152-53-4

Usage

Uses

Used in Pharmaceutical Industry:
Cycloguanil Hydrochloride is used as an antimalarial drug for its ability to inhibit the growth and proliferation of Plasmodium parasites, which are responsible for causing malaria. It is particularly effective against Plasmodium falciparum, the most prevalent and deadly species of malaria parasite.
Used in Antimalarial Drug Development:
Cycloguanil Hydrochloride is used as a key component in the development of new antimalarial drugs, due to its potent inhibitory effects on dihydrofolate reductase (DHFR). This enzyme is essential for the synthesis of nucleic acids and amino acids in Plasmodium parasites, making it a crucial target for antimalarial drug action.
Used in Research and Development:
Cycloguanil Hydrochloride is utilized in research and development for studying the mechanisms of action, resistance, and optimization of antimalarial drugs. Its activity against various Plasmodium species and its role in reducing parasitemia in animal models make it a valuable tool for understanding the biology of malaria and developing new treatment strategies.
Used in Public Health Initiatives:
Cycloguanil Hydrochloride is employed in public health initiatives aimed at combating malaria, particularly in regions where the disease is highly prevalent. Its inclusion in antimalarial drug formulations helps to reduce the burden of malaria and improve the overall health and well-being of affected populations.

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

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

Relevant academic research and scientific papers

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.

Synthesis and in vitro evaluation of 2,4-diamino-1,3,5-triazine derivatives as neuronal voltage-gated sodium channel blockers

Neuronal sodium channels blockers interfere with ion flux and have been used for managing neuropathic pain, epilepsy, and cerebral ischemic disorders. In the current study, four groups of 2,4-diamino-1,3,5-triazine derivatives were synthesized and investigated for their neuronal sodium channels binding activity. 5-Aryl-1,3,5-triazaspiro[5.5]undeca-1,3-diene-2,4-diamines (4a-4j) were found to have the best neuronal sodium binding activity among the four groups of triazines evaluated. Derivatives 4a-4j blocked the sodium channels with IC50 values ranged from 4.0 to 14.7 μM. The result from this study showed that analogues of 2,4-diamino-1,3,5-triazines could be used as leads for the discovery of neuronal sodium channels blockers for managing central nervous system related disorders.

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.

Crystallography, quantitative structure-activity relationships, and molecular graphics in a comparative analysis of the inhibition of dihydrofolate reductase from chicken liver and Lactobacillus casei by 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(substituted-phenyl)-s-triazines

The inhibition of dihydrofolate reductase fron chicken liver and from Lactobacillus casei has been studied with 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-(substituted-phenyl)-s-triazines. It was found that for the chicken enzyme, inhibitor potency for 101 triazines was correlated by a given equation. The mathematical models obtained from correlation analysis are compared with stereo color graphics models.