Journal
MOLECULES
Volume 20, Issue 4, Pages 7222-7244Publisher
MDPI
DOI: 10.3390/molecules20047222
Keywords
2; 4-diaminopyrimidine antifolates; dihydrofolate reductase (DHFR); Bacillus anthracis; pincer complexes; Heck coupling
Funding
- National Institutes of Allergy and Infectious Diseases of the NIH/NIAID [R01-AI090685]
- Sitlington Chair in Infectious Diseases
- NSF [BIR-9512269, CHE-0130835]
- Oklahoma State Regents for Higher Education
- W. M. Keck Foundation
- Conoco, Inc
- College of Arts and Sciences at Oklahoma State University
- University of Oklahoma
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The synthesis and evaluation of ten new dihydrophthalazine-appended 2,4-diaminopyrimidines as potential drugs to treat Bacillus anthracis is reported. An improved synthesis utilizing a new pincer catalyst, dichlorobis[1-(dicyclohexylphosphanyl)-piperidine]palladium(II), allows the final Heck coupling to be performed at 90 degrees C using triethylamine as the base. These milder conditions have been used to achieve improved yields for new and previously reported substrates with functional groups that degrade or react at the normal 140 degrees C reaction temperature. An analytical protocol for separating the S and R enantiomers of two of the most active compounds is also disclosed. Finally, the X-ray structure for the most active enantiomer of the lead compound, (S)-RAB1, is given.
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