Diaveridine

Names

[ Name ]:
Diaveridine

[Synonym ]:
Diaveridinum [INN-Latin]
Diaveridinum
DIAVERIDINE
2,4-Diamino-5-veratrylpyrimidine
5-(3,4-Dimethoxybenzyl)-2,4-pyrimidinediamine
2,4-diamino-5-(3,4-dimethoxy-benzyl)-pyrimidine
MFCD00057349
5-(3,4-dimethoxy-benzyl)-pyrimidine-2,4-diamine
5-[(3,4-dimethoxyphenyl)methyl]pyrimidine-2,4-diamine
Diaveridin
BW 49-210
Diaveridina
5-Veratryl-pyrimidin-2,4-diyldiamin
EINECS 226-333-3

Biological Activity

[Description]:

Diaveridine (EGIS-5645) is a dihydrofolate reductase (DHFR) inhibitor with a Ki of 11.5 nM for the wild type DHFR and also an antibacterial agent.

[Related Catalog]:

Signaling Pathways >> Cell Cycle/DNA Damage >> Antifolate

Signaling Pathways >> Anti-infection >> Bacterial

Research Areas >> Infection

[Target]

Ki: 11.5 nM (DHFR) [1] Bacterial[2]

[In Vitro]

Diaveridine is a dihydrofolate reductase (DHFR) inhibitor with a Ki of 11.5 nM for the wild type DHFR and also an antibacterial agent[1]. Treatments with Diaveridine for 90 min have a strong bactericidal effect on S. typhimurium TA1535, and no bacterial growth is observed at 10μg/mL or more. Without metabolic activation, treatment with Diaveridine for 48 h, but not 24 h, causes a dose-dependent, significant increase in the frequency of aberrant metaphases. At 100 μg/mL, 60% of the metaphases contain chromosome aberrations[2].

[In Vivo]

The sperm abnormality of the Diaveridine (DVD) treatment groups at all dose levels (Diaveridine, 128 to 512 mg/kg) shows no significant differences compare with the negative control group. There are no significant differences of micronucleus between the negative control group and the Diaveridine treatment groups (Diaveridine, 128 to 512 mg/kg). The chromosome aberration of the Diaveridine treatment groups at all dose levels and the negative control group are significantly lower than those in the positive control group treated with cyclophosphamide (P<0.05), indicating that Diaveridine at the doses studied does not cause abnormal chromosome aberration. The results demonstrate that the Diaveridine administration does not produce significant changes in the ratio of organ-to-body weight, compare with the negative control group in the end period of the study[3].

[Cell Assay]

Cells are cultured at 37°C in a humidified atmosphere of 5% CO2 in air. The growth medium is Eagle’s MEM supplemented with 10% fetal bovine serum. In the experiment without metabolic activation, the cells are treated for 24 or 48 h continuously without a medium change. In the experiment with metabolic activation, the cells are pulse treated with test compounds (including Diaveridine) at varying doses for 6 h and incubated for 18 h in fresh culture medium. Breakage type chromatid aberrations, exchange type chromatid aberrations, breakage type chromosome aberrations, and exchange type chromosome aberrations are scored. Gaps are also counted. Mitotic index is determined from scoring 2000 cells[2].

[Animal admin]

3]Fifty male ICR mice, weighing 25 to 35 g, are assigned to five groups randomly with 10 mice in each group. Mice in the experiment groups receive Diaveridine (DVD) via IG at ed 128 mg/kg (low doses), 256 mg/kg (medium doses), and 512 mg/kg (high doses) body weight for 5 consecutive days, respectively. Mice in negative and positive control groups receive IG 1% CMC-Na solvent and 40 mg/kg body weight of cyclophosphamide, respectively. The testing groups are administered 0.2 mL/10 g Diaveridine (mixed with 1% of CMC-Na, to obtain the concentration of 2 mg/mL.) body weight, once a day, for 5 days. The behavioral changes are recorded on the daily basis[3].

[References]

[1]. Sirichaiwat C et al. Target guided synthesis of 5-benzyl-2,4-diamonopyrimidines: their antimalarial activities and binding affinities to wild type and mutant dihydrofolate reductases from Plasmodium falciparum. J Med Chem 47:345-54 (2004).

[2]. Ono T, et al. The genotoxicity of diaveridine and trimethoprim. Environ Toxicol Pharmacol. 1997 Sep;3(4):297-306.

[3]. Wang J, et al. Acute, mutagenicity, teratogenicity and subchronic oral toxicity studies of diaveridine in rodents. Environ Toxicol Pharmacol. 2015 Sep;40(2):660-70.

[Related Small Molecules]

Chemical & Physical Properties

[ Density]:
1.3±0.1 g/cm3

[ Boiling Point ]:
506.1±60.0 °C at 760 mmHg

[ Melting Point ]:
232 - 236ºC

[ Molecular Formula ]:
C₁₃H₁₆N₄O₂

[ Molecular Weight ]:
260.292

[ Flash Point ]:
259.9±32.9 °C

[ Exact Mass ]:
260.127319

[ PSA ]:
96.28000

[ LogP ]:
1.09

[ Vapour Pressure ]:
0.0±1.3 mmHg at 25°C

[ Index of Refraction ]:
1.626

[ Storage condition ]:
2-8°C

MSDS

Click to get detail MSDS

Toxicological Information

CHEMICAL IDENTIFICATION

RTECS NUMBER :: UV8142000

CHEMICAL NAME :: 2,4-Pyrimidinediamine, 5-((3,4-dimethoxyphenyl)methyl)-

CAS REGISTRY NUMBER :: 5355-16-8

BEILSTEIN REFERENCE NO. :: 0258464

LAST UPDATED :: 199612

DATA ITEMS CITED :: 3

MOLECULAR FORMULA :: C13-H16-N4-O2

MOLECULAR WEIGHT :: 260.33

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 3679 mg/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 6028 mg/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

MUTATION DATA

TYPE OF TEST :: Mutation in microorganisms

TEST SYSTEM :: Bacteria - Salmonella typhimurium

DOSE/DURATION :: 5 ug/plate

REFERENCE :: MUREAV Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- Volume(issue)/page/year: 261,149,1991

Safety Information

[ Symbol ]:

GHS07

[ Signal Word ]:
Warning

[ Hazard Statements ]:
H315-H319-H335

[ Precautionary Statements ]:
P305 + P351 + P338

[ Personal Protective Equipment ]:
dust mask type N95 (US);Eyeshields;Gloves

[ Hazard Codes ]:
Xi:Irritant;

[ Risk Phrases ]:
R36/37/38

[ Safety Phrases ]:
S26-S36

[ RIDADR ]:
NONH for all modes of transport

[ WGK Germany ]:
2

[ RTECS ]:
UV8142000

[ HS Code ]:
2933599090

Synthetic Route

Click to get detail synthetic route

Precursor & DownStream

Precursor

DownStream

Customs

[ HS Code ]: 2933599090

[ Summary ]:
2933599090. other compounds containing a pyrimidine ring (whether or not hydrogenated) or piperazine ring in the structure. VAT:17.0%. Tax rebate rate:13.0%. . MFN tariff:6.5%. General tariff:20.0%

Articles

[Polarographic determination of diaveridine in biological samples].

Acta Pharm. Hung. 60(1) , 23-9, (1990)

Differential pulse polarographic method was applied for determination of diaveridine in plasma, whole blood and isolated organs (liver, spleen, kidney, thymus). Deproteinization of homogenized blood a...

Inhibitors of folic acid synthesis in the treatment of experimental Pneumocystis carinii pneumonia.

Antimicrob. Agents Chemother. 32(1) , 96-103, (1988)

Inhibitors of folic acid synthesis were compared alone and in different combinations in the therapy of pneumocystosis in immunosuppressed rats. Sulfonamides (sulfamethoxazole, sulfadiazine, and sulfad...

Demonstration of synergistic effects of sulfonamides and dihydrofolate reductase/thymidylate synthase inhibitors against Neospora caninum tachyzoites in cultured cells, and characterization of mutants resistant to pyrimethamine.

Am. J. Vet. Res. 57(1) , 68-72, (1996)

To examine the efficacies of combinations of 7 sulfonamides and 5 dihydrofolate reductase/thymidylate synthase (DHFR/TS) inhibitors against tachyzoites of Neospora caninum in cultured cells. Mutant ta...