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Cifone, Matthew T. ; He, YongLe ; Basu, Rajeswari , et al. J. Med. Chem.,2022,65(24):16510-16525. DOI: 10.1021/acs.jmedchem.2c01380 PubMed ID: 36459397
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Abstract: The relationship between drug-target residence time and the post-antibiotic effect (PAE) provides insights into target vulnerability. To probe the vulnerability of bacterial acetyl-CoA carboxylase (ACC), a series of heterobivalent inhibitors were synthesized based on pyridopyrimidine 1 and moiramide B (3) which bind to the biotin carboxylase and carboxyltransferase ACC active sites, resp. The heterobivalent compound 17, which has a linker of 50 ?, was a tight binding inhibitor of Escherichia coli ACC (Kiapp 0.2 nM) and could be displaced from ACC by a combination of both 1 and 3 but not just by 1. In agreement with the prolonged occupancy of ACC resulting from forced proximity binding, the heterobivalent inhibitors produced a PAE in E. coli of 1-4 h in contrast to 1 and 3 in combination or alone, indicating that ACC is a vulnerable target and highlighting the utility of kinetic, time-dependent effects in the drug mechanism of action.
Purchased from AmBeed: 14542-71-3 ; 112-27-6 ; 112-27-6 ; 2615-15-8 ; 2468-56-6 ; 2834-05-1 ; 13979-81-2 ; 85141-94-2 ; 20781-06-0 ; 688744-20-9 ; 13321-75-0 ; 2092351-86-3 ; 130445-13-5
CAS No. : | 20781-06-0 | MDL No. : | MFCD04973412 |
Formula : | C5H6N4O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GPWNWKWQOLEVEQ-UHFFFAOYSA-N |
M.W : | 138.13 | Pubchem ID : | 309176 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 2-ethoxy-ethanol; | EXAMPLE 60 6-(2,6-Dibromo-phenyl)-pyrido[2,3-d]pyrimidine-2,7-diamine To a solution of 0.23 g 60% sodium hydride suspension in 11.0 mL of 2-ethoxyethanol was added 4.18 g of <strong>[67197-53-9]2,6-dibromophenylacetonitrile</strong> and 2.00 g of 2,4-diaminopyrimidine-5-carboxaldehyde. The reaction was refluxed for 4 hours, cooled, and poured into ice water. The residue was washed well with acetonitrile then diethyl ether to give 3.62 g of 6-(2,6-dibromo-phenyl)-pyrido[2,3-d]pyrimidine-2,7-diamine, CIMS (1% NH3 in CH4): 422=M+ +C2 H5, 396 (Base), 394=M+ +H, 393=M+; mp 284-289 C. |
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