 100 • C for 15 h. Furthermore, this simple and sustainable protocol tolerates numerous functional groups, enabling the direct synthesis of substituted amidine derivatives 69 in yields up to 93%, as shown in Scheme 34 [160].…”

“…Additionally, other research groups have tested similar cyanide compounds with various amine sources using numerous reaction conditions and reagents to produce a broad range of amidine compounds. [157–159]…”

Biological evaluation of some novel 1,3-bis substituted-2-isopropylamidines by in silico molecular dynamics and simulation studies

“…25 An amidine-based ionic liquid was reported by Lucio et al that could be used as an electrolyte in Al batteries. 26 Yang et al reported the synthesis of a set of amidine derivatives of avibactam and their use as antibacterial agents by in vitro inhibition of b-lactamase, in combination with an antibiotic. 27 Scheme 2 Reported routes for the synthesis of amidines.…”

Amidine Syntheses from Classic to Contemporary for Medicinal Lead Compounds and Natural Products

“…The optimal compound ( 3 ) compound outperformed the starting Avibactam in a large percentage out of the bacterial strains tested. [ 72 ] Here and in the previous example, the amidine provided a functional linker connecting different functional groups to the core bactam.…”

A Comprehensive Review of Recent Synthetic Strategies and Functionalization of Amidines

“…Additionally, other research groups have tested similar cyanide compounds with various amine sources using numerous reaction conditions and reagents to produce a broad range of amidine compounds. [157][158][159] Debnath et al demonstrated an efficient Cu-catalyzed strategy for the synthesis of substituted amidines via nucleophilic 1,2addition of amines 4 derivatives into various aryl nitriles 51. This catalytic reaction proceeded smoothly in the presence of CuCl, Cs 2 CO 3 , and 2,2'-bipyridine as a ligand under an oxygen (O 2 ) atmosphere in 2,2,2-trifluoroethanol (TFE) solvent at 100 • C for 15 h. Furthermore, this simple and sustainable protocol tolerates numerous functional groups, enabling the direct synthesis of substituted amidine derivatives 69 in yields up to 93%, as shown in Scheme 34 [160].…”

“…Additionally, other research groups have tested similar cyanide compounds with various amine sources using numerous reaction conditions and reagents to produce a broad range of amidine compounds. [157–159]…”