Cycloguanil
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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]
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
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).
References
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- ↑ Modest, Edward J. (1956). "Chemical and Biological Studies on 1,2-Dihydro-s-triazines. II. Three-Component Synthesis". The Journal of Organic Chemistry 21 (1): 1–13. doi:10.1021/jo01107a001.
- ↑ Modest, Edward J.; Levine, Philip. (1956). "Chemical and Biological Studies on 1,2-Dihydro-s-triazines. III. Two-Component Synthesis". The Journal of Organic Chemistry. 21(1): 14–20. doi:10.1021/jo01107a002.
- ↑ Carrington, H. C.; Crowther, A. F.; Stacey, G. J. (1954). "Synthetic antimalarials. Part XLIX. The structure and synthesis of the dihydrotriazine metabolite of proguanil". Journal of the Chemical Society (Resumed): 1017. doi:10.1039/jr9540001017.
- ↑ Modest, Edward J.; Foley, George E.; Pechet, Maurice M.; Farber, Sidney (1952). "A SERIES OF NEW, BIOLOGICALLY SIGNIFICANT DIHYDROTRIAZINES". Journal of the American Chemical Society. 74 (3): 855–856. doi:10.1021/ja01123a532.
- ↑ Loo, Ti Li (1954). "1-p-Chlorophenyl-2,4-diamino-6,6-dimethyl-1,6-dihydro-1,3,5- triazine". Journal of the American Chemical Society. 76 (20): 5096–5099. doi:10.1021/ja01649a026.
- ↑ Edward J. Modest, U.S. patent 2900385 (1959 to Children s Cancer Research Foundation).
- ↑ Donald F. Worth, U.S. patent 3074947 (1963 to Parke).
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