152-53-4

Basic information

• Product Name: Cycloguanil Hydrochloride
• Synonyms: 1-(4-Chlorophenyl)-1,6-dihydro-6,6-dimethyl-1,3,5-triazine-2,4-diamine Hydrochloride;BN 2410;Chloroguanide Triazine Hydrochloride;Cycloguanil Hydrochloride;NSC 3074;1-(4-Chlorophenyl-d4)-1,6-dihydro-6,6-dimethyl-1,3,5-triazine-2,4-diamine Hydrochloride;Chloroguanide-d4 Triazine Hydrochloride;Cycloguanil-d4 Hydrochloride
• CAS NO: 152-53-4
• Molecular Formula: C₁₁H₁₄ClN₅*ClH
• Molecular Weight: 288.181
• Product Categories: Aromatics Compounds;aromatics;Bases & Related Reagents;Heterocycles;Intermediates & Fine Chemicals;Nucleotides;Pharmaceuticals;Isotope Labeled Compounds;Isotope Labelled Compounds
• Mol File: 152-53-4.mol
• Article Data: 4

Chemical Properties

• Melting Point: 210-2150C
• Boiling Point: 400.7°Cat760mmHg
• Flash Point: 196.1°C
• Appearance: /
• Density: g/cm³
• Vapor Pressure: 1.25E-06mmHg at 25°C
• Storage Temp.: -20?C Freezer
• Solubility: DMSO (Slightly, Sonicated), Methanol (Slightly), Water (Slightly)
• CAS DataBase Reference: Cycloguanil Hydrochloride(CAS DataBase Reference)
• NIST Chemistry Reference: Cycloguanil Hydrochloride(152-53-4)
• EPA Substance Registry System: Cycloguanil Hydrochloride(152-53-4)

Safety Data

• Hazardous Substances Data: 152-53-4(Hazardous Substances Data)

Usage

Description

Cycloguanil is the active metabolite of the antimalarial prodrug proguanil. Cycloguanil is formed from proguanil by the cytochrome P450 (CYP) isoforms CYP2C19 and CYP3A in human liver microsomes. It is an inhibitor of dihydrofolate reductase (DHFR; Kis = 1.5 and 0.79 nM for the P. falciparum and P. berghei enzymes, respectively). It is active against ten P. falciparum field isolates (IC50s = 0.12-1,400 μg/ml). Cycloguanil reduces parasitemia in a mouse model of P. berghei infection (ED50 = 2 mg/kg). It also reduces parasitemia in a rhesus monkey model of P. cynomolgi infection when administered at a dose of 0.3 mg/kg.

Chemical Properties

Crystalline Solid

Uses

Different sources of media describe the Uses of 152-53-4 differently. You can refer to the following data:
1. Labelled antimalarial drug
2. Antimalarial drug.

references

[1] foote s j, galatis d, cowman a f. amino acids in the dihydrofolate reductase-thymidylate synthase gene of plasmodium falciparum involved in cycloguanil resistance differ from those involved in pyrimethamine resistance[j]. proceedings of the national academy of sciences, 1990, 87(8): 3014-3017.[2] blakley r l. dihydrofolate reductase[j]. encyclopedia of molecular medicine, 1984.[3] birkett d j, rees d, andersson t, et al. in vitro proguanil activation to cycloguanil by human liver microsomes is mediated by cyp3a isoforms as well as by s‐mephenytoin hydroxylase[j]. british journal of clinical pharmacology, 1994, 37(5): 413-420.

InChI:InChI=1/C11H14ClN5.ClH/c1-11(2)16-9(13)15-10(14)17(11)8-5-3-7(12)4-6-8;/h3-6H,1-2H3,(H4,13,14,15,16);1H

Synthetic route

1-(4-chlorophenyl)biguanide hydrochloride (4022-81-5, 55307-40-9) + acetone (67-64-1) → cycloguanil hydrochloride (152-53-4)

Conditions	Yield
With hydrogenchloride; Triethyl orthoacetate In methanol at 20℃;	69%

4-chloro-aniline (106-47-8) + N-Cyanoguanidine (127099-85-8, 780722-26-1) + acetone (67-64-1) → cycloguanil hydrochloride (152-53-4)

Conditions	Yield
With hydrogenchloride Cyclocondensation;	62%
With hydrogenchloride In water Reflux;

dicyandiamide (127099-85-8, 780722-26-1) + 4-chloro-aniline (106-47-8) + acetone (67-64-1) → cycloguanil hydrochloride (152-53-4)

Conditions	Yield
With hydrogenchloride for 24h; Heating;	31%

cycloguanil hydrochloride (152-53-4) → N2-(4-chloro-phenyl)-6,6-dimethyl-1,6-dihydro-1,3,5-triazine-2,4-diamine (5405-65-2)

Conditions	Yield
In pyridine; ethanol for 12h; Heating;	95%
With sodium hydroxide In ethanol; water for 1h; pH=11; Dimroth rearrangement; Reflux;	2.11 g

Upstream product

• 4022-81-5 1-(4-chlorophenyl)biguanide hydrochloride 
• 67-64-1 acetone 
• 106-47-8 4-chloro-aniline 
• 127099-85-8 N-Cyanoguanidine 
• 127099-85-8 dicyandiamide 

Relevant articles and documents

An efficient synthesis of 1-aryl-4,6-diamino-1,2-dihydro-1,3,5-triazines

1-Aryl-4,6-diamino-1,2-dihydro-1,3,5-triazines bearing diverse substituents at C2 and on the aromatic ring have been synthesized in good yield from an acid-catalyzed reaction between corresponding arylbiguanide and carbonyl compound in the presence of triethyl orthoacetate as a water scavenger.

Development of a lead inhibitor for the A16V+S108T mutant of dihydrofolate reductase from the cycloguanil-resistant strain (T9/94) of Plasmodium falciparum

The Ala16Val+Ser108Thr (A16V+S108T) mutant of the Plasmodium falciparum dihydrofolate reductase (DHFR) is a key mutant responsible for cycloguanil-resistant malaria due to steric interaction between Val-16 and one of the C-2 methyl groups of cycloguanil. 4,6-Diamino-1,2-dihydrotriazines have been prepared, in which both methyl groups of cycloguanil are replaced by H or by H and an alkyl or phenyl group, and their inhibition constants against wild-type and mutant DHFR determined. The S108T mutation is considered to decrease cycloguanil binding further through the effect on the orientation of the p-chlorophenyl group. By moving the p-chloro-substituent to the m-position in the chlorophenyl group, the activity against the A16V+S108T mutant enzyme is improved, and this effect is reinforced by the p-chloro substituent in the 3,4-dichlorophenyl group. A lead compound has been found with inhibitory activity similar to that of cycloguanil against the wild-type DHFR and about 120-fold more effective than cycloguanil against the A16V+S108T mutant enzyme. The activity of this compound against P. falciparum clone (T9/94 RC17) which harbors the A16V+S108T DHFR is about 85-fold greater than cycloguanil.