Patrick DA, Bakunov SA, Bakunova SM, Suresh Kumar EV, Chen H, Jones SK, Wenzler T, Barzcz T, Werbovetz KA, Brun R, Tidwell RR
Synthesis and antiprotozoal activities of dicationic bis(phenoxymethyl)benzenes, bis(phenoxymethyl)naphthalenes, and bis(benzyloxy)naphthalenes. [JOURNAL ARTICLE]
Eur J Med Chem 2009 Mar 24.
A series of 37 dicationically substituted bis(phenoxymethyl)benzene bis(phenoxymethyl)naphthalene, and bis(benzyloxy)naphthalene analogues of pentamidine was prepared and evaluated for antiprotozoal activities and cytotoxicity in in vitro. 1,3-Bis(4-amidinophenoxymethyl)benzene (1) was the most active against Trypanosoma brucei rhodesiense (IC(50)=2.1nM). 1,3-Bis[4-(N-isopropylamidino)phenoxymethyl]benzene (2) was most active against Plasmodium falciparum (IC(50)=3.6nM) and displayed a selectivity index more than 50 times greater than that of pentamidine. Several other compounds displayed lower antiplasmodial IC(50) values and higher selectivity indices relative to pentamidine. 1,4-Bis(4-amidinophenoxymethyl)benzene (14) was the most active against Leishmania donovani (IC(50)=1.3muM). Compound 2 displayed the greatest activity against T. b. rhodesiense in vivo, curing three of four infected mice dosed intraperitoneally at 5mg/kgx4 days.
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