9-Amino-substituted acridines

By bonding two phenyl rings via a heteroatom bridge in the 2- and 2 -positions, the yellow acridine dyes (4a), the red to violet xanthene dyes (4b), or similarly colored thioxanthene dyes (4c) in the case of amino-substituted di- or triaiyl-methane dyes are obtained. Because of their rigid molecular skeletons these compounds fluoresce. Hydroxyxanthenes behave similarly (e.g., fluorescein) [2],... 

Fig. 3 (a) General reaction of reversible amine exchange between a 9-amino substituted acridine and a large excess of free amine, (b) Proposed mechanism of the amine exchange reaction via formation of a 9,9-diaminoacridine hemiaminal intermediate... 

Amino-substituted acridines are available by a thermal rearrangement of indazohum salts (2013OBC3558, 2014H(89)2356, 2015ZN(B)83), which were deprotonated with mild bases such as potassium phosphate whereupon a rearrangement to the acridines 147 took place (Scheme 56). A great variety of substitution patterns was realized. 

The pioneering work carried out in Germany in the 1920s showed that appropriately substituted aminoquinolines and amino-acridines afforded a series of synthetic compounds that exhibited antimalarial activity.The exigencies of the Second World War led to a massive program aimed at the same goal in this country. This work led to the development of two distinct structural classes of quinoline antimalarials the 4-amino-7-chloroquino-... 

Polymers containing chromophores such as acridine and azobenzene have also been prepared by palladium-catalyzed amination according to two approaches [222-224]. The first approach involved the polymerization of monomers containing the chromophore. For example, 4-aminoazobenzene was condensed with 1,3-dibromobenzene (Eq. (39)) or 4,4 -dibromobiphenyl ether to form polymeric materials with Mw values of 9.0 x 103 and 19 x 103, respectively. Alternatively, polymers prepared by polymerization of 4-bromostyrene or copolymerization of styrene and 4-bromostyrene were coupled with N-phenyl-4-amino azobenzene. Substitution of the aryl bromides by the amino azobenzene unit was essentially quantitative when using P(tBu)3 as the ligand. 

Reaction of the tetraketone 355 with nitroanilines in the presence of catalytic amount of P2O5 in ethanol gave 356. Reduction of the m-nitro group to the amine with Zn/HCl was successful whereas the p-nitro was unsuccessful. The reaction of 355 with N-amino ethyl piprazine or thiosemicarbazides in acetic acid gave the respective N-substituted acridines 356 (04ARK124). 

Fluorescence studies of the commercially important l,3-diphenyl-2-pyrazoline derivatives have been extended to a wide range of phenyl- and methyl-substituted derivatives. The fluorescence yields in non-polar solvents are all close to unity, with the exception of l,3,5,5-tetraphenyl-2-pyrazoline. This is not the case in methanol, when a large variation in yields is observed.85 (See the section on oxidation for other photochemical processes in these compounds.) By an examination of the fluorescence spectra and fluorescence excitation spectra of 9-amino-acridine at 4.2 K, the fine-structure fluorescence spectrum of the neutral molecule has been identified and investigated using laser excitation.88... 

New acridine-type compounds such as 470 can be synthesized from substituted 3-amino-lH-benzo[/]chromene-2-carbonitrile 469 and cyclohexanone using anhydrous zinc chloride catalyst under reflux (Scheme 103) (08CCL15). Standard reported yields are between 47% and 50%. 

Parke, Davis workers have reported on the effects of introducing distal and proximal hydrazine moieties into the structures of active acridines and 4-aminoquinolines [266, 267]. Substitution of a hydrazine moiety for the amine function at the distal position of compounds such as azacrin, quin-acrine, and chloroquine, had a deleterious effect on antimalarial activity. Several such compounds containing proximal hydrazino functions, however, showed activity greater than chloroquine 4,4 -(l,4-piperazinediyldi-imino) bis (7-chloroquinoline) (74) and 7-chloro-4-[(4-methyl-l-piperazinyl)amino] quinoline (75) had quinine coefficients of 27 and 28 respectively against P. berghei compared to chloroquine s 11, but these compounds were highly... 

A set of new two-carbon-tethered fused acridine/indoles 62 were synthesized via a AcOH-promoted domino reaction of indoline-2,3-dione 61 and C2-tethered indol-3-yl enaminones 57a (Scheme 12.22) [43]. The reaction was further expanded to prepare C-tethered fused acridine/pyridines pairs, N-substituted amino acids, N-cyclopropyl, and N-aryl-substituted fused acridine derivatives. In these domino processes, a fused acridine skeleton with concomitant formation of two new rings was readily achieved in good yields. 

Dehydroquinic acid, shikimic acid, and chorismic acid are carboxylated compounds containing a six-membered carbocyclic ring with one or two double bonds (Fig. 143). The secondary products derived from these substances either still contain the ring and the C -side chain of the acids (see the structure of the benzoic acid derivatives, of anthranilic and 3-hydroxyanthranilic esters, D 8, D 8.2, D 8.4 and D 8.4.1) or have additional rings (see the formulae of naphthoquinones and anthraquinones, D 8.1, of quinoline, acridine, and benzodiazepine alkaloids, D 8.3.2). The carbon skeletons may be substituted by isoprenoid side chains (see the structure of ubiquinones, D 8.3) and may carry different functional groups, e.g., hydroxy, carboxy, methoxy, and amino groups. 

The major problem in tuberculosis therapy is the buildup of resistance to the drug in use. Attempts at overcoming this difficulty took the form of additives such as substituted phenothiazines and acridines to retard emergence of resistance to INH 3i qj, combinations of drugs such as INH plus ethionamide, pyrazinamide, cycloserine or ethoxide . The biophysical aspects of the interaction of amino acridines with nucleic acids were reviewed 3,... 

A mixture of 6-chloro-2-methoxy-9-[ (2-hydroxyethyl) methylamino] acridine and ethylene glycol heated 15 min. at ca. 115° (6-chloro-2-methoxy-9-acridinyl)-2-hydroxyethyl ether. Y 83%.— The ar. amino group is labilized hy N,N-di-substitution. F. e. and limitations s. R. M. Peck, J. Org. Chem. 28, 1998 (1963). 

Kitani, K. The syntheses of 9-substituted acridines, ni. Reaction of 9-amino- and 9-(alkylamino) acridines with amines. Nippon Kagaku Kaishi 1954, 75, 477 80 Chem. Abstr. 1955, 49, 53549. 

The cell distribution of 3-amino-4-hydroxymethyl acridine derivatives 70 (Scheme 25), which has the N3—C4—16 substitution pattern, was studied by real-time fluorescence microscopy and SIMS structured illumination microscopy). The latter method required the introduction of an iodine atom at position 6 of the acridine which influences the Upophihcity but does not modify significantly the biological properties such as IC50 and subcellular localization (2009EJMC4758). A co-polymer 71 consisting of water-soluble maleic anhydride-containing poly[maleic anhydride-u/i-acrylic acid] (poly(MA-alt-AA) or MAAA) copolymer was modified with acriflavine (AF) which displayed antibacterial activity on EHEC and Staphylococcus aureus (2014MI2903). 

The mechanistic proposal. Scheme 41, involves an ortho-directed CH bond activation to form a metaUacycle followed by a complexation of the azide, nitrogen formation, and insertion to give a six-membered metal-lacy cle. An electrophihc aromatic substitution gives an 9-amino-8a,9-dihydroacridinium ion that aromatizes under formation of the aromatic amine to give the target acridines (2013JA12548). 

Amino-2,1,3-benzothiadiazole (237) is convertible into its anthranilic acid derivative (238), which is cyclized by phosphorus oxychloride to 6-chloro-[l,2,5]thiadiazolo[3,4-c]acridine (239). Replacement of its 6-halogeno-substituent produces derivatives such as (240). An analogous series of reactions provides 7,8,9,10-tetrahydro-analogues. The condensation of (237) and alkyl 2-oxocyclopentanecarboxylate yields derivatives of the [1,2,5]-thiadiazolo[3,4-h]quinoline ring system such as (241)—(243). Electrophilic substitutions of naphtho[l,2-d][2,l,3]thiadiazole (244) have been studied in some detail. Nitration produces a mixture of the 6- and... 

---