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Molecules 2014, 19(3), 3231-3246; doi:10.3390/molecules19033231
Article

Synthesis and Biological Evaluation of 2,4-Diaminopyrimidine-Based Antifolate Drugs against Bacillus anthracis

1
, 1
, 2,†
, 2
, 2
, 1,* , 2
, 1
 and 2
1 Department of Chemistry, Oklahoma State University, 107 Physical Sciences, Stillwater, OK 74078, USA 2 Department of Veterinary Pathobiology, Oklahoma State University, 250 McElroy Hall, Stillwater, OK 74078, USA Current Address: Department of Chemistry and Biochemistry, University of Oklahoma, 2610 Stephenson Life Sciences Research Center, Norman, OK 73019, USA
* Author to whom correspondence should be addressed.
Received: 11 January 2014 / Revised: 8 March 2014 / Accepted: 10 March 2014 / Published: 17 March 2014
(This article belongs to the Special Issue Heterocyclic and Medicinal Chemistry)
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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 Ki values to identify the most potent drug candidate.
Keywords: Gram-positive bacteria; Bacillus anthracis; 2,4-diaminopyrimidine; Heck reaction; antibiotic resistance; dihydrofolate reductase (DHFR); antifolates Gram-positive bacteria; Bacillus anthracis; 2,4-diaminopyrimidine; Heck reaction; antibiotic resistance; dihydrofolate reductase (DHFR); antifolates
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.

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Nammalwar, B.; Muddala, N.P.; Bourne, C.R.; Henry, M.; Bourne, P.C.; Bunce, R.A.; Barrow, E.W.; Berlin, K.D.; Barrow, W.W. Synthesis and Biological Evaluation of 2,4-Diaminopyrimidine-Based Antifolate Drugs against Bacillus anthracis. Molecules 2014, 19, 3231-3246.

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