Aminoacridine cation

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... 

First, it was shown that the bacteriostatic action of these topical antibacterials was proportional to the fraction ionized as cation (Albert, Rubbo and Goldacre, 1941). At first, it seemed puzzling that, of the five possible aminoacridines, two were highly anti-bacterial, whereas three had little activity. At that time, almost nothing was known about the ionization of heterocyclic bases, so we began to determine the values of a great many examples, and later we... 

Cationic resonances which make 3-and 9-aminoacridines strong bases... 

Acridine 2.16) is a weak base. With its pA a of5.3, it is only 1% ionized at pH 7.3. It turned out that the 3-amino- and 9-amino-acridines had a resonance in their cation that was lacking in the neutral species [e.g. 2.17) <—> 2.IS) and 2.19) <—> 2.20), respectively and this made them very strong bases. The other three aminoacridines could not, for reasons of valence, acquire this resonance stabilization and, hence, were very little stronger than acridine itself (see Table 2.2). We called this the 4-aminopyridinium type of base-strengthening resonance, because we had demonstrated it first in 4-aminopyridine. 

The first rigorous proof of a positive correlation between ionization and biological action was made 17 years later (Albert, Rubbo and Goldacre, 1941). This work showed that a quantitative relationship existed between antibacterial action and the percentage ionized as cations in the aminoacridine series. This correlation was then confirmed and extended (Albert etaL, 1945). 

Acridine 2.16) is a planar, feebly basic molecule. However, two of the five possible monoaminoacridines are rather strong bases, namely the 3- and 9-amino isomers this strength comes from the resonance immanent in their cations as explained in Section 2.2 (p. 33). For reasons of valency there can be no extra resonance in 2- or 4-aminoacridine, and there is little in the 1-isomer because an orthoc u nono d disposition of bonds (which it would require) is energetically unfavoured (Albert and Goldacre, 1946 Albert, Goldacre and Phillips, 1948). 

Cationic antibacterials that have the aminoacridine type of action... 

Representations of the cations of 9-aminoacridine 10.16) and its tetrahydro-derivative 10.19) are shown in Fig. 10.6. These have been built from spacefilling models which produce the correct interatomic and van der Waals distances. The non-coplanarity of the tetrahydro-derivative is clearly seen particularly in the side-view. 

Fig. 10.6 Space models of the cations of 9-aminoacridine (the two examples on the left) and its 1,2,3,4-tetrahydro-derivative (examples on right) (see p. 403).

An X-ray diffraction study of the proflavine—DNA complex gave direct evidence of intercalation, by showing one molecule of the aminoacridine stacked parallel to the base-pairs in a 1 3 ratio (Neville and Davies, 1966). Linear and circular dichroism studies of flowing solutions of all five monoaminoacridines (complexed to DNA) confirm that the acridine cations lie in planes parallel to those of the base-pairs Qackson and Mason, 1971). Finally, the free-energy of binding of aminoacridines to DNA was determined and found to be of the order... 

We have approached the problem by compairing the effect of mono and divalent cations on 9-aminoacridine fluorescence. We present experiments which investigate the cationic binding and propose a method for the evaluation of the association constant. 

Inhibition of polymerases. Two pieces of evidence point to the outside of the bacterial plasma membrane as the site of action of the aminoacridines. Firstly, there was no loss of antibacterial action when ionization (as cation) was increased from 70% to 100%, thus removing the more readily penetrating neutral species. Secondly, there was a great loss of activity when the aminoacridines were made more lipophilic (Albert, et al.y 1945). 

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