Design and synthesis of 3-(4-Ethylphenyl)-2-substituted amino-3H-quinazolin-4-ones as a novel class of analgesic and anti-inflammatory agents

Figures & data

Figure 1.  Lead molecule of quinazolines.

Scheme 1 Synthesis of 3-(2-ethylphenyl)-2-substitutedamino-3H-quinazolin-4-ones. Reagents and conditions: (a) DMSO, rt, 30 min; (b) (CH₃)₂SO₄, 5-10°C, 2 h; (c) Methyl anthranilate (3), K₂CO₃, ethanol reflux for 22 h; (d) 2% alcoholic NaOH, (CH₃)₂SO₄, rt, 1 h; (e) NH₂NH₂, K₂CO₃, ethanol reflux for 39 h; (f) (R₂R₁)CO; CH₃COOH reflux, 36 h.

Table I.  Analgesic activity of AS1-AS15.

		Percent Analgesic activity
Compound	Dose (mg/kg)	30 min	1 h	2 h	3 h
AS1	10	58 ± 1.36**	60 ± 1.39**	63 ± 1.63***	35 ± 1.81*
	20	70 ± 1.29***	73 ± 1.63***	77 ± 1.48***	41 ± 1.57*
AS2	10	60 ± 1.72***	65 ± 1.29***	68 ± 1.74***	40 ± 1.53*
	20	74 ± 1.48***	78 ± 1.64***	80 ± 1.82***	51 ± 1.48*
AS3	10	55 ± 1.62**	63 ± 1.57***	66 ± 1.94***	36 ± 1.93*
	20	58 ± 1.92**	74 ± 1.29***	78 ± 1.56***	42 ± 1.52*
AS4	10	44 ± 1.38*	47 ± 1.47*	53 ± 1.84*	33 ± 1.47*
	20	53 ± 1.58*	61 ± 1.52**	62 ± 1.92**	39 ± 1.94*
AS5	10	45 ± 1.26*	49 ± 1.83*	57 ± 1.68**	32 ± 1.43*
	20	56 ± 1.74**	61 ± 1.55**	63 ± 1.82***	40 ± 1.23*
AS6	10	42 ± 1.28*	46 ± 1.59*	48 ± 1.38*	31 ± 1.53*
	20	52 ± 1.49*	55 ± 1.48**	57 ± 1.54**	38 ± 1.22*
AS7	10	43 ± 1.72*	50 ± 1.54*	51 ± 1.39*	28 ± 1.85*
	20	55 ± 1.39*	55 ± 1.52**	58 ± 1.85**	39 ± 1.52*
AS8	10	37 ± 1.56*	38 ± 1.93*	44 ± 1.65*	31 ± 1.94*
	20	48 ± 1.82*	49 ± 1.56*	55 ± 1.86**	38 ± 1.43*
AS9	10	37 ± 1.54	42 ± 1.93*	45 ± 1.62*	29 ± 1.29*
	20	50 ± 1.82*	51 ± 1.67*	58 ± 1.43**	37 ± 1.85*
AS10	10	35 ± 1.43*	44 ± 1.52*	48 ± 1.59**	30 ± 1.23*
	20	46 ± 1.49*	53 ± 1.56*	56 ± 1.85**	39 ± 1.39*
AS11	10	37 ± 1.95*	46 ± 1.93*	50 ± 1.53*	30 ± 1.74*
	20	48 ± 1.64*	51 ± 1.46*	53 ± 1.49**	37 ± 1.84*
AS12	10	37 ± 1.63*	45 ± 1.45*	51 ± 1.90**	29 ± 1.22*
	20	46 ± 1.71*	51 ± 1.60*	58 ± 1.62**	35 ± 1.49*
AS13	10	48 ± 1.59*	53 ± 1.54*	57 ± 1.49**	31 ± 1.33*
	20	57 ± 1.93**	61 ± 1.39***	66 ± 1.73***	38 ± 1.69*
AS14	10	42 ± 1.83*	51 ± 1.58*	59 ± 1.60*	30 ± 1.60*
	20	55 ± 1.27**	59 ± 1.63***	67 ± 1.53**	36 ± 1.35*
AS15	10	43 ± 1.65*	46 ± 1.52*	53 ± 1.82*	32 ± 1.95*
	20	51 ± 1.60**	55 ± 1.72**	60 ± 1.59**	39 ± 1.39*
		2 ± 0.35	6 ± 0.49	4 ± 0.59	4 ± 0.91
Control Diclofenac	10	37 ± 1.69*	43 ± 1.42*	45 ± 0.92*	33 ± 0.96*
	20	46 ± 0.95*	55 ± 1.16**	62 ± 1.49***	39 ± 1.13*

Each value represents the mean ± SD (n = 6). Significance levels *p < 0.5, **p < 0.01and ***p < 0.001 as compared with the respective control.

Table II.  Anti-inflammatory activity of synthesized compounds (AS1-AS15).

		Percent protection
Compound	Dose (mg/kg)	30 min	1 h	2 h	3 h
AS1	10	41 ± 1.91*	45 ± 1.36**	46 ± 1.63**	30 ± 1.39*
	20	51 ± 1.57***	56 ± 1.52***	61 ± 1.57***	36 ± 1.71
AS2	10	46 ± 1.52**	48 ± 1.48*	53 ± 1.96***	33 ± 1.75*
	20	55 ± 1.57***	65 ± 1.52***	69 ± 1.65***	40 ± 1.28**
AS3	10	44 ± 1.85**	46 ± 1.28***	50 ± 1.94**	31 ± 1.75*
	20	53 ± 1.47***	62 ± 1.92***	66 ± 1.54***	39 ± 1.39**
AS4	10	32 ± 1.95*	36 ± 1.59	41 ± 1.48*	28 ± 1.65*
	20	43 ± 1.43**	48 ± 1.72**	52 ± 1.52***	35 ± 1.49*
AS5	10	35 ± 1.49*	40 ± 1.59**	41 ± 1.95**	27 ± 1.96*
	20	43 ± 1.94**	50 ± 1.83**	50 ± 1.54**	36 ± 1.69*
AS6	10	32 ± 1.53*	36 ± 1.34*	41 ± 1.93*	29 ± 1.53
	20	40 ± 1.48*	43 ± 1.58*	49 ± 1.50***	37 ± 1.82
AS7	10	31 ± 1.59*	35 ± 1.94*	38 ± 1.63**	28 ± 1.53*
	20	39 ± 1.63*	45 ± 1.74**	46 ± 1.68**	36 ± 1.94*
AS8	10	29 ± 1.50*	33 ± 1.34*	33 ± 1.93*	25 ± 1.74*
	20	37 ± 1.67*	42 ± 1.95**	42 ± 1.55**	33 ± 1.95*
AS9	10	32 ± 1.53*	34 ± 1.53*	37 ± 1.59*	28 ± 1.63*
	20	41 ± 1.39*	42 ± 1.65**	44 ± 1.48**	36 ± 1.35
AS10	10	33 ± 1.50*	36 ± 1.60*	41 ± 1.85*	28 ± 1.28*
	20	40 ± 1.53*	42 ± 1.83**	45 ± 1.83**	37 ± 1.65*
AS11	10	30 ± 1.39*	35 ± 1.49*	35 ± 1.63*	27 ± 1.59*
	20	41 ± 1.63*	44 ± 1.63**	46 ± 1.39**	36 ± 1.39*
AS12	10	31 ± 1.52*	32 ± 1.59*	32 ± 1.74*	28 ± 1.73*
	20	40 ± 1.73*	42 ± 1.36**	43 ± 1.49*	36 ± 1.65*
AS13	10	36 ± 1.02	41 ± 1.60*	34 ± 1.38*	29 ± 1.49*
	20	44 ± 1.49**	50 ± 1.63**	43 ± 1.60**	37 ± 1.54
AS14	10	32 ± 1.81*	34 ± 1.52	37 ± 1.54**	29 ± 1.59*
	20	45 ± 1.49**	47 ± 1.40**	48 ± 1.50***	36 ± 1.62*
AS15	10	36 ± 1.51*	35 ± 1.73*	36 ± 1.74*	26 ± 1.47*
	20	45 ± 1.63**	48 ± 1.96**	49 ± 1.53**	37 ± 1.93*
		5.1 ± 0.29	6.1 ± 0.27	5.7 ± 0.32	3.2 ± 0.93
Control Diclofenac	10	32 ± 0.63*	38 ± 1.58*	39 ± 1.97*	33 ± 0.93*
	20	45 ± 1.61**	52 ± 0.92***	60 ± 1.52***	42 ± 1.36**

Each value represents the mean ± SD (n = 6). Significance levels *p < 0.5, **p < 0.01 and ***p < 0.001 as compared with the respective control.

Table III.  Evaluation of ulcerogenicity index.

Compound	Ulcer index
AS1	0.53 ± 1.35*
AS2	0.51 ± 1.39*
AS3	0.48 ± 1.61*
AS4	0.55 ± 1.84*
AS5	0.57 ± 1.67*
AS6	0.59 ± 1.94*
AS7	0.63 ± 1.05*
AS8	0.77 ± 1.63*
AS9	0.83 ± 1.55*
AS10	0.78 ± 1.61*
AS11	0.80 ± 1.72*
AS12	0.74 ± 1.73*
AS13	0.61 ± 1.39*
AS14	0.67 ± 1.44*
AS15	0.63 ± 1.55*
Control	0.15 ± 0.32
Diclofenac	1.65 ± 0.59**
Aspirin	1.73 ± 0.41**

Each value represents the mean ± SD (n = 6). Significance levels *p < 0.05 and **p < 0.01 as compared with the respective control.