5-Substituted 3-chlorokenpaullone derivatives are potent inhibitors of Trypanosoma brucei bloodstream forms

Mechanistic and biological characterisation of novelN5-substituted paullones targeting the biosynthesis of trypanothione inLeishmania

“…This led to the assumption that N 5 -substituted paullones will lose affinity for kinases, a hypothesis that was confirmed with a subset of 3-chlorokenpaullones with N-benzylacetamide substituent at N 5 showing potent and selective anti-T. b. brucei activity and lack of inhibition of mammalian kinases at 10 mM (e.g. compound 3a) 21 . Further evidence that attainment of selectivity is possible within the paullone scaffold was provided by the inclusion of a N-[2-(methylamino)ethyl]acetamide side chain on position 5 of 9-trifluoromethyl paullone (FS-554) or 3-chlorokenpaullones (MOL2008), which yielded potent and selective inhibitors of L. infantum TryS (IC 50 ¼ 0.35 mM and 0.15 mM, respectively) 10,20 .…”

“…Previous reports show that 3-chlorokenpaullones containing substitutions at position N 5 are species-specific TryS inhibitors 10,20,21 . However, the contribution of the paullone scaffold to enzyme inhibition was unknown.…”

“…In contrast, less polar substitutions (e.g. 3-chlorokenpaullones with N-benzylacetamide substituent at N 5 ) rendered better and moderate inhibitors of TryS from T. cruzi (IC 50 $10 mM) or T. brucei TryS (IC 50 $30 mM) 21 , suggesting species-specific differences at the enzyme binding site interacting with the N 5 -group of paullones. The most active inhibitors of TcTryS (IC 50 $10 mM) allowed the chemical validation of the enzyme and of T(SH) 2 as a key metabolite for T. cruzi proliferation and drug-resistance 11 .…”

“…In the search of novel scaffolds targeting TryS inhibition, we recently reported the identification of a subset of N 5 -substituted paullones f7,12-dihydroindolo[3,2-d] [1]benzazepin-6(5H)-onesg ( Figure 1) 10,20,21 . Substitutions at position N 5 of paullones render them almost inactive against kinases 21,22 while the nature of the substituent conferred species-selectivity towards TryS.…”

“…In the search of novel scaffolds targeting TryS inhibition, we recently reported the identification of a subset of N 5 -substituted paullones f7,12-dihydroindolo[3,2-d] [1]benzazepin-6(5H)-onesg ( Figure 1) 10,20,21 . Substitutions at position N 5 of paullones render them almost inactive against kinases 21,22 while the nature of the substituent conferred species-selectivity towards TryS. Indeed, the inclusion of a N-(2-methylamino)ethyl)acetamide group on 9-trifluoromethyl paullone (FS-554) or 3-chlorokenpaullones (MOL2008) (Figure 1) produced the most potent inhibitors of LiTryS so far reported with an IC 50 value of 0.35 mM and 0.15 mM, respectively 10,20 .…”