- Polyamine derivatives as inhibitors of trypanothione reductase and assessment of their trypanocidal activities
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Trypanothione reductase (TR) occurs exclusively in trypanosomes and leishmania, which are the etiological agents of many diseases. TR plays a vital role in the andoxidant defenses of these parasites and inhibitors of TR have potential as antitrypanosomal agents. We describe the syntheses of several spermine and spermidine derivatives and the inhibiting effects of these compounds on T. cruzi TR. All of the inhibiting compounds displayed competitive inhibition of TR-mediated reduction of trypanothione disulfide. The three most effective compounds studied were N4,N8-bis(3-phenylpropyl)spermine (12), N4N8-bis(2-naphthylmethyl)spermine (14), and N1,N8-bis(2-naphthylmethyl)spermidine (21), with K(i) values of 3.5, 5.5 and 9.5 μM, respectively. Compounds 12, 14, and 21 were found to be potent trypanocides in vitro with IC50 values ranging from 0.19 to 0.83 μM against four T. brucei ssp. strains. However, these compounds did not prolong the lives of mice infected with trypanosomes. This work indicates that certain polyamine derivatives which target a unique gathway in Trypanosomatidae have potential as antitrypanosomal agents.
- O'Sullivan, Mary C.,Zhou, Qibing,Li, Zhili,Durham, Timothy B.,Rattendi, Donna,Lane, Schennella,Bacchi, Cyrus J.
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p. 2145 - 2155
(2007/10/03)
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The reaction of spermine with aromatic aldehyde leads to an equilibrated system between the bis imine form 1′ and the hexahydropyrimidine form 1. In contrary the formaldehyde adduct of spermine exist only on the hexahydropyrimidine form 9. 1-1′ is readily hydrolyzed by HCl with regeneration of the aldehyde and spermine. The NaBH4 reduction of 1-1′ leads to the dibenzyl spermine 8 and the phosphonate adducts 2 or 6 are obtained from 1-1′ and a hydrogen phosphonate. These last two reactions failed with 9. Inversely 9 and 1-1′ reacts equably well with tetramethyl chloro dioxaphospholane with formation of cyclic phosphinamidates 10 and 5. In the second case a kinetic intermediate 3 can be observed by 31P NMR.
- Bailly, Theodorine,Burgada, Ramon
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- Antimalarial Polyamine Analogues
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A series of novel tetraamines of the general formula RNH(CH2)xNH(CH2)yNH(CH2)xNHR was synthesized and examined for activity against growth of Plasmodium falciparum in vitro.Within the series, dibenzyl analogues (R = benzyl) were found to be the most effec
- Edwards, M. L.,Stemeric, D. M.,Bitonti, A. J.,Dumont, J. A.,McCann, P. P.,et al.
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p. 569 - 574
(2007/10/02)
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