Design, synthesis and in vitro antiproliferative activity of new thiazolidinedione-1,3,4-oxadiazole hybrids as thymidylate synthase inhibitors

Figures & data

Figure 1. Molecular docking of the active compounds 9, 10 and 5FU against Thimidylate synthase (TS) protein 6QXG. A: Binding mode of 9, 10 and 5FU at TS binding site 3D plot. B: Binding mode of 9, 10 and 5FU at TS binding site 2D plot. 5FU: -5-fluorouracil.

Scheme 1. Synthesis of thiazolidinedione-1,3,4-oxadiazole hybrids.

Table 1. Pharmacokinetics/ADME predictions of the target compounds 7–21.

No.	Lipinski parameters					nROTB^e	TPSA^f	% ABS^g	BBB^h	GI ABS^i
	MW^a	HBA^b	HBD^c	iLogP^d	Violations
7	394	6	0	3.3	0	5	110.83	70.76	No	High
8	430	6	0	3.62	0	5	110.83	70.76	No	High
9	430	6	0	3.5	0	5	110.83	70.76	No	High
10	474	6	0	3.69	0	5	110.83	70.76	No	High
11	408	6	0	3.6	0	5	110.83	70.76	No	High
12	410	7	1	3.21	0	5	131.06	63.78	No	High
13	408	6	0	3.46	0	5	110.83	70.76	No	High
14	439	8	0	2.87	0	6	156.65	54.98	No	Low
15	408	6	0	3.79	0	5	110.83	70.76	No	High
16	424	7	0	3.39	0	7	120.06	67.60	No	High
17	460	7	0	3.81	0	7	120.06	67.60	No	High
18	494	7	0	3.17	0	7	120.06	67.60	No	High
19	474	7	0	3.74	0	7	120.06	67.60	No	High
20	474	7	0	3.84	0	7	120.06	67.60	No	High
21	475	8	0	3.22	0	7	132.95	63.13	No	Low

^aMolecular weight.

^bHydrogen bond acceptor.

^cHydrogen bond donor.

^d Partition coefficient.

^eNumber of rotatable bonds.

^fTopological polar surface area.

^gAbsorption %.

^hBlood brain barrier.

ⁱGastro-intestinal absorption.

Table 2. The IC₅₀ (µM) of the synthesised compounds (7–21) against tested human cancer cell line (MCF-7 and HCT-116)^a.

Compound	MCF-7^b	HCT-116^c
7	53.50	57.34
8	56.0	56.76
9	7.74	12.84
10	7.87	16.14
11	58.37	68.13
12	56.28	58.64
13	56.3	58.64
14	43.37	42.21
15	47.8	39.60
16	58.4	67.10
17	65.17	55.5
18	>100	>100
19	61.6	69.50
20	>100	>100
21	61.95	63.15
5-FU^d	34.82	40.51

^aIC₅₀ values are the concentrations that cause 50% inhibition of cancer cell growth. Data represent the mean values ± standard deviation of three independent experiments performed in triplicate.

^bBreast cancer (MCF-7); colorectal cancer (HCT-116).

^c5-FU: 5-florouracil was used as a reference drug (positive control).

Bold values: significant cytotoxicity compared to standard drug 5-FU.

Table 3. In vitro thymidylate synthase (TS) activity of the active compounds 9, 10, 14, 15 and PTX.

Compounds	IC50 (µM)
9	1.67
10	2.21
14	9.4
15	7.9
PTX	8.2

IC₅₀ values are the mean ± SD of three separate experiments. PTX: Pemetrexed.

Table 4. Docking scores of active compounds 9 and 10 against human thymidylate synthase protein 6QXG.

Compound	Docking score	Amino acid residue
9	−9.09	Cys 195, Tyr 135 and Asn 226
10	−8.67	Leu 221, Asn 226 and Tyr 230
5-FU	−4.22	Phe 80, Arg 78, Thy306 and Ile307