Effects of Structural Variations on the Rates of Enzymatic and Nonenzymatic Hydrolysis of Carbonate and Carbamate Esters

Nassar, Munir N.; Agha, Bushra J.; Digenis, George A.

doi:10.1002/jps.2600810321

Cited by 10 publications

(4 citation statements)

References 12 publications

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“…Peptidyl carbamate esters (RNHCOOR‘) and thiocarbamates (RNHCOSR‘) with appropriate substitutions have been designed that are stable to enzymatic hydrolysis and specifically inhibit PPE and HLE with no effect on trypsin or chymotrypsin. − Two inhibitors are MeO-Suc-Ala-Ala-Pro-CH 2 -N(CH(CH 3 ) 2 )-CO-ONp ( K i = 4.24 × 10 -5 M) and MeO-Suc-Ala-Ala-Pro-CH 2 -N(CH(CH 3 ) 2 )-CO 2 -Ph ( K i = 3.00 × 10 -5 M, 23 , Figure ). The inhibitors in Figure are carbamate analogues that have the peptide portion placed on the nitrogen ( 23 ) or the peptide portion placed on the ester oxygen ( 22 ) .…”

Section: B Carbamatesmentioning

confidence: 99%

Irreversible Inhibitors of Serine, Cysteine, and Threonine Proteases

et al. 2002

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Section: B Carbamatesmentioning

confidence: 99%

Irreversible Inhibitors of Serine, Cysteine, and Threonine Proteases

et al. 2002

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“…Triggerable but noneliminating prodrug 5 was synthesized as a control prodrug. The 4-nitrobenzylmethyl group can still be reduced by NTR, but the stability of the amide bond − prevents self-immolation. Synthesis occurred over two steps from Boc-protected ciprofloxacin 6 using a peptide coupling reagent (HBTU) to form the amide bond followed by HCl-mediated removal of the Boc group (Scheme ).…”

Section: Resultsmentioning

confidence: 99%

Site-Specific Antimicrobial Activity of a Dual-Responsive Ciprofloxacin Prodrug

Ross,

Lawer,

Sircombe

et al. 2024

J. Med. Chem.

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Bacterial infections create distinctive microenvironments with a unique mix of metabolites and enzymes compared with healthy tissues that can be used to trigger the activation of antibiotic prodrugs. Here, a single and dual prodrug masking the C3 carboxylate and C7 piperazine of the fluoroquinolone, ciprofloxacin, responsive to nitroreductase (NTR) and/or hydrogen sulfide (H2S), was developed. Masking both functional groups reduced the activity of the prodrug against Staphylococcus aureus and Escherichia coli, increasing its minimum inhibitory concentration (MIC) by ∼512-fold (S. aureus) and ∼8000-fold (E. coli strains), while masking a single group only increased the MIC by ∼128-fold. Bacteria subjected to prolonged prodrug exposure did not show any increase in resistance. Triggering assays demonstrated the conversion of prodrugs to ciprofloxacin, and in a murine infection model, responsive prodrugs showed antibacterial activity comparable to that of ciprofloxacin, suggesting in vivo activation of prodrugs. Thus, the potential for site-specific antibiotic treatment with reduced threat of resistance is demonstrated.

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“…In our case, the lacking nitroester group was replaced by a carbonate diester. The advantage of this (nitroester → carbonate diester) replacement is its high similarity, good synthetic availability (via activated carbonate derivatives) and the reasonable chemical stability of the compounds (Nassar et al, ). In Figure , the structures of the relevant compounds are shown.…”

Section: Resultsmentioning

confidence: 99%

Development of highly sensitive and selective antibodies for the detection of the explosive pentaerythritol tetranitrate (PETN) by bioisosteric replacement

et al. 2015

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An improved antibody against the explosive pentaerythritol tetranitrate (PETN) was developed. The immunogen was designed by the concept of bioisosteric replacement, which led to an excellent polyclonal antibody with extreme selectivity and immunoassays of very good sensitivity. Compounds such as nitroglycerine, 2,4,6-trinitrotoluene, 1,3,5-trinitrobenzene, hexogen (RDX), 2,4,6-trinitroaniline, 1,3-dinitrobenzene, octogen (HMX), triacetone triperoxide, ammonium nitrate, 2,4,6-trinitrophenol and nitrobenzene were tested for potential cross-reactivity. The detection limit of a competitive enzyme-linked immunosorbent assay was determined to be around 0.5 µg/l. The dynamic range of the assay was found to be between 1 and 1000 µg/l, covering a concentration range of three decades. This work shows the successful application of the bioisosteric concept in immunochemistry by exchange of a nitroester to a carbonate diester. The antiserum might be used for the development of quick tests, biosensors, microtitration plate immunoassays, microarrays and other analytical methods for the highly sensitive detection of PETN, an explosive frequently used by terrorists, exploiting the extreme difficulty of its detection.

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Effects of Structural Variations on the Rates of Enzymatic and Nonenzymatic Hydrolysis of Carbonate and Carbamate Esters

Cited by 10 publications

References 12 publications

Irreversible Inhibitors of Serine, Cysteine, and Threonine Proteases

Irreversible Inhibitors of Serine, Cysteine, and Threonine Proteases

Site-Specific Antimicrobial Activity of a Dual-Responsive Ciprofloxacin Prodrug

Development of highly sensitive and selective antibodies for the detection of the explosive pentaerythritol tetranitrate (PETN) by bioisosteric replacement

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