5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidine-2,4-diamine

• ChemBase ID: 323
• Molecular Formular: C14H18N4O3
• Molecular Mass: 290.31772
• Monoisotopic Mass: 290.13789046
• SMILES: O(c1cc(Cc2c(nc(nc2)N)N)cc(OC)c1OC)C
• Canonical SMILES: COc1cc(Cc2cnc(nc2N)N)cc(c1OC)OC
• InChI: InChI=1S/C14H18N4O3/c1-19-10-5-8(6-11(20-2)12(10)21-3)4-9-7-17-14(16)18-13(9)15/h5-7H,4H2,1-3H3,(H4,15,16,17,18)
• InChIKey: IEDVJHCEMCRBQM-UHFFFAOYSA-N

NAMES AND DATABASE IDS

Names

• IUPAC name: 5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidine-2,4-diamine
• IUPAC Traditional name: trimethoprim; 5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidine-2,4-diamine
• Brand Name: Abacin; Abaprim; Alprim; Apo-Sulfatrim; Bactin; Bactramin; Bactrim; Bactrim DS; Bactrim Pediatric; Baktar; Chemotrim; Co-Trimoxazole; Comox; Cotrim; Cotrim D.S.; Drylin; Eusaprim; Fectrim; Gantaprim; Gantrim; Idotrim; Imexim; Instalac; Ipral; Kepinol; Laratrim; Lidaprim; Methoprim; Microtrim; Monoprim; Monotrim; Monotrimin; Nopil; Oraprim; Priloprim; Primosept; Primsol; Proloprim; Septra; Septra DS; Septra Grape; Septrin; Sigaprim; Sulfamethoprim; Sulfamethoprim-DS; Sulfamethoxazole & Trimethoprim; Sulfatrim; Sulfatrim Pediatric; Sulfatrim-DS; Sulfatrim-SS; Sulfotrim; Sulmeprim; Sulmeprim Pediatric; Sulprim; Sumetrolim; Supracombin; Suprim; Syraprim; Teleprim; Thiocuran; Tiempe; Tmp-Ratiopharm; Trigonyl; Trimanyl; Trimesulf; Trimeth/Sulfa; Trimethioprim; Trimethopriom; Trimetoprim; Trimexazole; Trimogal; Trimopan; Trimpex; Trimpex 200; Triprim; Unitrim; Uretrim; Uro-Septra; Uroplus; Uroplus DS; Uroplus SS; Wellcoprim
• Synonyms: Trimethoprim; 5-(3,4,5-Trimethoxybenzyl)-2,4-pyrimidinediamine; 2,4-Diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine; Trimethoprim; 5-(3,4,5-trimethoxybenzyl)pyrimidine-2,4-diamine; Trimpex; 2,4-Diamino-5-[3,4,5-trimethoxy-benzyl]pyrimidine; 5-[(3,4,5-Trimethoxyphenyl)methyl]-2,4-pyrimidinediamine; 2,4-Diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidine; Instalac; Monotrim; Proloprim; Syraprim; Tiempe; Trimanyl; Uretrim; Wellcoprim; 2,4-二氨基-5-(3,4,5-三甲氧基苄基)嘧啶; 甲氧苄啶

Database IDs

• CAS Number: 738-70-5
• EC Number: 212-006-2
• MDL Number: MFCD00036761
• Beilstein Number: 625127
• PubChem SID: 160963786; 24889615; 24278201; 46507125; 24870616
• PubChem CID: 5578
• CHEBI ID: 45924
• ATC CODE: QJ51EA01; J01EA01
• CHEMBL: 22
• Chemspider ID: 5376
• DrugBank ID: DB00440
• KEGG ID: D00145
• Unique Ingredient Identifier: AN164J8Y0X
• Wikipedia Title: Trimethoprim
• Medline Plus: a684025

CALCULATED PROPERTIES

JChem

• Acid pKa: 17.334406
• H Acceptors: 7
• H Donor: 2
• LogD (pH = 5.5): 0.020083463
• LogD (pH = 7.4): 1.0960962
• Log P: 1.2839073
• Molar Refractivity: 81.5094 cm^3
• Polarizability: 29.759577 Å^3
• Polar Surface Area: 105.51 Å^2
• Rotatable Bonds: 5
• Lipinski's Rule of Five: true

ALOGPS 2.1

• Log P: 1.26
• LOG S: -2.67
• Solubility (Water): 6.15e-01 g/l

PROPERTIES

Physical Property

• Solubility: 12.1 mg/mL; Chloroform; chloroform/ethanol (1:1): soluble50 mg/mL, clear, colorless; DMF; DMSO; DMSO: soluble; Methanol (hot)
• Apperance: Off-White Solid; white powder
• Melting Point: 192-195°C; 199-203 °C; 199-203°C
• Hydrophobicity(logP): 0.6

Safety Information

• Storage Condition: 2-8°C; Refrigerator
• Storage Warning: IRRITANT
• RTECS: UV8225000
• European Hazard Symbols: Toxic (T)
• UN Number: 2811
• German water hazard class: 3
• Hazard Class: 6.1
• Packing Group: III
• Australian Hazchem: 2X
• Risk Statements: R:25
• Safety Statements: S:28-29-36/37/39-45
• EU Classification: T2
• EU Hazard Identification Number: 6.1B
• Emergency Response Guidebook(ERG) Number: 154
• TSCA Listed: false
• Personal Protective Equipment: Eyeshields, Gloves, type N95 (US), type P1 (EN143) respirator filter
• Storage Temperature: 2-8°C

Pharmacology Properties

• Target: Others
• Admin Routes: Oral
• Bioavailability: 90–100%
• Excretion: renal 50–60%
• Half Life: 8–10 hours
• Metabolism: hepatic
• Legal Status: POM (UK); S4 (Australia)
• Pregnancy Category: B3 (Australia); C (US)
• Gene Information: human ... DHFRP1(573971), KCNH1(3756)rat ... Dhfr(24312)
• Mechanism of Action: Bacterial biosynthesis of nucleic acids and proteins is blocked by interference with normal bacterial metabolism of folinate; Binding to bacterial enzyme is stronger than to the corresponding mammalian enzyme; Blocks production of tetrahydrofolate from dihydrofolate; Folate antagonist; Reversible dihydrofolate-reductase-inhibitor

Product Information

• Purity: ≥98% (TLC); ≥99.0% (HPLC)
• Grade: VETRANAL™, analytical standard
• Salt Data: Free Base
• Suitability: suitable for 1694 per US EPA
• Application(s): Active against common urinary-tract pathogens except for Pseudomonas aeruginosa; Active against Haemophilus-influenzae.; Antibacterial agent; Antiseptic; Inhibits dihydrofolate reductase from bacterial sources and from malaria parasites
• Quality: crystallized
• Pharmacopeia Traceability: traceable to BP 344; traceable to PhEur T220000; traceable to USP 1692505
• Empirical Formula (Hill Notation): C14H18N4O3

DETAILS

MP Biomedicals - 02195527

Crystalline
A specific inhibitor of formylation.

DrugBank - DB00440

• Drug Groups: approved
• Description: A pyrimidine inhibitor of dihydrofolate reductase, it is an antibacterial related to pyrimethamine. The interference with folic acid metabolism may cause a depression of hematopoiesis. It is potentiated by sulfonamides and the trimethoprim-sulfamethoxazole combination is the form most often used. It is sometimes used alone as an antimalarial. Trimethoprim resistance has been reported. [PubChem]
• Indication: For the treatment of urinary tract infections, uncomplicated pyelonephritis (with sulfamethoxazole) and mild acute prostatitis. May be used as pericoital (with sulfamethoxazole) or continuous prophylaxis in females with recurrent cystitis. May be used as an alternative to treat asymptomatic bacteriuria during pregnancy (only before the last 6 weeks of pregnancy). Other uses include: alternative agent in respiratory tract infections (otitis, sinusitus, bronchitis and pneumonia), treatment of Pneumocystis jirovecii pneumonia (acute or prophylaxis), Nocardia infections, and traveller's diarrhea.
• Pharmacology: Trimethoprim is a pyrimidine analogue that disrupts folate synthesis, an essential part of the thymidine synthesis pathway. Inhibition of the enzyme starves the bacteria of nucleotides necessary for DNA replication.The drug, therefore, exhibits bactericidal activity.
• Toxicity: LD₅₀=4850 (orally in mice)
• Affected Organisms: Gram negative and gram positive bacteria
• Biotransformation: Hepatic metabolism to oxide and hydroxylated metabolites.
• Absorption: Readily and almost completely absorbed in the GI tract with peak serum concentrations attained 1-4 hours after oral administration. Widely distributed to tissues and fluids including kidney, lung, seminal fluid, aqueous humour, middle ear fluid, sputum, vaginal secretions, bile, bone and CSF.
• Half Life: 8-11 hours in adults with normal renal function
• Protein Binding: 42-46% bound to plasma proteins
• Elimination: Ten to twenty percent of trimethoprim is metabolized, primarily in the liver; the remainder is excreted unchanged in the urine.; After oral administration, 50% to 60% of trimethoprim is excreted in the urine within 24 hours, approximately 80% of this being unmetabolized trimethoprim. Trimethoprim also passes the placental barrier and is excreted in human milk.
• References: Brumfitt W, Hamilton-Miller JM: Reassessment of the rationale for the combinations of sulphonamides with diaminopyrimidines. J Chemother. 1993 Dec;5(6):465-9. [Pubmed] ; Brumfitt W, Hamilton-Miller JM: Limitations of and indications for the use of co-trimoxazole. J Chemother. 1994 Feb;6(1):3-11. [Pubmed] ; Bean DC, Livermore DM, Papa I, Hall LM: Resistance among Escherichia coli to sulphonamides and other antimicrobials now little used in man. J Antimicrob Chemother. 2005 Nov;56(5):962-4. Epub 2005 Sep 8. [Pubmed] ; Felmingham D, Reinert RR, Hirakata Y, Rodloff A: Increasing prevalence of antimicrobial resistance among isolates of Streptococcus pneumoniae from the PROTEKT surveillance study, and compatative in vitro activity of the ketolide, telithromycin. J Antimicrob Chemother. 2002 Sep;50 Suppl S1:25-37. [Pubmed] ; Johnson JR, Manges AR, O'Bryan TT, Riley LW: A disseminated multidrug-resistant clonal group of uropathogenic Escherichia coli in pyelonephritis. Lancet. 2002 Jun 29;359(9325):2249-51. [Pubmed]
• External Links: Wikipedia; RxList; Drugs.com

Sigma Aldrich - T7883

Application
Primarily used as an antibacterial agent. Dihydrofolate reductase inhibitor with selectivity for the prokaryote enzyme.
Trimethoprim is primarily used as an antibacterial agent. It has dihydrofolate reductase inhibitor activity with selectivity for the prokaryote enzyme. It is used to treat urinary tract infections, mild acute prostatitis, recurrent cystitis, asymptomatic bacteriuria during pregnancy and respiratory tract infections1.
Other Notes
Specific inhibitor of formulation. Widely used in studies on dihydrofolate reductase2,3.
Biochem/physiol Actions
The combination of trimethoprim and sulfamethoxazole interferes with the cellular metabolism of folic acid in the bacterial cell by blocking the biosynthesis of nucleotides. Trimethoprim binds to dihydrofolate reductase and inhibits the reduction of dihydrofolic acid (DHF) to tetrahydrofolic acid (THF). THF is an essential precursor in the thymidine synthesis pathway and interference with this pathway inhibits bacterial DNA synthesis1.
Protocols & Applications
Antibiotic Selector for application, solubility, solution stability, working concentration, and mode of action information

Sigma Aldrich - 92131

Application
Primarily used as an antibacterial agent. Dihydrofolate reductase inhibitor with selectivity for the prokaryote enzyme.
Trimethoprim is primarily used as an antibacterial agent. It is used in susceptibility studies of Mycobacterium tuberculosis 1 and mechanism of resistance studies in Haemophilus influenzae 2.
Biochem/physiol Actions
Inhibits the synthesis of tetrahydrofolate by procaryote specific dihydrofolate reductase (DHFR).
Trimethoprim is a dihydrofolate reductase inhibitor with selectivity for the prokaryote enzyme.
Other Notes
Specific inhibitor of formulation. Widely used in studies on dihydrofolate reductase3,4.

Sigma Aldrich - 46984

Application
Commission Regulation (EU) No 37/2010 of 22 December 2009 on pharmacologically active substances and their classification regarding maximum residue limits in foodstuffs of animal origin
Primarily used as an antibacterial agent. Dihydrofolate reductase inhibitor with selectivity for the prokaryote enzyme.
Other Notes
Specific inhibitor of formulation. Widely used in studies on dihydrofolate reductase1,2.
Legal Information
VETRANAL is a trademark of Sigma-Aldrich Co. LLC

Sigma Aldrich - 02718

Application
Primarily used as an antibacterial agent. Dihydrofolate reductase inhibitor with selectivity for the prokaryote enzyme.
Other Notes
Specific inhibitor of formulation. Widely used in studies on dihydrofolate reductase1,2.

Toronto Research Chemicals - T795615

Antibacterial.

REFERENCES

• Mol. Pharmacol., 1: 126, (1965).
• Brumfitt W, Hamilton-Miller JM: Reassessment of the rationale for the combinations of sulphonamides with diaminopyrimidines. J Chemother. 1993 Dec;5(6):465-9. Pubmed
• Brumfitt W, Hamilton-Miller JM: Limitations of and indications for the use of co-trimoxazole. J Chemother. 1994 Feb;6(1):3-11. Pubmed
• Bean DC, Livermore DM, Papa I, Hall LM: Resistance among Escherichia coli to sulphonamides and other antimicrobials now little used in man. J Antimicrob Chemother. 2005 Nov;56(5):962-4. Epub 2005 Sep 8. Pubmed
• Felmingham D, Reinert RR, Hirakata Y, Rodloff A: Increasing prevalence of antimicrobial resistance among isolates of Streptococcus pneumoniae from the PROTEKT surveillance study, and compatative in vitro activity of the ketolide, telithromycin. J Antimicrob Chemother. 2002 Sep;50 Suppl S1:25-37. Pubmed
• Johnson JR, Manges AR, O'Bryan TT, Riley LW: A disseminated multidrug-resistant clonal group of uropathogenic Escherichia coli in pyelonephritis. Lancet. 2002 Jun 29;359(9325):2249-51. Pubmed
• Manius, G.J., et al.: Anal. Profiles Drug Subs., 7, 445 (1978)
• Roth, B., et al.: J. Med. Chem., 23, 379 (1978)
• Brogden, R.N., et al.: Drugs, 23, 405 (1978)
• Brossi, A. et al., J. Med. Chem., 1971, 14, 462, (synth)
• Burchall, J.J., Antibiotics (N.Y.), 1975, 3, 304, (rev)
• Koetzle, T.F. et al., J.A.C.S., 1976, 98, 2074, (cryst struct)
• Manius, G.J., Anal. Profiles Drug Subst., 1978, 7, 445, (rev, synth, props, anal)
• Sigel, C.W., Handb. Exp. Pharmacol., 1983, 64, 163, (rev, metab)
• Roth, B. et al., J. Med. Chem., 1980, 23, 379; 535, (synth)
• Brogden, R.N. et al., Drugs, 1982, 23, 405, (rev, pharmacol)
• Bryan, R.F. et al., Acta Cryst. C, 1987, 43, 2412, (cryst struct)
• Huovinen, P., Antimicrob. Agents Chemother., 1987, 31, 1451, (rev, props)
• Martindale, The Extra Pharmacopoeia, 30th edn., Pharmaceutical Press, 1993, 219
• Negwer, M., Organic-Chemical Drugs and their Synonyms, 7th edn., Akademie-Verlag, 1994, 4092
• Lewis, R.J., Sax's Dangerous Properties of Industrial Materials, 8th edn., Van Nostrand Reinhold, 1992, TKX000; TKZ000