Design, synthesis and biological activity evaluation of a new class of 2,4-thiazolidinedione compounds as insulin enhancers

Figures & data

Figure 1. The protein structure of insulin^20–22.

Figure 2. The structure of NIDDM drugs.

Figure 3. The protein structure of PPAR^52–58.

Figure 4. Design of 2,4-thiazolidinedione compounds.

Scheme 1. The synthetic route of 2,4-thiazolidinedione compounds.

Figure 5. In vitro activities of PPARγ agonists activity.

Table 1. In vitro the activation of test compounds on PPARα, PPARβ and PPARγ.

Compounds	R1	X1	X2	log p	pKa	EC50 ± SD^a（μmol/l）
						PPARα	PPARβ	PPARγ
6a	–H	C	C	2.68	10.43	ia^b	ia	0.08 ± 0.02
6b	–H	C	N	1.77	10.38	12.90 ± 1.29	9.18 ± 0.89	1.29 ± 0.53
6c	–H	N	C	1.92	10.00	13.02 ± 1.56	ia	0.45 ± 0.21
6d	–H	N	N	1.38	9.78	ia	12.19 ± 1.21	3.22 ± 0.65
6e	–CH3	C	C	3.26	9.77	ia	ia	0.03 ± 0.01
6f	–CH3	C	N	2.56	9.65	ia	ia	0.10 ± 0.10
6g	–CH3	N	C	2.83	9.45	ia	ia	0.08 ± 0.03
6h	–CH3	N	N	2.01	9.41	10.56 ± 1.86	ia	0.28 ± 0.13
6i	–OH	C	C	2.80	9.03	ia	ia	0.07 ± 0.02
6j	–OH	C	N	2.11	9.01	ia	14.53 ± 1.20	0.34 ± 0.15
6k	–OH	N	C	2.32	8.66	ia	ia	0.21 ± 0.11
6l	–OH	N	N	1.45	8.58	9.34 ± 1.01	10.11 ± 1.12	2.68 ± 0.46
Rosiglitazone	/	/	/	/	/	9.05 ± 1.15	12.23 ± 1.35	0.08 ± 0.02
DMSO	/	/	/	/	/	ia	ia	ia

^a Data represent the mean values from at least eight independent experiments each in triplicate (n ≥ 8).

^b ia = inactive.

Table 2. The oral glucose tolerance test.

Compounds	Dose (mg kg^−1 d^−1)	Blood glucose levels^a (mmol l^−1)
		0 h	1 h	2 h
6a	10	3.376 ± 0.361	6.342 ± 2.011	3.368 ± 1.341
6e	10	3.312 ± 0.301	6.003 ± 1.876	2.953 ± 0.876
6f	10	3.216 ± 0.315	6.651 ± 2.413	4.121 ± 1.922
6g	10	3.112 ± 0.279	6.445 ± 2.220	3.677 ± 1.730
6i	10	3.218 ± 0.317	6.401 ± 2.112	3.265 ± 1.236
Rosiglitazone	10	3.265 ± 0.345	6.351 ± 2.004	3.654 ± 1.232
DMSO	10	3.471 ± 0.211	8.756 ± 2.102	4.371 ± 1.621

^a Data represent the mean values from at least 10 independent experiments each in triplicate (n ≥ 10).

Table 3. The effect of compounds on blood glucose under insulin load.

Compounds	Dose (mg kg^−1 d^−1)	Blood glucose levels^a (mmol l^−1)
		0 h	1 h	2 h
6a	10	5.644 ± 1.035	1.801 ± 0.531	2.498 ± 1.136
6e	10	5.411 ± 1.002	1.762 ± 0.453	2.463 ± 1.211
6f	10	5.714 ± 1.465	1.903 ± 0.611	2.602 ± 1.143
6g	10	5.613 ± 1.246	1.843 ± 0.544	2.566 ± 1.224
6i	10	5.592 ± 1.134	1.792 ± 0.541	2.501 ± 1.025
Rosiglitazone	10	5.613 ± 1.124	1.811 ± 0.497	2.513 ± 1.072
DMSO	10	5.214 ± 0.761	1.842 ± 0.513	3.024 ± 1.671

^a Data represent the mean values from at least 10 independent experiments each in triplicate (n ≥ 10).

Table 4. The cytotoxicity and acute toxicity tests.

Compounds	Cell survival rate^a (%)					LD50 ± SD^b(mg kg^−1)
	10^−6 mol l^−1	10^−5 mol l^−1	10^−4 mol l^−1	10^−3 mol l^−1	10^−2 mol l^−1
6a	100	99.9 ± 0.11	99.3 ± 0.26	98.1 ± 0.28	93.1 ± 1.21	2313.6 ± 1.26
6e	100	100	100	99.1 ± 0.08	94.3 ± 1.02	2451.2 ± 1.24
6f	100	99.8 ± 0.09	99.2 ± 0.31	98.3 ± 0.45	89.6 ± 1.34	2013.6 ± 1.43
6g	100	100	99.8 ± 0.09	98.6 ± 0.44	90.5 ± 1.54	2138.8 ± 1.36
6i	100	100	99.9 ± 0.02	98.8 ± 0.29	92.1 ± 1.43	2268.9 ± 1.25
Rosiglitazone	99.8 ± 0.05	99.5 ± 0.21	98.1 ± 0.61	97.2 ± 0.71	86.5 ± 2.41	2246.1 ± 1.56

^a Data represent the mean values from at least ten independent experiments each in triplicate (n ≥ 10).

^b Data represent the mean values from at least three independent experiments each in triplicate (n ≥ 3).