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

Nagendra Prasad Muddala; Baskar Nammalwar; Subhashini Selvaraju; Christina R Bourne; Mary Henry; Richard A Bunce; K Darrell Berlin; Esther W Barrow; William W Barrow

doi:10.3390/molecules20047222

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

Molecules. 2015 Apr 21;20(4):7222-44. doi: 10.3390/molecules20047222.

Authors

Nagendra Prasad Muddala¹, Baskar Nammalwar², Subhashini Selvaraju³, Christina R Bourne⁴, Mary Henry⁵, Richard A Bunce⁶, K Darrell Berlin⁷, Esther W Barrow⁸, William W Barrow⁹

Affiliations

¹ Department of Chemistry, Oklahoma State University, 107 Physical Sciences, Stillwater, OK 74078, USA. muddala@okstate.edu.
² Department of Chemistry, Oklahoma State University, 107 Physical Sciences, Stillwater, OK 74078, USA. baskar@okstate.edu.
³ Department of Chemistry, Oklahoma State University, 107 Physical Sciences, Stillwater, OK 74078, USA. subhas@okstate.edu.
⁴ Department of Chemistry and Biochemistry, University of Oklahoma, 101 Stephenson Parkway, Norman, OK 73019, USA. cbourne@ou.edu.
⁵ Department of Veterinary Pathobiology, Oklahoma State University, 250 McElroy Hall, Stillwater, OK 74078, USA. henrym@okstate.edu.
⁶ Department of Chemistry, Oklahoma State University, 107 Physical Sciences, Stillwater, OK 74078, USA. rab@okstate.edu.
⁷ Department of Chemistry, Oklahoma State University, 107 Physical Sciences, Stillwater, OK 74078, USA. kdb@okstate.edu.
⁸ Department of Veterinary Pathobiology, Oklahoma State University, 250 McElroy Hall, Stillwater, OK 74078, USA. esther.barrow@okstate.edu.
⁹ Department of Veterinary Pathobiology, Oklahoma State University, 250 McElroy Hall, Stillwater, OK 74078, USA. bill.barrow@okstate.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology
Bacillus anthracis / drug effects*
Catalysis
Crystallography, X-Ray
Models, Molecular
Molecular Structure
Palladium / chemistry*
Phthalazines / chemical synthesis*
Phthalazines / chemistry
Phthalazines / pharmacology
Pyrimidines / chemistry*

Substances

Anti-Bacterial Agents
Phthalazines
Pyrimidines
2,4-diaminopyrimidine
Palladium

Abstract

Publication types

MeSH terms

Substances

Grants and funding