Synthesis and anticonvulsant activity of 3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide/carbothioamide analogues

Figures & data

Figure 1.  Suggested pharmacophore model playing anticonvulsant activity.

Table 1.  Physical constant of 3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide/carbothioamide.

Compound	Ar^1	Ar^2	Yield (%)	Mp (°C)	Rf^a
4a	4-Pyridinyl-	4-Fluorophenyl-	72	186	0.56
4b	2-Chlorophenyl-	4-Bromophenyl-	68	130	0.79
4c	4-Fluorophenyl-	4-Bromophenyl-	72	144	0.71
4d	3,4-Dimethoxyphenyl-	4-Bromophenyl-	88	168	0.45
4e	4-Methoxyphenyl-	4-Bromophenyl-	66	164	0.54
4f	4-Pyridinyl-	4-Chlorophenyl-	72	116	0.81
4g	3,4-Dimethoxyphenyl-	4-Chlorophenyl-	84	136	0.88
4h	Phenyl-	4-Chlorophenyl-	82	166	0.85
4i	4-Pyridinyl-	3-Chloro-4-fluorophenyl-	72	230	0.55
4j	2-Chlorophenyl-	H	68	242	0.69
4k	3,4-Dimethoxyphenyl-	H	78	216	0.68
4l	Phenyl-	H	72	220	0.52
4m	3,4-Dimethoxyphenyl-	H	66	262	0.55
4n	Phenyl-	H	76	232	0.67

^aMobile phase: benzene-acetone (9:1).

Scheme 1.  Synthetic protocol: (a) Reagents: MeOH/NaOH and (b) Ar²NHCXNHNH₂/AcOH.

Table 2.  6 Hz psychomotor seizure test and neurotoxicity of 3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide/carbothioamide analogues.

Compound	ADD no.	Intraperitoneal injection in mice
		Time (h) to peak effect (N/F)^a					Toxicity^b
		0.25	0.5	1.0	2.0	4.0	0.25	0.5	1.0	2.0
4a	433042	1/4	1/4	0/4	0/4	0/4	1/4	0/4^c	2/4^c	0/4
4b	434074	0/4	2/4	1/4	0/4	0/4	0/4	0/4	0/4	0/4
4c	434075	3/4	3/4	3/4	3/4	2/4	0/4	0/4	0/4	0/4
4d	434076	1/4	0/4	0/4	0/4	0/4	0/4	0/4	0/4	0/4
4e	434078	4/4	3/4	2/4	0/4	0/4	0/4	0/4	0/4	0/4
4f	439068	4/4	2/4	3/4	1/4	0/4	0/4	0/4	0/4	0/4
4g	439071	3/4	3/4	4/4	2/4	0/4	0/4	0/4	0/4	0/4
4h	439072	1/4	1/4	2/4	0/4	0/4	0/4	0/4	0/4	0/4
4i	439063	0/4	0/4	0/4	0/4	0/4	0/4	0/4	0/4	0/4
4j	434090	1/4	1/4	2/4	1/4	0/4	0/4	0/4	0/4	0/4
4k	434092	4/4	1/4	2/4	2/4	1/4	0/4	0/4	0/4	0/4
4l	434093	2/4	2/4	3/4	2/4	1/4	0/4	0/4	0/4	0/4
4m	434098	1/4	2/4	1/4	1/4	0/4	0/4	0/4	0/4	0/4
4n	434099	1/4	3/4	1/4	1/4	0/4	0/4	0/4	0/4	0/4

ADD no., Antiepileptic Drug Development Number (National Institute of Neurodegenerative Disorders and Stroke, National Institute of Health, USA).

^aN/F, number of animals active or toxic over the number tested at a dose of 100 mg/kg.

^bTime interval in hours.

^cClonic seizure.

Table 3.  Anticonvulsant activity of 3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide analogues.

Compound	ADD no.	MES		scMET		Toxicity
		0.5 h	4.0 h	0.5 h	4.0 h	0.5 h	4.0 h
4f	439068	300	300	300	300	300^a	300^b
4g	439071	300	–	–	–	300	–
4h	439072	300	–	300	–	300^c	–
4i	439063	300	300	–	–	300	–
Phenytoin^d	–	30	30	–	–	100	100
Carbamazepine^d	–	30	100	100	300	100	300
Sodium valproate^d	–	–	–	300	–	–	–

ADD no., Antiepileptic Drug Development Number (National Institute of Neurodegenerative Disorders and Stroke, National Institute of Health, USA); MES, maximal electroshock; scMET, subcutaneous metrazol.

^aLoss of righting reflex.

^bRespiratory failure.

^cDeath.

^dActivity reported²⁵.

Table 4.  Evaluation of compound, 4f and 4j in the MES test and toxicity after oral administration to rat.

Compound	Oral administration to rat (30 mg/kg)
	0.25 h	0.5 h	1.0 h	2.0 h	4.0 h
MES (4f)	0/4	0/4	2/4	1/4	0/4
Toxicity	0/4	0/4	0/4	0/4	0/4
MES (4j)	1/4	2/4	2/4	2/4	1/4
Toxicity	0/4	0/4	0/4	0/4	0/4

MES, maximal electroshock.

Pandeya SN, Raja AS, Stables JP. Synthesis of isatin semicarbazones as novel anticonvulsants–role of hydrogen bonding. J Pharm Pharm Sci 2002;5:266–271.

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