Synthesis and activity of azaterphenyl diamidines against Trypanosoma brucei rhodesiense and Plasmodium falciparum.
A series of azaterphenyl diamidines has been synthesized and evaluated for in vitro antiprotozoal activity against both Trypanosoma brucei rhodesiense (T. b. r.) and Plasmodium falciparum (P. f.) and in vivo efficacy in the STIB900 acute mouse model for T. b. r. Six of the 13 compounds showed IC(50) values less than 7 nM against T. b. r. Twelve of those exhibited IC(50) values less than 6 nM against P. f. and six of those showed IC(50) values 0.6 nM, which are more than 25-fold as potent as furamidine. Moreover, two of them showed more than 40-fold selectivity for P. f. versus T. b. r. Three compounds 15b, 19d and 19e exhibited in vivo efficacy against T. b. r. much superior to furamidine, and equivalent to or better than azafuramidine. The antiparasitic activity of these diamidines depends on the ring nitrogen atom(s) location relative to the amidine groups and generally correlates with DNA binding affinity.
Hu
Laixing
L
Department of Chemistry, Georgia State University, Atlanta, GA 30303-3083, USA.
Arafa
Reem K
RK
Ismail
Mohamed A
MA
Patel
Alpa
A
Munde
Manoj
M
Wilson
W David
WD
Wenzler
Tanja
T
Brun
Reto
R
Boykin
David W
DW
D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D020128:Inhibitory Concentration 50; D016778:Malaria, Falciparum / Q000188:drug therapy; D051379:Mice; D021261:Parasitic Sensitivity Tests; D010419:Pentamidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects*; D014353:Trypanosomiasis, African / Q000188:drug therapy
D000981:Antiprotozoal Agents; D010419:Pentamidine
Antimicrob Agents Chemother. 1994 Sep;38(9):1890-8
7810995
J Med Chem. 2009 Apr 9;52(7):2016-35
19267462
J Med Chem. 2003 Oct 23;46(22):4761-9
14561095
Curr Med Chem Anticancer Agents. 2005 Jul;5(4):389-408
16101490
Mol Pharmacol. 2006 Nov;70(5):1585-92
16912218
Biochemistry. 1996 May 7;35(18):5655-61
8639524
Fundam Clin Pharmacol. 2003 Apr;17(2):171-81
12667227
Curr Opin Investig Drugs. 2006 Feb;7(2):147-57
16499285
Antimicrob Agents Chemother. 2006 Jun;50(6):2185-91
16723581
Malar J. 2009 May 14;8:104
19442305
Trends Parasitol. 2003 Nov;19(11):488-94
14580959
J Am Chem Soc. 2002 Nov 20;124(46):13680-1
12431090
J Biol Chem. 1999 Sep 17;274(38):27128-38
10480928
Antimicrob Agents Chemother. 2007 Aug;51(8):2801-10
17517831
J Med Chem. 1999 Jun 17;42(12):2260-5
10377232
J Med Chem. 1998 Jan 1;41(1):124-9
9438029
Bioorg Med Chem Lett. 2008 Jan 1;18(1):247-51
18006310
Biophys J. 2004 Feb;86(2):1028-41
14747338
Anticancer Drug Des. 1999 Feb;14(1):47-60
10363027
Xenobiotica. 2005 Mar;35(3):211-26
16019947
J Am Chem Soc. 1948 Mar;70(3):1257-61
18909204
J Med Chem. 1995 Mar 17;38(6):912-6
7699707
Acta Trop. 2008 Oct;108(1):6-10
18722336
J Med Chem. 2005 Sep 22;48(19):5942-54
16161998
Expert Opin Investig Drugs. 2005 Aug;14(8):957-72
16050790
J Med Chem. 2006 Aug 24;49(17):5324-32
16913722
Biochemistry. 2005 Nov 15;44(45):14701-8
16274217
Nat Med. 1995 Jun;1(6):525-7
7585116
J Med Chem. 1996 Nov 8;39(23):4554-62
8917643
J Med Chem. 1986 May;29(5):727-33
2422377
J Am Chem Soc. 2007 Nov 7;129(44):13732-43
17935330