Sulfonamide derivatives of thiazolidin-4-ones with anticonvulsant activity against two seizure models: synthesis and pharmacological evaluation

Figures & data

Figure 1.  Anticonvulsant agents showing required pharmacophoric elements.

Scheme 1.  Synthetic route to the titled compounds 4a–w. Reagents and conditions: (a) HClSO₄, 0°C; (b) NH₂NH₂.H₂O, 0°C, ethanol; (c) CH₃COOH, RCOR₁, reflux; (d) HSCH₂COOH, ZnCl₂, reflux.

Table 1.  Physical characterization data of compounds 4a–w.

Compound	R	R1	Mol. formula	% Yield	Mp (°C)	Rf^a	Log P^b
4a	H	CH3	C17 H17 Br N2 O4 S2	75	165	0.74	2.88
4b	2-OH	CH3	C17H17BrN2O5S2	62	162	0.70	2.14
4c	3-OH	CH3	C17H17BrN2O5S2	69	158	0.79	2.14
4d	4-OH	CH3	C17H17BrN2O5S2	62	163	0.81	2.14
4e	2,4-OH	CH3	C17H17BrN2O6S2	65	142	0.84	1.42
4f	2-OCH3	CH3	C18H19BrN2O5S2	74	175	0.73	2.79
4g	3-OCH3	CH3	C18H19BrN2O5S2	69	168	0.76	2.79
4h	4-OCH3	CH3	C18H19BrN2O5S2	70	163	0.64	2.79
4i	2,4-OCH3	CH3	C19H21BrN2O6S2	56	135	0.75	2.59
4j	3,4-OCH3	CH3	C19H21BrN2O6S2	63	148	0.78	2.61
4k	2-Cl	CH3	C17H16BrClN2O4S2	78	155	0.69	3.47
4l	3-Cl	CH3	C17H16BrClN2O4S2	71	178	0.65	3.47
4m	4-Cl	CH3	C17H16BrClN2O4S2	68	150	0.68	3.47
4n	2,4-Cl	CH3	C17H15BrCl2N2O4S2	63	159	0.72	4.08
4o	4-Br	CH3	C17H16Br2N2O4S2	78	137	0.87	3.65
4p	2-NO2	CH3	C17H16BrN3O6S2	74	167	0.84	2.61
4q	3-NO2	CH3	C17H16BrN3O6S2	79	169	0.81	2.61
4r	4-NO2	H	C17H16BrN3O6S2	70	176	0.76	2.61
4s	H	H	C16H15BrN2O4S2	76	138	0.53	2.33
4t	2-CH3	H	C17H17BrN2O4S2	68	149	0.64	2.79
4u	3-CH3	H	C17H17BrN2O4S2	63	142	0.60	2.79
4v	4-CH3	H	C17H17BrN2O4S2	66	135	0.68	2.79
4w	4-N(CH3)2	H	C18H20BrN3O4S2	73	109	0.90	2.44

Note. Elemental analyses for C, H, and N were within ±0.4% of the theoretical values.

^aSolvent system used was toluene/ethyl acetate/formic acid (5:4:1).

^bLog P was calculated using ACD lab version 8.0.

Table 2.  Anticonvulsant and neurotoxicity data of compounds 4a–w.

Compound	MES		scPTZ		Neurotoxicity		Ethanol potentiation test^a
	0.5 h	4 h	0.5 h	4 h	0.5 h	4 h
4a	300	(–)	X	X	X	X	X
4b	100	300	300	(–)	(–)	(–)	(–)
4c	30	100	300	(–)	300	(–)	(+)
4d	100	300	100	300	(–)	(–)	(+)
4e	100	100	100	300	300	(–)	(–)
4f	300	(–)	X	X	X	X	X
4g	(–)	(–)	X	X	X	X	X
4h	300	300	X	X	X	X	X
4i	300	300	X	X	X	X	X
4j	100	300	(–)	(–)	300	(–)	(–)
4k	100	300	(–)	300	(–)	300	(–)
4l	100	(–)	300	300	(–)	(–)	(+)
4m	30	100	100	300	(–)	(–)	(+)
4n	300	300	X	X	X	X	X
4o	30	100	300	(–)	300	300	(–)
4p	300	(–)	X	X	X	X	X
4q	100	300	300	300	300	(–)	(–)
4r	300	(–)	X	X	X	X	X
4s	100	300	300	(–)	(–)	(–)	(+)
4t	300	300	X	X	X	X	X
4u	300	(–)	X	X	X	X	X
4v	(–)	300	X	X	X	X	X
4w	100	300	100	100	300	(–)	(–)
Phenytoin	30	30	(–)	(–)	100	100	X

Note. Doses of 30, 100, and 300 mg/kg were administered ip. The figures indicate the minimum dose whereby bioactivity was demonstrated in half or more mice. (–), absence of activity at maximum dose administered (300 mg/kg); (X) not tested.

^aEthanol potentiation test: (+), half or more animals passed the test; (–), half or more animals failed the test.

Table 3.  In vitro GABA-transaminase inhibition assay of selected compounds.

Compound	Percentage inhibition of GABA-T^a
	0.5 h	1.0 h	2.0 h	3.0 h	4.0 h
Control	—	—	—	—	—
4c	5	8	10	10	12
4m	—	—	5	4	8
4o	—	10	15	18	30

^aIn vitro enzyme inhibition was carried out at a concentration of 500 µM for compounds.

Table 4.  Distance ranges between essential structural elements C, D, and HBD.

Compound	C–HBD^a	C–D^a	D–HBD^a
Basic structure of compounds 4a–w	3.379	2.419	1.452
Carbamazepine	6.517	3.931	5.554
Phenytoin	3.042	3.868	2.497
Lamotrigine	5.807	3.301	4.598
Zonisamide	4.058	5.651	6.729
Rufinamide	2.407	7.474	5.209
Dezinamide	4.481	5.909	2.948
Remacemide	3.211	9.811	6.635
Diazepam	4.793	4.827	1.497

^aDistance calculated for 3D optimized structures using ACD/Chemsketch/3-D viewer version 2.0 program.