Cycloguanil: Difference between revisions

{{Short description|Chemical compound}}

{{Drugbox

| Watchedfields = changed

| verifiedrevid = 443546900

| IUPAC_name = 1-(4-chlorophenyl)-6,6-dimethyl-1,3,5-triazine-2,4-diamine

| image = Cycloguanil.svg

| image2 = cycloguanil_sf.png

<!--Clinical data-->

| tradename =

| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->

| pregnancy_US = <!-- A / B / C / D / X -->

| pregnancy_category =

| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 -->

| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII -->

| legal_UK = <!-- GSL / P / POM / CD / Class A, B, C -->

| legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V -->

| legal_status =

| routes_of_administration =

<!--Pharmacokinetic data-->

| bioavailability =

| protein_bound =

| metabolism =

| elimination_half-life =

| excretion =

<!--Identifiers-->

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 516-21-2

| ATC_prefix = P01

| ATC_suffix = BB02

| PubChem = 9049

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank =

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = 26RM326WVN

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 747

<!--Chemical data-->

| C=11 | H=14 | Cl=1 | N=5

'''Cycloguanil''' is a [[dihydrofolate reductase inhibitor]],<ref name="pmid10348748">{{cite journal | vauthors = Srivastava IK, Vaidya AB | title = A mechanism for the synergistic antimalarial action of atovaquone and proguanil | journal = Antimicrobial Agents and Chemotherapy | volume = 43 | issue = 6 | pages = 1334–9 | date = June 1999 | pmid = 10348748 | pmc = 89274 | doi = 10.1128/AAC.43.6.1334 }}</ref> 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.<ref>{{cite journal | vauthors = Watkins WM, Sixsmith DG, Chulay JD | title = The activity of proguanil and its metabolites, cycloguanil and p-chlorophenylbiguanide, against Plasmodium falciparum in vitro | journal = Annals of Tropical Medicine and Parasitology | volume = 78 | issue = 3 | pages = 273–8 | date = June 1984 | pmid = 6385887 | doi = 10.1080/00034983.1984.11811816 | url = http://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+54-05-7 | format = Free full text }}</ref> 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.<ref>{{cite journal | vauthors = Thapar MM, Gupta S, Spindler C, Wernsdorfer WH, Björkman A | title = Pharmacodynamic interactions among atovaquone, proguanil and cycloguanil against Plasmodium falciparum in vitro | journal = Transactions of the Royal Society of Tropical Medicine and Hygiene | volume = 97 | issue = 3 | pages = 331–7 | date = May 2003 | pmid = 15228254 | doi = 10.1016/S0035-9203(03)90162-3 | doi-access = free }}</ref>

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.<ref>{{cite journal | vauthors = Walzer PD, Foy J, Steele P, White M | title = Synergistic combinations of Ro 11-8958 and other dihydrofolate reductase inhibitors with sulfamethoxazole and dapsone for therapy of experimental pneumocystosis | journal = Antimicrobial Agents and Chemotherapy | volume = 37 | issue = 7 | pages = 1436–43 | date = July 1993 | pmid = 8363372 | pmc = 187990 | doi = 10.1128/AAC.37.7.1436 }}</ref>

==Synthesis==

[[File:Cycloguanil synthesis.svg|thumb|center|500px|Synthesis:<ref>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.</ref><ref>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.</ref><ref>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.</ref><ref>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.</ref><ref>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.</ref> Patents:<ref>Edward J. Modest, {{US patent|2900385}} (1959 to Children s Cancer Research Foundation).</ref><ref>Donald F. Worth, {{US patent|3074947}} (1963 to Parke).</ref>]]

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 ==

{{reflist}}

[[Category:Chlorobenzene derivatives]]