5-Aminoimidazoles

In this review, we are concerned with simple derivatives of the amine (15). These are sufficiently stable to be accessible but reactive enough to be useful synthetic intermediates. 

An up-to-date summary of this class of aminoimidazoles (4) is contained in a recent review [92AHC(53)85]. The parent molecule (4 R1 = R2 = R3 = H) is unstable and has been isolated only as its hydrochloride salt (82S592). A number of substituted derivatives have been described, but studies of this class of heterocyclic amine remain limited. 

2-Aminoimidazole (16) has also been identified as a metabolite from marine sponges (74MI1) and has been implicated as an in vivo progenitor of a class of marine pigments (92TL4385). 

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The recently reported rearrangement (1581) of 2-allylamino-4-carboxamido-5-aminothiazoIes to 4-aminoimidazole-5-carboxamide in presence of sodium bicarbonate probably involves the electrophilic reactivity of C-2, which allows the ring opening. 

The pathways for thiamine biosynthesis have been elucidated only partiy. Thiamine pyrophosphate is made universally from the precursors 4-amino-5-hydroxymethyl-2-methylpytimidinepyrophosphate [841-01-0] (47) and 4-methyl-5-(2-hydroxyethyl)thiazolephosphate [3269-79-2] (48), but there appear to be different pathways ia the eadier steps. In bacteria, the early steps of the pyrimidine biosynthesis are same as those of purine nucleotide biosynthesis, 5-Aminoimidazole ribotide [41535-66-4] (AIR) (49) appears to be the sole and last common iatermediate ultimately the elements are suppHed by glycine, formate, and ribose. AIR is rearranged in a complex manner to the pyrimidine by an as-yet undetermined mechanism. In yeasts, the pathway to the pyrimidine is less well understood and maybe different (74—83) (Fig. 9). 

Substances of this type have hitherto received little attention. One of the reasons appears to be the limited possibilities of preparation. The only known method of preparation, described by Woolley et ai./ proceeds from the derivatives of 4-aminoimidazole-5-carboxylic acid. The amide of this acid (142) is treated with nitrous acid to yield 4-hydroxyimidazo [4,5-d]-i -triazine (2-azahypoxanthine) (143), the amidine (144) yielding the 4-amino derivative (2-azaadenine) (145) under the same conditions. 2-Azahypoxanthine was probably obtained in the same way earlier but was not identified. ... 

Theoretical studies of the relative stabilities of tautomers 14a and 14b were carried out mostly at the semiempirical level. AMI and PM3 calculations [98JST(T)249] of the relative stabilities carried out for a series of 4(5)-substituted imidazoles 14 (R = H, R = H, CH3, OH, F, NO2, Ph) are mostly in accord with the conclusion based on the Charton s equation. From the comparison of the electronic spectra of 4(5)-phenylimidazole 14 (R2 = Ph, R = R3 = H) and 2,4(5)-diphenylimidazole 14 (R = R = Ph, R = H) in ethanol with those calculated by using ir-electron PPP method for each of the tautomeric forms, it follows that calculations for type 14a tautomers match the experimentally observed spectra better (86ZC378). The AMI calculations [92JCS(P1)2779] of enthalpies of formation of 4(5)-aminoimidazole 14 (R = NH2, R = R = H) and 4(5)-nitroimidazole 14 (R = NO2, R = R = H) point to tautomers 14a and 14b respectively as being energetically preferred in the gas phase. Both predictions are in disagreement with expectations based on Charton s equation and the data related to basicity measurements (Table III). These inconsistencies may be... 

These findings accord with the semiempirical AMI calculations [92JCS(P1)2779] of the heats of formation of all theoretically possible tautomeric forms of 4-aminoimidazole 53. The most stable are the tautomers 53a AHf = 213 kJ mol ) and 53d AHf = 215 kJ mol ) (Scheme 29). All... 

No minor tautomers were detected for 2-aminoimidazoles fused with benzo and naphtho rings 54-56 [76AHC(S1), p. 430 84CHEC-I(5)345 96CHEC-II(3)77]. 

Iminoimidazolin-4-ones 227b are the only tautomers detected for 4-hydroxy-2-aminoimidazoles (R = H, Ph R = H) (91KGS62). Similar tautomeric forms are also characteristic of l-methyJ-2-imino-5-benzylideneim-idazole-4-one 228 (91KGS62) and 3-amino-l,2,4-triazol-5-ones 229 (R = R = H, COMe) (Scheme 78) [76AHC(S1), p. 482]. 

Only equivocal chemical evidence appears to be available for the unsubstituted aminoimidazoles. The failure of 2-aminoimidazole to undergo diazotization was originally interpreted to indicate that it existed in the imino form more recently, the 4-amino analog has been reported to behave as a normal aromatic amine. The infrared spectra of substituted aminoimidazoles of type 192 193 were con-... 

Therapeutic Function Treatment of liver diseases Chemical Name 5-aminoimidazole-4-carboxamide orotate Common Name AICA orotate Structural Formula a... 

One of the steps in the biosynthesis of a nucleotide called inosine monophosphate is the formation of aminoimidazole ribonucleotide from formyjglycin-amidine ribonucleotide. Propose a mechanism. 

Aminoimidazole-4-carboxamide ribonucleoside (also known as AICA riboside or AICAR). An adenosine analogue that is taken up into cells by adenosine transporters and converted by adenosine kinase to the monophosphorylated nucleotide form, ZMP. ZMP is an analogue of AMP that activates the AMP-activated protein kinase (AMPK), for which acadesine or AICAR can be used as a pharmacological activator. 

The first pharmacological agent shown to activate AMPK was 5-aminoimidazole-4-carboxamide (AICA) riboside, also known as acadesine. This adenosine analogue is taken up into cells by adenosine transporters and phosphoiylated by adenosine kinase to the mono-phosphorylated form, AICA ribotide or ZMP. ZMP accumulates inside cells to higher concentrations than the concentration of AICA riboside present in the medium, and it mimics both effects of AMP on AMPK system (allosteric activation and inhibition of... 

For quantitative work, it is necessary to estimate the concentration of 5-amino-l-(P-D-ribofuranosyl)imidazole in aqueous solution. It seems that the only available method is the Bratton-Marshall assay, which was originally developed for the estimation of arylamines in biological fluids. The principle of the method is the spectrometric estimation of a salmon-pink colored dyestuff obtained by diazotation in situ, followed by coupling with /V-( 1 -naphthyl)ethyl-enediamine.65 The only remaining problem then is to know the molar extinction of this dye because pure samples of AIRs are not available. A value of 16800 at 520 nM was obtained for the dyes prepared from a model compound, 5-amino-l-cyclohexylimidazole-4-carboxylic acid (54), which is crystalline. A comparable molar extinction can be expected for the dye prepared from imidazole 55, if the carboxyl group does not exert too much influence on the chromophore. Actually, its influence is perceptible even with the naked eye, the dyestuff prepared from 53 having a somewhat different, wine-red color, with max>520 nM. The molar extinction for 55 is 17400 at 500 nM. When the decarboxylation of 54 was conducted under mild acidic conditions (pH 4.8, 50°C, 1 hour), estimation of 5-aminoimidazole 55 by the Bratton-Marshall method led to the conclusion that the reaction was almost quantitative.66 Similar conditions for the final decarboxylation were adopted in the preparation of samples of AIRs labeled with stable isotopes.58... 

The antitumour drug temozolomide 24 (R = Me) has been attracting attention and two new routes have been develqjed. One starts from 5-aminoimidazole-4-caiboxamide, whilst the other starts from 5-diazoimidazole-4-carboxamide which reacts with trimethylsilyl isocyanate to give 8-carbamoylimidazo[5,l-[Pg.272]

Aminoimidazole-4-Carboxamide Ribonucleotide Transformylase Carbonic Anhydrase II DNA Gyrase... 

Aminoimidazole-4-carboxamide ribonucleotide (AlCAR) transformylase inhibitor, Ki = 154 nM, IC50 = 600 nM... 

Li C, Xu L, Wolan DW, Wilson lA, Olson AJ. Virtual screening of human 5-aminoimidazole-4-carboxamide ribonucleotide transformylase against the NCI diversity set by use of AutoDock to identify novel nonfolate inhibitors. J Med Chem 2004 47 6681-90. 

Oro s experiment (Oro, 1960) was very simple he heated ammonium cyanide to 343 K and was able to detect adenine after a few days. Shortly afterwards, he showed that five molecules of HCN combined to give one of adenine (Oro, 1961). An intermediate, aminomalonitrile, can be converted to 4-aminoimidazole-5-carboxamide in two different ways (Sanchez et al., 1966a, b) (Fig. 4.4) ... 

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