Chiral resolution, determination of absolute configuration, and biological evaluation of (1,2-benzothiazin-4-yl)acetic acid enantiomers as aldose reductase inhibitors

Figures & data

Figure 1. Chemical structures of aldose reductase inhibitors.

Scheme 1. Reagents and conditions: (a) Ph₃P=CHCOOCH₃, PhCH₃, reflux; (b) H₂, 10% Pd/C, MeOH, AcOEt; (c) 1,4-dioxane, NaOH; (d) HOBT, EDCI, CHCl₃, DMF, room temperature; (e) l-(−)-alpha-methylbenzylamine, Et₃N; (f) 1,4-dioxane, 6 N HCl, reflux.

Figure 2. The principle of the PGME method.

Figure 3. Δδ values obtained for the PGME amides (−)-6 and (+)-6.

Table 1. Biological activity data for 1,2-benzothiazine 1,1-dioxide acetic acid derivatives.

Compound	ALR2 IC50* (μM)	ALR1 (% of inhibition)†
(rac)-(±)-1	0.676 (0.589–0.763)	14.7
(R)-(−)-1	0.120 (0.084–0.156)	7.5
(S)-(+)-1	4.174 (3.692–4.656)	11.8
Epalrestat	0.086 (0.059–0.112)	73.6

*IC₅₀ (95% CL) values represent the concentration required to produce 50% enzyme inhibition.

†The inhibitory effect was estimated at a concentration of 10 μM.

Figure 4. Molecular docking of inhibitors (R)-1 and (S)-1 into the active site of ALR2. A and B presents docking for (R)-1, while C and D for (S)-1, respectively. Ligands are shown as stick models, while the selected and labeled protein residues are presented (A and C) in line representation and (B and D) in surface representation. Docked poses of compounds are shown in cyan (C), red (O), blue (N), yellow (S) and gray (F); hydrogen bonds are shown as yellow dashed lines.