9-Chloro and 9-amino-2-methoxyacridines bearing different substituents in position 7, as well as their corresponding unsubstituted dimeric and tetrameric complexes, were investigated for in vitro antiproliferative properties against Leishmania infantum compared to toxicity towards human monocytes. The results clearly confirmed that several compounds of the 2-methoxyacridine series, together with their corresponding dimeric and tetrameric derivatives, had strong in vitro antiparasitic properties. Antileishmanial activity was shown to depend on the nature of both 7-and 9-substituted groups in monoacridines, while it varied according to the nature of the 9-substituted group and the length of the linker among bis-and tetra-acridines. The effects of acridine derivatives on DNA synthesis raised the hypothesis that DNA metabolism constituted their main target in Leishmania promastigotes; however, secondary effects on other biochemical pathways, including protein and lipid metabolism, were observed, suggesting that acridine compounds could be considered multitarget drugs.

A series of 7,9-disubstituted acridine dimers and tetramers have been synthesized from nucleophilic attack of 2-bromomethyl-9-chloro-7-methoxy acridine 5 by different alkyl diamines.Acridine derivatives have a wide range of biological applications, especially as antitumor agents. 1 Because of its planar structure, the acridine chromophore has excellent DNA binding properties. 2 Since bis-intercalation would theoretically increase DNA binding, the synthesis of polyacridinic compounds as potential bis-intercalating agents has been extensively studied. 3 Some mono-and bibridged acridine dimers have recently been prepared in our laboratory. 4Hence we synthesized new polyintercalands containing two or four acridine moieties linked at position 2. The key intermediate for these preparations was 2-bromomethyl-9-chloro-7-methoxyacridine 5. Nucleophilic attack of 5 by different alkyl diamines gave two series of new 7,9-disubstituted polyacridinic compounds: dimers 6-8 and tetramers 9-11.2-Bromomethyl-9-chloro-7-methoxyacridine 5 was prepared in three steps (Scheme 1): an Ullmann condensation between 2-bromo-5-methoxy benzoic acid 1 and p-toluidine 2 yielded 5-methoxy-4'-methyl-N-phenylanthranilic acid 3, 5 which was then cyclized with phosphorus oxide chloride to give 9-chloro-7-methoxy-2-methylacridine 4. 6 Finally, benzylic photobromination of 4, using 1,3-dibromo-5,5'-dimethylimidazolidine-2,4-dione (DBDMI) in cyclohexane and under nitrogen atmosphere, led to 5. 7 Already used as bromination agent at benzylic position, 8 DBDMI gave higher yield (73%, Scheme 1) than the commonly employed N-bromosuccinimide. 9 Note that DBDMI must be added at two times to avoid the formation of the dibromomethyl compound. Moreover because of its lower toxicity, cyclohexane was chosen rather than the usual carbon tetrachloride.The main step of the synthesis of both dimers 6a-c and tetramers 9a-d was the nucleophilic attack of 5 by an alkyl diamine containing a variable number of (CH 2 ) groups. 10,11 The reaction was performed in CH 2 Cl 2 under reflux (Schemes 2 and 3) and yielded compounds 6 and 9. Scheme 2 a) 2 HN-(CH 2 ) n -NH 2 (1.2 equiv. mol.), CH 2 Cl 2 , 5 h, reflux; b) (NH 4 ) 2 CO 3 , phenol, 5 h, 60°C; c) HBr 48%, 3 days. Scheme 1 a) K 2 CO 3 , Cu, DME, 3 h, reflux; b) POCl 3 , 15 min, 80°C and 30 min, 120°C; c) DBDMI, C 6 H 12 , hn, 12 h.

The preparation of symmetric 2,2'-dimethoxy-10,10'-biacridinyl-9,9'-dione atropisomers were obtained by the oxidative coupling of 9(10H)-acridinone with 1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-dione J. Heterocyclic Chem., 45, 67 (2008).Acridine derivatives are well known therapeutic agents due to their wide range of pharmacological and biological activities [1], and many C 2 -symmetry derivatives have been reported in the literature [2]. We reported previously the prep artion of symmetrical heterocyclic host compounds related to bianthryl [3] using unsubstituted 9,9-biacridinyl [4]; but no inclusion compounds were observed with these derivatives. On the other hand 2,2'-dimethoxy-9,9'-biacridines atropisomers proved useful in molecular recognition showing a 'scissor-like' host conformation and guest inclusion of chloroform in their crystalline structure [5]. Recently we obtained the first chiral (aR)-(-)-9,9'-biacridinyl-2,2'-diol atropisomer enantiomerically pure by derivatization and recrystallisation [6]. Hence we were interested in the preparation of new C 2 symmetry derivatives bridged at positions 10,10' and report now the synthesis of 2,2'-dimethoxy-10,10'-biacridinyl-9,9'-diones using the corresponding methoxy-9(10H)-acridinones 4a and 4b.Our approach towards this synthesis was based on the preparation of the 2-methoxy-and 2-methoxy-7-methyl-9(10H)-acridinones (4a) and (4b) followed by oxidative coupling to yield the desired acridinone dimers.First, 4'-methoxyphenyl-N-anthranilic acid (3a) and 5-methoxy-4'-methyl-N-phenylanthranilic acid (3b) were prepared by Ullmann's reaction between 2-bromo-benzoic acid and 4-alkylanilines (2a) and (2b). Compound 3a was obtained by a modified procedure of Krishnegowda using EtOH as solvant and 2-bromobenzoïc acid [7]; while use of dimethoxyethane instead of 1-pentanol under reflux yielded 3b [8] (Scheme 1). The cyclization of 3a,b could be performed by FriedelCrafts acylation in polyphosphoric acid or in sulfuric acid but the best yields were obtained in polyphosphoric acid after purification leading to 2-methoxy-9(10H)-acridinone (4a) and 2-methoxy-7-methyl -9(10H)-acridinone (4b) in 65 % and 95 % yield respectively. Demethylation was also observed performing the cyclization of anthranilic acid (3b) in sulfuric acid; leading to the hydroxy derivative 2-hydroxy-7-methyl-acridin-9(10H)-one (5) in 89 % yield (Scheme 2). Then, we tried the oxidative homocoupling of 2-methoxy-9(10H)-acridinone (4a) and 2-methoxy-7-methyl-9(10H)-acridinone (4b), according to Graebe's procedure with sodium bichromate in acetic acid [9] successfully used in the laboratory for the preparation of 10,10'-biacridinyl-9,9'-dione derivatives, [4] and also with tris(acetyl-acetonato)cobalt(III), in deuteriodimethyl-

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