Polyamine derivatives as inhibitors of trypanothione reductase and assessment of their trypanocidal activities

Synthesis and Antiprotozoal Evaluation of New N4‐(Benzyl)spermidyl‐linked bis(1,3,5‐thiadiazinane‐2‐thiones)

“…Chemistry The starting N 4 -benzyl polyamine 1 was previously synthesized according to a reported methodology by O'Sullivan et al [16] via a protection-deprotection strategy using ethyl trifluoroacetate as the selective protective group for primary amines in the presence of secondary amines. The synthetic route leading to derivatives 5 from the benzylated spermidine is depicted in Scheme 1.…”

Dibenzosuberyl substituted polyamines and analogs of clomipramine as effective inhibitors of trypanothione reductase; molecular docking, and assessment of trypanocidal activities

“…37 However charge is not the sole factor in the binding of compounds to TR, since the polyamine spermine does not inhibit TR. 65 There is previous kinetic evidence for the binding of more than one inhibitor molecule to the large active site of TR. 58 Additionally, crystal structures of TR with bound quinacrine mustard, 43 and TR with a diarylpyrrole 32 show two molecules located in the active site.…”

“…[64][65][66][67][68][69][70][71][72][73][74][75][76] Other intriguing factors influenced us including: evidence that conjugation of biologically active moieties to polyamines can potentiate their pharmacological profiles; 77 further reports of polyamine-aryl conjugates with activities against a range of trypanosomatids; 63,[78][79][80] and the potential of polyamine-DBS conjugates to exploit trypanosomatid polyamine transporters to become accumulated into parasites [81][82][83][84] (except for African trypanosomes (T. brucei) which do not readily assimilate exogenous polyamines 85 ). Consequently we also prepared spermidine and spermine derivatives with N-substituted DBS groups.…”

Parasite-specific trypanothione reductase as a drug target molecule

“…Spermidine and spermine derivatives with hydrophobic aromatic substituents are competitive inhibitors of TR (O'Sullivan et al 1997;Li et al 2001). In a series of N-(3-phenylpropyl) substituted polyamines, the inhibitory potency increased with the increasing number of the substituent, N 1 ,N 1 ,N 4 ,N 8 ,N 12 -penta(3-phenylpropyl) spermine (compound 10)…”

“…Interestingly, the respective hexa-substituted derivative was 1.5 orders of magnitude less effective, suggesting that the active site of TR cannot accommodate the larger steric bulk (Li et al 2001). Most of these compounds also displayed in vitro trypanocidal activity against T. brucei with IC 50 values below 1 lM (O'Sullivan et al 1997;Li et al 2001).…”