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Molecules 2015, 20(4), 7222-7244; doi:10.3390/molecules20047222

Evaluation of New Dihydrophthalazine-Appended 2,4-Diaminopyrimidines against Bacillus anthracis: Improved Syntheses Using a New Pincer Complex

1
Department of Chemistry, Oklahoma State University, 107 Physical Sciences, Stillwater, OK 74078, USA
2
Department of Chemistry and Biochemistry, University of Oklahoma, 101 Stephenson Parkway, Norman, OK 73019, USA
3
Department of Veterinary Pathobiology, Oklahoma State University, 250 McElroy Hall, Stillwater, OK 74078, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Received: 20 March 2015 / Revised: 14 April 2015 / Accepted: 15 April 2015 / Published: 21 April 2015
(This article belongs to the Section Medicinal Chemistry)
View Full-Text   |   Download PDF [1999 KB, uploaded 21 April 2015]   |  

Abstract

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 °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 °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. View Full-Text
Keywords: 2,4-diaminopyrimidine antifolates; dihydrofolate reductase (DHFR); Bacillus anthracis; pincer complexes; Heck coupling 2,4-diaminopyrimidine antifolates; dihydrofolate reductase (DHFR); Bacillus anthracis; pincer complexes; Heck coupling
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Muddala, N.P.; Nammalwar, B.; Selvaraju, S.; Bourne, C.R.; Henry, M.; Bunce, R.A.; Berlin, K.D.; Barrow, E.W.; Barrow, W.W. Evaluation of New Dihydrophthalazine-Appended 2,4-Diaminopyrimidines against Bacillus anthracis: Improved Syntheses Using a New Pincer Complex. Molecules 2015, 20, 7222-7244.

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