1-Aminoacridines

Aminoacridines such as proflavine (Fig. 10.75) are topical antibacterial agents which were used in the Second World War for the treatment of surface wounds. Their mechanism of action is described in Chapter 6. 

The earlier hypothesis put forward by Ehrlich that methylene blue exerts antimalarial activity paved the way for the discovery of a number of acridine analogues. The 9-aminoacridine analogues, however, are found to be extremely toxic in nature and, therefore, they have been successfully replaced by the 4-aminoquinoline analogues to a great extent. A few typical examples of this category are discussed below  

Mepacrine Hydrochloride BAN, Quinacrine Hydrochloride USAN, Mepacrine INN, 

6-Chloro-9-[[4-(diethylamino)-l-methylbutyl] amino]-2-methoxy-acridine dihydroehloride dihydrate 1, 4-Pentane-diamine, N -(6-chloro-2-methoxy-9-acridinyl)-N N -diethyl-, dihydroehloride, dihydrate Aerinamine Mepacrine Hydroehloride BP Em. P Int. P Ind. P  

It essentially consists of the following steps if) Preparation of the side chain  

2-Hydroxy triethylamine hydrochloride is obtained by the interaction of ethylene oxide and diethylamine in the presenee of methanol and hydrochloric acid which on chlorination with thionylchloride yields 1-chloro-triethylamine. 

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Aminoacridine hydrochloride monohydrate (Acramine yellow, Monacrin) [52417-22-8] M 248.7, m >355 , pKj 4.7, pKj 9.99. Recrystd from boiling H2O (charcoal Ig in 300 mL) to give pale yellow crystals with a neutral reaction. It is one of the most fluorescent substances known. At 1 1000 dilution in H2O it is pale yellow with only a faint fluorescence but at 1 100,000 dilution it is colourless with an intense blue fluorescence. [Albert and Ritchie Org Synth Coll Vol III 53 7955 Falk and Thomas Pharm J 153 158 1944.] See entry in Chapter 4 for the free base. 

The chemical reactions of 3-aminopyridines, 3-aminoquinoIines, etc. in which the amino group is beta to the hetero atom or is attached to a benzenoid ring are similar to those of aniline (cf. references 282, 290), and it has been generally accepted that these compounds exist overwhelmingly in the amino form. 2-Aminoacridine was not considered to exist as 231 (R = H), because 231 (R Me) shows reac-... 

Ultraviolet spectral data, including the similarity between 9-aminoacridine and 9-aminoanthracene, led Craig and ShorU to conclude that all the aminoacridines exist as such. The infrared solution spectra of the aminoacridines and aminoquinolines support the amino formulation similarly, infrared and ultraviolet spectral data have demonstrated that aminoisoquinolines also exist as such." The pX method was used to show that the value of piCj- for 9-aminophenanthridine (236, R =H) is 2.8, and ultraviolet spectral data are consistent with this conclusion when the fact that the dimethylamino derivative (236, R — Me) exhibits considerable steric hindrance to planarity is taken into consideration. ... 

The mono- and some di-aminoacridines, 6- and 7-aminoquin-oline, and 3-aminopyridine form monocations in which protonation occurs preferentially at the ring nitrogen atom. However, ultraviolet spectral data show that 1,9-diaminoacridine (237, R = NH2) undergoes proton addition on the amino groups in preference to the cyclic nitrogen atom, whereas l-amino-9-methylacridine (237, R = Me) is monoprotonated principally at the amino group in ethanol... 

Primary halides are more reactive than secondary compounds quaternary salt formation does not occur with tertiary halides, elimination always occurring to give the hydriodide and an olefln, Also, the larger the alkyl group the slower is the reaction this is shown by the very slow reaction of dodecyl bromide with quinoline, and even butyl iodide is much slower to react than methyl iodide. The longer chain primary halides commonly undergo elimination rather than cause quaternization for example, n-octyl and cetyl iodides give only the hydriodides when heated with 9-aminoacridine. ... 

JCS(F)1297 (aminoacridine) 97NKK393 (aminopyridine) 97SA(A)1723 (aminoacridine) 98CL169 (2-(pyrrolyl)ethenyl)... 

Thus, at pH 7.3, 9-aminoacridine, which exists at this pH entirely as the cation, will inhibit the growth of Streptococcus pyogenes at a dilution of 1 160000 the... 

Although these are no longer used as explosives, they are formed from diphenylamine that is used as a stabilizer for nitrocellulose explosives. The metabolism of nitrodiphenylamines has been examined under anaerobic conditions, and phenazine and 4-aminoacridine that are cyclization products of the initially formed 2-aminodiphenylamine have been identified (Drzyzga et al. 1996). 

C13HuN2+ 4 C19H23IN8012P 21 H20 9-Aminoacridine-5-iodocytidylyl-(3 — 5 )-guanosine ACRACG40 43 302... 

Aminoacridines, substituted, 22, 7 2-Aminobenzothiazolc, 22, 18 o-Aminobenzyl alcohol, 21, 10 o-Aminobenzyl cyanide, 22, 23, 25 2-Amino- -cymenx, 22, 9 u-Aminodiethyiacetic acid, 22, 13 4-Amino-2,6-dimethylpyrimidine, 24,... 

Several complexes that involve intercalation of an acridine in a portion of a nucleic acid have been studied by X-ray crystallographic techniques. These include complexes of dinucleoside phosphates with ethidium bromide, 9-aminoacridine, acridine orange, proflavine and ellipticine (65-69). A representation of the geometry of an intercalated proflavine molecule is illustrated in Figure 6 (b) this is a view of the crystal structure of proflavine intercalated in a dinucleoside phosphate, cytidylyl- -S ) guano-sine (CpG) (70, TV). For comparison an example of the situation before such intercalation is also illustrated in Figure 6 (a) by three adjacent base pairs found in the crystal structure of a polynucleotide (72, 73). In this latter structure the vertical distance (parallel to the helix axis) between the bases is approximately... 

Aminoacridine, 22, 5 basic strength of, 22, 8 9-Aminoacridine hydrochloride, fluorescence of, 22, 7... 

Fermentation, 22, 53 Ferric nitrate, 23, 20 Fieser s solution, 21, 110 Filter fabric, Pyrex glass, 22, 33, 65 Vinyon, 22, 33, 67 Filter paper, hardened, 22, 45 Fischer indole synthesis, 22, 98 Flash distillation, 21, 85 Flask, modified Claisen, 22, 11 Fluorescence of 9-aminoacridine hydrochloride, 22, 7 Formaldehyde, 20, 60 Formalin, 22, 66 Formic acid, 20, 66, 102 23, 43 Formic acid, chloro-, benzyl ester, 23, 13... 

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