Synthesis and anticonvulsant activity of some 2-(2-{1-[substituted phenyl]ethylidene}hydrazinyl)-4-(4-methoxy-phenyl)-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile

Figures & data

Figure 1.  Nifuroxazide.

Figure 2.  N’-(4-fluoro-benzylidene)-2-(2-oxobenzo[d]oxazol-3(2H)-yl) aceto-hydrazide.

Scheme 1.  Reagents and Conditions: (i) K₂CO₃, Abs. alcohol, reflux, (ii) Hydrazine hydrate, Abs. alcohol, reflux, (iii) Aromatic ketone, Glacial acetic acid, reflux.

Table 1.  Anticonvulsant, neurotoxicity screening and CNS depression study of compounds 3–16.

Compound	Anticonvulsant activity				Neurotoxicity screening		CNS depression study
	MES		scPTZ		NT
	After 0.5 h	After 4 h	After 0.5 h	After 4 h	After 0.5 h	After 4 h	Duration of immobility (Mean ± SEM)^c	% Increase of immobility
3	100	300	300	300	(-)	300	110 ± 1.41***	89.22
4	30	100	100	100	(-)	300	82.16 ± 0.94***	41.38
5	(-)	300	300	300	(-)	300	X	X
6	100	300	100	300	300	300	90 ± 1.06***	54.92
7	100	300	100	300	300	300	97.5 ± 1.38***	67.70
8	300	(-)	300	300	(-)	300	X	X
9	30	100	30	100	100	300	83.34 ± 0.42***	43.44
10	100	300	-	-	100	300	88.67 ± 1.14***	52.55
11	100	300	-	-	(-)	(-)	125.5 ± 1.17***	116.05
12	100	300	300	300	(-)	(-)	137.84 ± 0.94***	137.30
13	(-)	(-)	-	-	(-)	300	X	X
14	100	300	300	300	(-)	300	120 ± 1.29***	106.53
15	300	300	300	300	X	X	X	X
16	300	300	300	300	300	300	X	X
Phenytoin^b	30	30	-	-	(-)	(-)	-	-
Carbamazepine^b	30	100	100	100	(-)	(-)	84.34 ± 1.85***	45.18
Control							58.17 ± 1.01***	-

^aDoses of 30, 100, 300 mgkg⁻¹ were administered i.p. Test compounds were suspended in 0.5% methylcellulose/water mixture or in polyethylene glycol (PEG). Figures in the table indicate the minimum dose with bioactivity demonstrated in half or more of the mice. The dash (-) indicates the absence of activity at maximum dose administered (300 mgkg⁻¹). X denotes not tested.

^bData from references^20,21.

^cDose = 300 mgkg⁻¹; n = 6; ***p < 0.001, Data were analysed by unpaired students “t” test.

Table 2.  Comparison of distance between the essential structural elements of existing drugs and synthesized compounds.

Site 1	Site 2	Average distances for existing drugs (12)	Distance of synthesized compounds
HA5	D6	3.59 ± 1.04	5.51
HA5	HD7	2.41 ± 0.31	2.46
HA5	R12	4.73 ± 0.61	6.20
D6	HD7	4.15 ± 1.43	3.50
D6	R12	5.00 ± 1.68	6.03
HD7	R12	4.92 ± 1.25	6.61

Figure 3.  ADDRRR-24 hypothesis and the distance between critical pharmacophoric elements.

Figure 4.  Fitness of the most active compounds 4 and 9 on the Pharmacophore.

Arpana R, Nadeem S, Suroor AK, Haque SE, Bhat MA. N-{[(6-Substituted-1,3-benzothiazole-2-yl)amino]carbonothioyl}-2/4-substituted benzamides: Synthesis and pharmacological evaluation. Eur J Med Chem 2008;43:1114–1122.

 PubMed Web of Science ®Google Scholar

Flaherty PT, Greenwood TD, Manheim AL, Wolfe JF. Synthesis and evaluation of N-(phenylacetyl)trifluoromethanesulfonamides as anticonvulsant agents. J Med Chem 1996;39:1509–1513.

 PubMed Web of Science ®Google Scholar