Synthesis and biological evaluation of 2,4-diaminopyrimidine-based antifolate drugs against Bacillus anthracis

Baskar Nammalwar; N Prasad Muddala; Christina R Bourne; Mary Henry; Philip C Bourne; Richard A Bunce; Esther W Barrow; K Darrell Berlin; William W Barrow

doi:10.3390/molecules19033231

Synthesis and biological evaluation of 2,4-diaminopyrimidine-based antifolate drugs against Bacillus anthracis

Molecules. 2014 Mar 17;19(3):3231-46. doi: 10.3390/molecules19033231.

Authors

Baskar Nammalwar¹, N Prasad Muddala², Christina R Bourne³, Mary Henry⁴, Philip C Bourne⁵, Richard A Bunce⁶, Esther W Barrow⁷, K Darrell Berlin⁸, William W Barrow⁹

Affiliations

¹ Department of Chemistry, Oklahoma State University, 107 Physical Sciences, Stillwater, OK 74078, USA. baskar@okstate.edu.
² Department of Chemistry, Oklahoma State University, 107 Physical Sciences, Stillwater, OK 74078, USA. muddala@okstate.edu.
³ Department of Veterinary Pathobiology, Oklahoma State University, 250 McElroy Hall, Stillwater, OK 74078, USA. cbourne@ou.edu.
⁴ Department of Veterinary Pathobiology, Oklahoma State University, 250 McElroy Hall, Stillwater, OK 74078, USA. henrym@okstate.edu.
⁵ Department of Veterinary Pathobiology, Oklahoma State University, 250 McElroy Hall, Stillwater, OK 74078, USA. pcbourne@yahoo.com.
⁶ Department of Chemistry, Oklahoma State University, 107 Physical Sciences, Stillwater, OK 74078, USA. rab@okstate.edu.
⁷ Department of Veterinary Pathobiology, Oklahoma State University, 250 McElroy Hall, Stillwater, OK 74078, USA. esther.barrow@okstate.edu.
⁸ Department of Chemistry, Oklahoma State University, 107 Physical Sciences, Stillwater, OK 74078, USA. kdb@okstate.edu.
⁹ Department of Veterinary Pathobiology, Oklahoma State University, 250 McElroy Hall, Stillwater, OK 74078, USA. bill.barrow@okstate.edu.

Abstract

Due to the innate ability of bacteria to develop resistance to available antibiotics, there is a critical need to develop new agents to treat more resilient strains. As a continuation of our research in this area, we have synthesized a series of racemic 2,4-diaminopyrimidine-based drug candidates, and evaluated them against Bacillus anthracis. The structures are comprised of a 2,4-diaminopyrimidine ring, a 3,4-dimethoxybenzyl ring, and an N-acryloyl-substituted 1,2-dihydrophthalazine ring. Various changes were made at the C1 stereocenter of the dihydrophthalazine moiety in the structure, and the biological activity was assessed by measurement of the MIC and K(i) values to identify the most potent drug candidate.

Publication types

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

MeSH terms

Bacillus anthracis / drug effects*
Binding Sites
Folic Acid Antagonists / chemical synthesis*
Folic Acid Antagonists / pharmacology*
Microbial Sensitivity Tests
Models, Molecular
Molecular Conformation
Protein Binding
Pyrimidines / chemical synthesis*
Pyrimidines / pharmacology*
Tetrahydrofolate Dehydrogenase / chemistry

Substances

Folic Acid Antagonists
Pyrimidines
2,4-diaminopyrimidine
Tetrahydrofolate Dehydrogenase

Abstract

Publication types

MeSH terms

Substances

Grants and funding