Development of new thiazolidine-2,4-dione hybrids as aldose reductase inhibitors endowed with antihyperglycaemic activity: design, synthesis, biological investigations, and in silico insights

Figures & data

Figure 1. Design of new 5-arylidene-2,4-TZDs-based hybrids as ARIs based on some reported AR inhibitors.

Scheme 1. Synthetic pathway for the target 4-nitro-phenacyl tethered thiazolidine-2,4-dione hybrids 5a–k.

Scheme 2. Synthetic pathway for the target benzothiazole tethered thiazolidine-2,4-dione hybrids 8a–h.

Table 1. IC₅₀ values of the tested compounds 5a–k and 8a–h against human aldose reductase.

Comp.	R	AR inhibition, IC50 (μM)
5a	4-NO2	0.22
5b	4-Cl	0.46
5c	4-Br	0.49
5d	4-F	0.57
5e	4-CH3	0.55
5f	4-OCH3	0.28
5g	3,4,5-triOCH3	0.72
5h	3-NO2	0.51
5k	3-Br	0.41
8a	4-NO2	1.98
8b	4-Cl	0.16
8c	4-Br	0.21
8d	4-F	0.33
8e	4-CH3	0.29
8f	4-OCH3	0.94
8g	3,4,5-triOCH3	0.27
8h	3,4-diOCH3	0.45
Epalrestat	–	0.10

Figure 2. Lineweaver–Burk plot showing kinetics of aldose reductase in the absence and presence of different concentrations of 8b.

Figure 3. In vivo hypoglycaemic effect of compound 8b in STZ-induced diabetes model after 6 weeks of treatment. Data shown are averages of six independent experiments *p > 0.05 and ****p > 0.0001.

Figure 4. Molecular docking of 8b in the active site of aldose reductase PDB: 3g5e. (A) Compound 8b (green) aligned with the co-crystallised ligand (red). (B) 3D binding interaction of the hybrid 8b with active site residues of aldose reductase. (C) 2D interaction of compound 8b with active site residues of aldose reductase.

Table 2. Calculated parameters for Lipinski’s rule and Veber’s standards for the hybrids 5a, 5f, 8b, 8c, 8e, and 8g.

Comp.	Mwt^a	nHBA^b	nHBD^c	LogP^d	nVs^e	nRB^f	TPSA^g	% ABS^h
Lipinski^i	≤500	≤10	≤5	≤5	≤1	–	–	–
Veber^j	–	–	–	–	–	≤10	≤140	–
5a	413.36	10	0	3.92	0	6	146.09	58.59
5f	398.39	8	0	3.94	0	6	109.50	71.22
8b	386.88	4	0	5.38	1	3	50.27	91.65
8c	431.33	4	0	5.59	1	3	50.27	91.65
8e	366.46	4	0	5.09	1	3	50.27	91.65
8g	442.51	7	0	4.15	0	6	77.96	82.10
Epalrestat	319.40	4	1	2.76	0	4	89.70	78.05

^a Molecular weight.

^b Number of hydrogen bond acceptors.

^c Number of hydrogen bond donors.

^d Lipophilicity (O/W).

^e Number of Lipinski rule violations.

^f Number of rotatable bonds.

^g Topological polar surface area.

^h Percentage of oral absorption.

ⁱ Reference values of Lipinski.

^j Reference values of Veber.

Table 3. ADMET profile for the active hybrids 5a, 5f, 8b, 8c, 8e, and 8g.

Comp.	HIA	Caco2	MDCK	BBB	CYP3A4 inhibition	PgP inhibition	Carcinogenicity
5a	77.05	0.79	1.98	0.10	Non	Inhibitor	Negative
5f	94.80	0.99	1.03	0.21	Inhibitor	Inhibitor	Negative
8b	98.38	37.30	0.55	1.74	Non	Inhibitor	Negative
8c	97.94	41.54	0.02	1.86	Non	Inhibitor	Positive
8e	99.08	25.04	0.87	1.65	Non	Inhibitor	Negative
8g	100.00	23.56	0.26	0.35	Inhibitor	Inhibitor	Negative
Epalrestat	99.52	21.44	99.45	0.18	Non	Inhibitor	Negative

HIA: human intestinal absorption (%); Caco2: permeability through cells derived from human colon adenocarcinoma (nm/s); MDCK: permeability through Madin-Darby canine kidney cells (nm/s); tool for rapid permeability; BBB: blood–brain barrier penetration; CYP3A4: cytochrome P450 3A4; PgP: P-glycoprotein.