Synthesis and antiprotozoal activities of benzyl phenyl ether diamidine derivatives

• Synthesis of 33 novel dicationic benzyl phenyl ether (BPE) derivatives.
• 62 Cationic BPE derivatives tested against 3 protozoan parasites.
• Trypanosoma brucei rhodesiense: 18 analogues highly potent (IC50 values 3–35 nM).
• Plasmodium falciparum: 13 analogues highly potent (IC50 values 4–35 nM).
• A prodrug cured 4/4 mice infected with T. b. rhodesiense STIB900 in 4 daily 25/kg oral doses.

Sixty-two cationic benzyl phenyl ether derivatives (36 amidines and 26 prodrugs) were prepared and assayed for activities in vitro and in vivo against Trypanosoma brucei rhodesiense (STIB900), and in vitro against Plasmodium falciparum (K1) and Leishmania donovani axenic amastigotes. 3-Amidinobenzyl 4-amidino-2-iodo-6-methoxyphenyl ether dihydrochloride (55, IC50 = 3.0 nM) and seven other compounds exhibited IC50 values below 10 nM against T. b. rhodesiense in vitro. The 2-bromo-4,4′-diamidino analogue 19 (IC50 = 4.0 nM) and 12 other analogues were more potent than pentamidine (IC50 = 46 nM) against P. falciparum. The 3′,4-diamidino-2,6-diiodo analogue 49 (IC50 = 1.4 μM) and two other compounds were more effective than pentamidine (IC50 = 1.8 μM) against L. donovani. A prodrug, 3′,4-bis(N″-methoxy)amidino-2-bromo derivative 38, was the most efficacious against trypanosome infected mice, attaining 4/4 cures in four daily 25 mg/kg oral doses, and the 2-chloro-4,4′-diamidine 18 cured 3/4 mice in four daily 5 mg/kg intraperitoneal doses.

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