Cycloguanil

Cycloguanil is a dihydrofolate reductase inhibitor,^[1] and is a metabolite of the antimalarial drug proguanil; its formation in vivo has been thought to be primarily responsible for the antimalarial activity of proguanil.^[2] However, more recent work has indicated that, while proguanil is synergistic with the drug atovaquone (as in the combination Malarone), cycloguanil is in fact antagonistic to the effects of atovaquone, suggesting that, unlike cycloguanil, proguanil may have an alternative mechanism of antimalarial action besides dihydrofolate reductase inhibition.^[3]

Cycloguanil

Clinical data
ATC code	P01BB02 (WHO)
Identifiers
IUPAC name 1-(4-chlorophenyl)-6,6-dimethyl-1,3,5-triazine-2,4-diamine
CAS Number	516-21-2 Y
PubChem CID	9049
ChemSpider	8697 Y
UNII	26RM326WVN
ChEMBL	ChEMBL747 Y
CompTox Dashboard (EPA)	DTXSID9022867
Chemical and physical data
Formula	C11H14ClN5
Molar mass	251.72 g·mol−1
3D model (JSmol)	Interactive image
SMILES Clc1ccc(cc1)N2C(=N/C(=N\C2(C)C)N)\N
InChI InChI=1S/C11H14ClN5/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) Y Key:QMNFFXRFOJIOKZ-UHFFFAOYSA-N Y
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Although cycloguanil is not currently in general use as an antimalarial, the continuing development of resistance to current antimalarial drugs has led to renewed interest in studying the use of cycloguanil in combination with other drugs.^[4]

Synthesis

Synthesis:^{[5][6][7][8][9]} Patents:^[10][11]

The reaction between 4-chloroaniline [106-47-8] (1) and dicyandiamide (aka 2-cyanoguanidine) [461-58-5 ] (2) gives 4-chlorophenylbiguanide [5304-59-6] (3). The condensation of this immediately with acetone to form the aminal cycloguanil (4).