Development of Novel Oxotriazinoindole Inhibitors of Aldose Reductase: Isosteric Sulfur/Oxygen Replacement in the Thioxotriazinoindole Cemtirestat Markedly Improved Inhibition Selectivity

Inhibition of aldose reductase (AR), the first enzyme
of the polyol
pathway, is a promising approach in treatment of diabetic complications.
We proceeded with optimization of the thioxotriazinoindole scaffold
of the novel AR inhibitor cemtirestat by replacement of sulfur with
oxygen. A series of 2-(3-oxo-2H-[1,2,4]­triazino­[5,6-b]­indol-5­(3H)-yl)­acetic acid derivatives
(OTIs), designed by molecular modeling and docking, were synthesized.
More electronegative and less bulky oxygen of OTIs compared to the
sulfur of the original thioxotriazinoindole congeners was found to
form a stronger H-bond with Leu300 of AR and to render larger rotational
flexibility of the carboxymethyl pharmacophore. AR inhibitory activities
of the novel compounds were characterized by the IC50 values
in a submicromolar range. Markedly enhanced inhibition selectivity
relative to the structurally related aldehyde reductase was recorded.
To conclude, structure modification of the original carboxymethylated
thioxotriazinoindole cemtirestat by isosteric replacement of sulfur
with oxygen in combination with variable N(2) simple substituents
provided novel analogues with increased AR inhibition efficacy and
markedly improved selectivity.