Utilization of the 1,2,3,5-thiatriazolidin-3-one 1,1-dioxide scaffold in the design of potential inhibitors of human neutrophil proteinase 3

Abstract

The S' subsites of human neutrophil proteinase 3 (Pr 3) were probed by constructing diverse libraries of compounds based on the 1,2,3,5-thiatriazolidin-3-one 1,1-dioxide using combinational and click chemistry methods. The multiple points of diversity embodied in the heterocyclic scaffold render it well-suited to the exploration of the S' subsites of Pr 3. Molecular modeling studies suggest that further exploration of the S' subsites of Pr 3 using the aforementioned heterocyclic scaffold may lead to the identification of highly selective, reversible competitive inhibitors of Pr 3.

Figure 1

Mercury drawing of compound 13a, showing the 50% thermal ellipsoids. Hydrogen atoms have been omitted for clarity.

Figure 2

Inhibitor (II) design rationale.

Figure 3

Compound 13g bound to Pr3. The structure was generated from molecular simulation. Ligand rendered as CPK-colored sticks. Receptor surface colors correspond to: yellow = nonpolar, white = polar alkyls, blue = polar N, cyan = polar H, red = O.

Figure 4

Inhibitory activity of selected compounds against human neutrophil elastase and proteinase 3.

Figure 5

Mechanism of transition state inhibitor.

Scheme 1

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Scheme 3

Scheme 4