Evidence map›Paper›PMID 25435253›Full record

ArticleBioorganic & medicinal chemistry2015

Modified 2,4-diaminopyrimidine-based dihydrofolate reductase inhibitors as potential drug scaffolds against Bacillus anthracis.

Baskar Nammalwar, Christina R Bourne, Nancy Wakeham, Philip C Bourne, Esther W Barrow, N Prasad Muddala, Richard A Bunce, K Darrell Berlin, William W Barrow

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Bioorganic & medicinal chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

6 citing papers in PubMed.

  1. Article
  2. Article
  3. Review
  4. Article
  5. Review
  6. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors.

Baskar NammalwarDepartment of Chemistry, Oklahoma State University, 107 Physical Sciences, Stillwater, OK 74078, USA.
Christina R BourneDepartment of Veterinary Pathobiology, Oklahoma State University, 250 McElroy Hall, Stillwater, OK 74078, USA.
Nancy WakehamDepartment of Veterinary Pathobiology, Oklahoma State University, 250 McElroy Hall, Stillwater, OK 74078, USA.
Philip C BourneDepartment of Veterinary Pathobiology, Oklahoma State University, 250 McElroy Hall, Stillwater, OK 74078, USA.
Esther W BarrowDepartment of Veterinary Pathobiology, Oklahoma State University, 250 McElroy Hall, Stillwater, OK 74078, USA.
N Prasad MuddalaDepartment of Chemistry, Oklahoma State University, 107 Physical Sciences, Stillwater, OK 74078, USA.
Richard A BunceDepartment of Chemistry, Oklahoma State University, 107 Physical Sciences, Stillwater, OK 74078, USA. Electronic address: rab@okstate.edu.
K Darrell BerlinDepartment of Chemistry, Oklahoma State University, 107 Physical Sciences, Stillwater, OK 74078, USA.
William W BarrowDepartment of Veterinary Pathobiology, Oklahoma State University, 250 McElroy Hall, Stillwater, OK 74078, USA.

Funding

Broad-spectrum Antifolates for Treatment of Drug Resistant Bacillus anthracisR01AI090685 · NIAID · OKLAHOMA STATE UNIVERSITY STILLWATER · PI BUNCE, RICHARD A · 2010 to 2014
$3.9M
NIAID NIH HHS R01 AI090685NIAID NIH HHS R01-AI090685
6 · The paper itself

Abstract

The current Letter describes the synthesis and biological evaluation of dihydrophthalazine-appended 2,4-diaminopyrimidine (DAP) inhibitors (1) oxidized at the methylene bridge linking the DAP ring to the central aromatic ring and (2) modified at the central ring ether groups. Structures 4a-b incorporating an oxidized methylene bridge showed a decrease in activity, while slightly larger alkyl groups (CH2CH3 vs CH3) on the central ring oxygen atoms (R(2) and R(3)) had a minimal impact on the inhibition. Comparison of the potency data for previously reported RAB1 and BN-53 with the most potent of the new derivatives (19 b and 20a-b) showed similar values for inhibition of cellular growth and direct enzymatic inhibition (MICs 0.5-2 μg/mL). Compounds 29-34 with larger ester and ether groups containing substituted aromatic rings at R(3) exhibited slightly reduced activity (MICs 2-16 μg/mL). One explanation for this attenuated activity could be encroachment of the extended R(3) into the neighboring NADPH co-factor. These results indicate that modest additions to the central ring oxygen atoms are well tolerated, while larger modifications have the potential to act as dual-site inhibitors of dihydrofolate reductase (DHFR).

Indexed as

Anti-Bacterial AgentsBacillus anthracisFolic Acid AntagonistsModels, MolecularProtein BindingPyrimidinesStructure-Activity Relationship2,4-diaminopyrimidineAnti-Bacterial AgentsFolic Acid AntagonistsPyrimidinesAntibioticsAntifolatesAntimicrobial agentsBacillus anthracis inhibitionDihydrofolate reductase

Identifiers

PMID25435253
PMCPMC4278362

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.