Risedronate metal complexes potentially active against Chagas disease.
In the search for new metal-based drugs for the treatment of Chagas disease, the most widespread Latin American parasitic disease, novel complexes of the bioactive ligand risedronate (Ris, (1-hydroxy-1-phosphono-2-pyridin-3-yl-ethyl)phosphonate), [M(II)(Ris)(2)]·4H(2)O, where M═Cu, Co, Mn and Ni, and [Ni(II)(Ris)(2)(H(2)O)(2)]·H(2)O were synthesized and characterized by using analytical measurements, thermogravimetric analyses, cyclic voltammetry and infrared and Raman spectroscopies. Crystal structures of [Cu(II)(Ris)(2)]·4H(2)O and [Ni(II)(Ris)(2)(H(2)O)(2)]·H(2)O were solved by single crystal X-ray diffraction methods. The complexes, as well as the free ligand, were evaluated in vitro against epimastigotes and intracellular amastigotes of the parasite Trypanosoma cruzi, causative agent of Chagas disease. Results demonstrated that the coordination of risedronate to different metal ions improved the antiproliferative effect against T. cruzi, exhibiting growth inhibition values against the intracellular amastigotes ranging the low micromolar levels. In addition, this strong activity could be related to high inhibition of farnesyl diphosphate synthase enzyme. On the other hand, protein interaction studies showed that all the complexes strongly interact with albumin thus providing a suitable means of transporting them to tissues in vivo.
Demoro
Bruno
B
DEC, Facultad de Química, Universidad de la República, Gral. Flores 2124, C. C. 1157, 11800 Montevideo, Uruguay.
Caruso
Francesco
F
Rossi
Miriam
M
Benítez
Diego
D
Gonzalez
Mercedes
M
Cerecetto
Hugo
H
Parajón-Costa
Beatriz
B
Castiglioni
Jorge
J
Galizzi
Melina
M
Docampo
Roberto
R
Otero
Lucía
L
Gambino
Dinorah
D
D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy*; D056831:Coordination Complexes / Q000737:chemistry* / Q000627:therapeutic use*; D012968:Etidronic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D051228:Geranyltranstransferase / Q000378:metabolism; D008956:Models, Chemical; D000068296:Risedronic Acid; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000378:metabolism / Q000472:pathogenicity; D014961:X-Ray Diffraction
D056831:Coordination Complexes; D051228:Geranyltranstransferase; D000068296:Risedronic Acid; D012968:Etidronic Acid
J Pharm Sci. 2005 Apr;94(4):893-911
15736193
J Inorg Biochem. 2009 Apr;103(4):609-16
19091422
Bioorg Med Chem. 2006 Aug 15;14(16):5503-9
16709457
PLoS Negl Trop Dis. 2010 Jul 13;4(7):e740
20644616
Trends Parasitol. 2006 Dec;22(12):583-8
17049308
Met Ions Biol Syst. 2004;41:379-419
15206123
J Med Chem. 2001 Mar 15;44(6):909-16
11300872
Curr Drug Targets Infect Disord. 2001 May;1(1):51-61
12455233
Mini Rev Med Chem. 2005 May;5(5):499-519
15892691
Eur J Med Chem. 2004 Apr;39(4):377-82
15072846
J Biol Inorg Chem. 2008 Jun;13(5):723-35
18322709
Eur J Biochem. 2000 Feb;267(4):1206-13
10672032
Spectrochim Acta A Mol Biomol Spectrosc. 2008 Aug;70(3):519-23
17869166
Eur J Med Chem. 2006 Nov;41(11):1231-9
16828524
J Med Chem. 2006 Jun 1;49(11):3322-31
16722651
Curr Top Med Chem. 2002 Nov;2(11):1187-213
12171581
Comp Biochem Physiol A Mol Integr Physiol. 2007 Apr;146(4):601-20
16626984
J Biol Chem. 1999 Nov 19;274(47):33609-15
10559249
J Inorg Biochem. 2008 May-Jun;102(5-6):1033-43
18226837
Int J Antimicrob Agents. 2004 Mar;23(3):273-85
15164969
J Med Chem. 2002 Jan 31;45(3):676-84
11806719
J Inorg Biochem. 2009 Mar;103(3):411-8
19187969
J Inorg Biochem. 2009 Oct;103(10):1300-6
19361864
J Med Chem. 2006 Jun 1;49(11):3060-3
16722624
J Inorg Biochem. 2002 Feb;88(3-4):260-7
11897339
Dalton Trans. 2007 Nov 7;(41):4681-4
17940649
Trends Parasitol. 2005 Nov;21(11):508-12
16150644
J Inorg Biochem. 2007 Jan;101(1):74-9
17027974
J Med Chem. 2009 Dec 10;52(23):7339-59
19606868
Int J Antimicrob Agents. 2004 Mar;23(3):286-90
15164970
Acta Crystallogr A. 2008 Jan;64(Pt 1):112-22
18156677
J Med Chem. 2002 Aug 15;45(17):3721-38
12166945
Trends Parasitol. 2003 Nov;19(11):495-501
14580960
J Biol Chem. 2001 Sep 7;276(36):33930-7
11435429
J Med Chem. 2005 Apr 21;48(8):2957-63
15828834