The Trypanocidal Activity of Amidine Compounds Does Not Correlate with Their Binding Affinity to Trypanosoma Cruzi Kinetoplast DNA

Overview

Journal Antimicrob Agents Chemother

Publisher American Society for Microbiology

Specialty Pharmacology

Date 2011 Aug 3

PMID 21807972

Citations 13

Authors

A Daliry

M Q Pires

C F Silva

R S Pacheco

M Munde

C E Stephens

A Kumar

M A Ismail

Z Liu

A A Farahat

S Akay

P Som

Q Hu

D W Boykin

W D Wilson

S L de Castro

M N C Soeiro

Affiliations

Soon will be listed here.

Abstract

Due to limited efficacy and considerable toxicity, the therapy for Chagas' disease is far from being ideal, and thus new compounds are desirable. Diamidines and related compounds such as arylimidamides have promising trypanocidal activity against Trypanosoma cruzi. To better understand the mechanism of action of these heterocyclic cations, we investigated the kinetoplast DNA (kDNA) binding properties and trypanocidal efficacy against T. cruzi of 13 compounds. Four diamidines (DB75, DB569, DB1345, and DB829), eight arylimidamides (DB766, DB749, DB889, DB709, DB613, DB1831, DB1852, and DB2002), and one guanylhydrazone (DB1080) were assayed in thermal denaturation (T(m)) and circular dichroism (CD) studies using whole purified T. cruzi kDNA and a conserved synthetic parasite sequence. The overall CD spectra using the whole kDNA were similar to those found for the conserved sequence and were indicative of minor groove binding. Our findings showed that some of the compounds that exhibited the highest trypanocidal activities (e.g., DB766) caused low or no change in the T(m) measurements. However, while some active compounds, such as DB766, induced profound alterations of kDNA topology, others, like DB1831, although effective, did not result in altered T(m) and CD measurements. Our data suggest that the strong affinity of amidines with kDNA per se is not sufficient to generate and trigger their trypanocidal activity. Cell uptake differences and possibly distinct cellular targets need to be considered in the final evaluation of the mechanisms of action of these compounds.

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References

Onn I, Kapeller I, Abu-Elneel K, Shlomai J . Binding of the universal minicircle sequence binding protein at the kinetoplast DNA replication origin. J Biol Chem. 2006; 281(49):37468-76. DOI: 10.1074/jbc.M606374200. View

de Meirelles M, de Araujo Jorge T, De Souza W . Interaction of Trypanosoma cruzi with macrophages in vitro: dissociation of the attachment and internalization phases by low temperature and cytochalasin B. Z Parasitenkd. 1982; 68(1):7-14. DOI: 10.1007/BF00926652. View

Estevez A, Simpson L . Uridine insertion/deletion RNA editing in trypanosome mitochondria--a review. Gene. 1999; 240(2):247-60. DOI: 10.1016/s0378-1119(99)00437-0. View

Ray D . Conserved sequence blocks in kinetoplast minicircles from diverse species of trypanosomes. Mol Cell Biol. 1989; 9(3):1365-7. PMC: 362734. DOI: 10.1128/mcb.9.3.1365-1367.1989. View

Arafa R, Brun R, Wenzler T, Tanious F, Wilson W, Stephens C . Synthesis, DNA affinity, and antiprotozoal activity of fused ring dicationic compounds and their prodrugs. J Med Chem. 2005; 48(17):5480-8. DOI: 10.1021/jm058190h. View

Silva C, Meuser Batista M, Mota R, de Souza E, Stephens C, Som P . Activity of "reversed" diamidines against Trypanosoma cruzi "in vitro". Biochem Pharmacol. 2007; 73(12):1939-46. DOI: 10.1016/j.bcp.2007.03.020. View

Morel C, Chiari E, Camargo E, Mattei D, Romanha A, Simpson L . Strains and clones of Trypanosoma cruzi can be characterized by pattern of restriction endonuclease products of kinetoplast DNA minicircles. Proc Natl Acad Sci U S A. 1980; 77(11):6810-4. PMC: 350379. DOI: 10.1073/pnas.77.11.6810. View

Liu B, Liu Y, Motyka S, Agbo E, Englund P . Fellowship of the rings: the replication of kinetoplast DNA. Trends Parasitol. 2005; 21(8):363-9. DOI: 10.1016/j.pt.2005.06.008. View

de Souza E, Oliveira G, Boykin D, Kumar A, Hu Q, Soeiro M . Trypanocidal activity of the phenyl-substituted analogue of furamidine DB569 against Trypanosoma cruzi infection in vivo. J Antimicrob Chemother. 2006; 58(3):610-4. DOI: 10.1093/jac/dkl259. View

10.

Mathis A, Bridges A, Ismail M, Kumar A, Francesconi I, Anbazhagan M . Diphenyl furans and aza analogs: effects of structural modification on in vitro activity, DNA binding, and accumulation and distribution in trypanosomes. Antimicrob Agents Chemother. 2007; 51(8):2801-10. PMC: 1932548. DOI: 10.1128/AAC.00005-07. View

11.

Das B, Boykin D . Synthesis and antiprotozoal activity of 2,5-bis(4-guanylphenyl)furans. J Med Chem. 1977; 20(4):531-6. DOI: 10.1021/jm00214a014. View

12.

de Souza E, Lansiaux A, Bailly C, Wilson W, Hu Q, Boykin D . Phenyl substitution of furamidine markedly potentiates its anti-parasitic activity against Trypanosoma cruzi and Leishmania amazonensis. Biochem Pharmacol. 2004; 68(4):593-600. DOI: 10.1016/j.bcp.2004.04.019. View

13.

Lanteri C, Tidwell R, Meshnick S . The mitochondrion is a site of trypanocidal action of the aromatic diamidine DB75 in bloodstream forms of Trypanosoma brucei. Antimicrob Agents Chemother. 2007; 52(3):875-82. PMC: 2258549. DOI: 10.1128/AAC.00642-07. View

14.

Daliry A, da Silva P, da Silva C, Meuser Batista M, de Castro S, Tidwell R . In vitro analyses of the effect of aromatic diamidines upon Trypanosoma cruzi. J Antimicrob Chemother. 2009; 64(4):747-50. DOI: 10.1093/jac/dkp290. View

15.

Sun T, Zhang Y . Pentamidine binds to tRNA through non-specific hydrophobic interactions and inhibits aminoacylation and translation. Nucleic Acids Res. 2008; 36(5):1654-64. PMC: 2275129. DOI: 10.1093/nar/gkm1180. View

16.

de Souza E, Silva P, Nefertiti A, Ismail M, Arafa R, Tao B . Trypanocidal activity and selectivity in vitro of aromatic amidine compounds upon bloodstream and intracellular forms of Trypanosoma cruzi. Exp Parasitol. 2010; 127(2):429-35. DOI: 10.1016/j.exppara.2010.10.010. View

17.

Pacheco R, Grimaldi Jr G, Momen H, Morel C . Population heterogeneity among clones of New World Leishmania species. Parasitology. 1990; 100 Pt 3:393-8. DOI: 10.1017/s0031182000078677. View

18.

Gonzalez A . Nucleotide sequence of a Trypanosoma cruzi minicircle. Nucleic Acids Res. 1986; 14(22):9217. PMC: 311941. DOI: 10.1093/nar/14.22.9217. View

19.

Wilson W, Tanious F, Mathis A, Tevis D, Hall J, Boykin D . Antiparasitic compounds that target DNA. Biochimie. 2008; 90(7):999-1014. PMC: 2515095. DOI: 10.1016/j.biochi.2008.02.017. View

20.

Ismail M, Brun R, Easterbrook J, Tanious F, Wilson W, Boykin D . Synthesis and antiprotozoal activity of aza-analogues of furamidine. J Med Chem. 2003; 46(22):4761-9. DOI: 10.1021/jm0302602. View