Synthesis and characterization of quinazoline derivatives: search for hybrid molecule as diuretic and antihypertensive agents

Figures & data

Figure 1. Chemical structure of active chemotherapeutic Diuretic and antihypertensive agents (Metolazone and Prazosin, Diazoxide) and rationally designed template for targeted compound (20).

Scheme 1. Synthesis of N-(substituted-4-oxo-2-substituted-phenylquinazolin-3-(4H)-yl)substituted benzenesulfonamide derivatives.

Table 1. Diuretic activity data shown by compounds 1–25.

					Diuresis
Compound	Dose (mg/kg/body wt.)	Total Urinary Output (mL)	Normal Saline Intake (mL)	Urinary Excretion (%)	Diuretic action	Diuretic activity	Lipschitz value
1	2	4.66 ± 0.156**	4.52 ± 0.197	103.09	0.81	0.50	0.56
2	2	5.56 ± 0.197^ns	5.28 ± 0.186	105.30	0.96	0.60	0.68
3	2	4.39 ± 0.226**	4.63 ± 0.187	94.81	0.76	0.47	0.53
4	2	4.41 ± 0.195**	4.40 ± 0.141	100.22	0.76	0.47	0.54
5	2	5.71 ± 0.027^ns	4.98 ± 0.413	114.65	0.99	0.62	0.70
6	2	5.18 ± 0.034^ns	5.15 ± 0.258	100.58	0.90	0.56	0.63
7	2	7.57 ± 0.148**	5.05 ± 0.240	149.90	1.31	0.82	0.93
8	2	5.63 ± 0.029^ns	4.87 ± 0.313	115.60	0.97	0.61	0.69
9	2	7.24 ± 0.153**	5.59 ± 0.268	129.51	1.25	0.78	0.89
10	2	5.96 ± 0.422^ns	4.21 ± 0.273	141.56	1.03	0.64	0.73
11	2	5.53 ± 0.225^ns	4.26 ± 0.291	129.81	0.96	0.60	0.68
12	2	6.85 ± 0.245**	4.41 ± 0.238	155.32	1.19	0.74	0.84
13	2	6.75 ± 0.215*	4.41 ± 0.305	153.06	1.17	0.73	0.82
14	2	7.86 ± 0.019**	4.54 ± 0.145	173.12	1.36	0.85	0.96
15	2	8.05 ± 0.028**	5.47 ± 0.236	147.16	1.40	0.87	0.99
16	2	5.81 ± 0.149^ns	5.26 ± 0.251	110.45	1.01	0.63	0.71
17	2	4.85 ± 0.136**	4.03 ± 0.203	120.34	0.84	0.53	0.60
18	2	5.21 ± 0.129^ns	5.12 ± 0.195	101.75	0.90	0.56	0.63
19	2	10.58 ± 0.244**	4.22 ± 0.174	250.71	1.84	1.15	1.30
20	2	11.46 ± 0.257**	4.36 ± 0.166	262.84	1.99	1.25	1.41
21	2	5.18 ± 0.110^ns	4.19 ± 0.288	123.62	0.90	0.56	0.63
22	2	6.83 ± 0.170**	3.82 ± 0.281	178.79	1.18	0.74	0.84
23	2	4.37 ± 0.271**	4.40 ± 0.129	99.31	0.76	0.47	0.53
24	2	4.79 ± 0.035**	4.34 ± 0.129	110.36	0.85	0.52	0.58
25	2	4.92 ± 0.220*	3.46 ± 0.149	142.19	0.85	0.53	0.60
CONT.	–	5.75 ± 0.0132**	5.17 ± 0.259	111.21	1.00	0.63	0.70
UREA	1000	8.12 ± 0.180**	5.3 ± 0.225	153.20	1.41	0.89	1.00
Metolazone	1	9.15 ± 0.175**	5.02 ± 0.234	182.27	1.59	1.00	1.12

Each value represents the means ± SEM (n = 6). CONT. = control.

*p < 0.05, **p < 0.01 (Dunnett’s multiple comparison test).

^nsNot significant.

Table 2. Diuretic activity data shown by some active compound.

					Diuresis
Compounds	Dose (mg/kg/body wt.)	Total Urinary Output (mL)	Normal Saline Intake (mL)	Urinary Excretion (%)	Diuretic action	Diuretic activity	Lipschitz value
7	1	6.49 ± 0.013**	4.02 ± 0.148	161.44	1.12	0.70	0.79
9	1	6.30 ± 0.016**	4.20 ± 0.169	150.00	1.09	0.68	0.77
14	1	6.77 ± 0.022**	4.19 ± 0.269	161.57	1.17	0.73	0.83
15	1	7.18 ± 0.019**	4.90 ± 0.138	146.53	1.24	0.77	0.88
19	1	8.19 ± 0.019**	4.70 ± 0.322	174.25	1.42	0.89	1.00
20	1	9.18 ± 0.022**	4.73 ± 0.149	193.23	1.59	1.00	1.13
CONT.	–	5.75 ± 0.0132**	5.17 ± 0.259	111.21	1.00	0.62	0.70
UREA	1000	8.12 ± 0.180**	5.3 ± 0.225	153.20	1.41	0.88	1.00
Metalazone	1	9.15 ± 0.175**	5.02 ± 0.234	182.27	1.59	1.00	1.12

Each value represents the means ± SEM (n = 6). CONT. = control.

**p < 0.01 (Dunnett’s multiple comparison test).

Figure 2. Graph showing decrease in the systolic blood pressure (SBP) exhibited by compounds (1–25) and standard as compared to control.

Table 3. Antihypertensive activity data shown by compounds 1–25.

	Average systolic blood pressure (mmHg) at time (min)
Compd. (5 mg/kg)	0	15	30	60	120	180	240	300	360	600	720	900	MAP (Mean ± SEM)	% Inhibition in SBP	% Reduction in MAP
1	194 ± 2	190 ± 1	187 ± 3	182 ± 2	178 ± 1	172 ± 2	170 ± 2	166 ± 1	165 ± 2	176 ± 2	181 ± 2	183 ± 3	178 ± 2.67^ns	08.24	15.75
2	195 ± 2	193 ± 1	186 ± 1	178 ± 2	167 ± 1	158 ± 3	146 ± 2	142 ± 1	138 ± 3	140 ± 2	156 ± 2	165 ± 2	163 ± 5.93**	15.97	30.75
3	193 ± 2	189 ± 2	183 ± 1	175 ± 2	165 ± 3	158 ± 2	150 ± 2	146 ± 1	138 ± 3	143 ± 3	151 ± 2	156 ± 2	162 ± 5.37**	16.49	32.16
4	194 ± 1	189 ± 1	183 ± 2	175 ± 1	164 ± 3	158 ± 2	148 ± 1	139 ± 2	138 ± 3	146 ± 2	155 ± 4	163 ± 2	162 ± 5.49**	16.49	31.75
5	193 ± 3	188 ± 1	182 ± 2	177 ± 1	168 ± 2	162 ± 3	153 ± 3	145 ± 2	135 ± 3	147 ± 2	158 ± 1	166 ± 2	164 ± 5.20**	15.46	29.91
6	195 ± 3	190 ± 2	186 ± 1	182 ± 3	176 ± 2	171 ± 1	165 ± 3	159 ± 4	152 ± 2	164 ± 2	169 ± 1	174 ± 2	173 ± 3.72^ns	10.82	20.83
7	196 ± 3	192 ± 3	189 ± 2	175 ± 2	163 ± 3	150 ± 2	147 ± 3	131 ± 3	128 ± 2	130 ± 2	140 ± 2	158 ± 1	158 ± 7.17**	18.55	36.16
8	196 ± 3	194 ± 3	189 ± 2	184 ± 2	178 ± 1	175 ± 2	169 ± 4	163 ± 1	159 ± 3	173 ± 1	180 ± 1	184 ± 1	178 ± 3.34^ns	08.24	15.75
9	194 ± 3	188 ± 1	180 ± 2	172 ± 3	165 ± 4	158 ± 2	143 ± 1	136 ± 2	129 ± 4	133 ± 2	141 ± 1	154 ± 2	157 ± 6.39**	19.07	36.66
10	195 ± 1	192 ± 2	187 ± 2	182 ± 3	178 ± 1	166 ± 2	158 ± 2	150 ± 1	140 ± 3	145 ± 1	165 ± 2	170 ± 2	169 ± 5.29*	12.88	25.41
11	194 ± 2	191 ± 1	187 ± 2	180 ± 1	175 ± 2	162 ± 1	156 ± 2	151 ± 1	138 ± 3	143 ± 1	160 ± 2	165 ± 3	166 ± 5.37**	14.94	27.58
12	195 ± 3	190 ± 2	183 ± 3	175 ± 2	169 ± 2	162 ± 2	153 ± 3	148 ± 2	140 ± 1	148 ± 2	155 ± 3	162 ± 2	165 ± 5.09**	14.43	29.41
13	194 ± 2	190 ± 1	186 ± 2	178 ± 1	170 ± 1	165 ± 2	160 ± 1	154 ± 2	152 ± 1	158 ± 3	170 ± 2	174 ± 2	170 ± 4.03*	12.37	23.50
14	195 ± 2	187 ± 3	181 ± 1	175 ± 2	168 ± 2	159 ± 2	146 ± 4	132 ± 2	125 ± 3	136 ± 4	143 ± 2	152 ± 1	158 ± 6.61**	18.55	36.16
15	193 ± 1	188 ± 1	181 ± 2	171 ± 3	160 ± 4	150 ± 2	145 ± 1	135 ± 2	124 ± 4	132 ± 2	142 ± 1	155 ± 2	156 ± 6.54**	19.58	38.08
16	195 ± 3	191 ± 2	186 ± 1	181 ± 3	175 ± 2	171 ± 1	164 ± 3	159 ± 3	153 ± 2	163 ± 2	168 ± 1	174 ± 2	173 ± 3.74^ns	10.82	21.08
17	194 ± 2	191 ± 3	184 ± 2	175 ± 2	164 ± 3	151 ± 3	149 ± 2	136 ± 2	135 ± 3	148 ± 2	150 ± 2	154 ± 1	160 ± 5.90**	17.52	33.50
18	195 ± 2	192 ± 1	186 ± 2	183 ± 2	177 ± 3	168 ± 2	160 ± 3	150 ± 1	145 ± 3	152 ± 1	163 ± 2	172 ± 3	170 ± 4.83*	12.37	24.16
19	194 ± 2	189 ± 1	179 ± 2	165 ± 2	154 ± 3	148 ± 2	139 ± 3	129 ± 2	123 ± 1	131 ± 4	142 ± 2	151 ± 1	154 ± 6.86**	20.61	39.83
20	193 ± 1	187 ± 1	171 ± 2	158 ± 4	147 ± 2	132 ± 1	125 ± 2	119 ± 4	116 ± 2	130 ± 1	148 ± 2	152 ± 2	148 ± 7.36**	23.71	46.25
21	194 ± 2	191 ± 2	184 ± 3	178 ± 1	166 ± 1	155 ± 2	149 ± 1	138 ± 3	130 ± 2	140 ± 4	150 ± 2	162 ± 2	161 ± 6.19**	17. 01	33.00
22	196 ± 3	193 ± 3	189 ± 2	184 ± 2	179 ± 3	172 ± 2	165 ± 1	160 ± 2	154 ± 1	168 ± 2	173 ± 3	181 ± 4	176 ± 3.80^ns	09.27	18.25
23	193 ± 1	189 ± 2	185 ± 1	182 ± 2	179 ± 3	172 ± 3	165 ± 2	162 ± 3	150 ± 1	166 ± 2	175 ± 1	187 ± 2	178 ± 2.87^ns	08.24	16.25
24	193 ± 2	189 ± 1	188 ± 2	183 ± 1	175 ± 2	172 ± 1	163 ± 3	159 ± 4	153 ± 2	163 ± 2	169 ± 1	174 ± 2	173 ± 3.69^ns	10.82	21.00
25	194 ± 2	186 ± 2	180 ± 1	165 ± 3	159 ± 4	149 ± 3	143 ± 1	136 ± 2	134 ± 3	148 ± 1	153 ± 2	168 ± 1	159 ± 5.62**	18.04	34.25
prazosin	195 ± 3	188 ± 1	170 ± 2	157 ± 1	149 ± 1	133 ± 2	124 ± 1	120 ± 3	117 ± 2	133 ± 1	150 ± 2	157 ± 1	149 ± 7.37**	23.19	45.16
diazoxide	194 ± 4	186 ± 2	170 ± 1	158 ± 3	150 ± 4	134 ± 2	126 ± 4	122 ± 1	119 ± 3	135 ± 4	148 ± 2	155 ± 3	149 ± 7.03**	23.19	44.66
Toxic control	195 ± 2	195 ± 3	194 ± 1	195 ± 2	194 ± 3	195 ± 4	194 ± 2	195 ± 3	194 ± 3	193 ± 3	194 ± 3	195 ± 2	194 ± 0.19**	–
Control	100 ± 2	101 ± 1	103 ± 2	105 ± 1	102 ± 2	103 ± 1	101 ± 2	103 ± 3	99 ± 1	102 ± 1	98 ± 2	98 ± 1	101 ± 0.62	–

All values were expressed as Mean ± SEM (*p ≤ 0.05), each group comprised 6 animals (i.e. n = 6).

Toxic control group was compared with control group. All the treatment groups were compared with toxic control group and p < 0.05 was considered to be significant.

**p < 0.01, *p < 0.05 and ^nsnonsignificant.

Figure 3. Graph showing changing in blood glucose concentration exhibited by some potent compounds and compared with diazoxide.

Table 4. Evaluation of anti-diabetic potential.

		Blood glucose concentration (mg/dl) ± S.E.M.
Compd.	Dose (mg/kg body wt.)	0 h	1 h	6 h	12 h	24 h	48 h
Control	5 ml (CMC)	90.7 ± 0.610	90.6 ± 0.428	90.7 ± 0.725	92.6 ± 0.899	93.2 ± 0.996	91.1 ± 0.785
7	5 mg	87.0 ± 1.207*	87.3 ± 1.244	86.9 ± 1.124	89.8 ± 0.491	89.6. ± 0.874	89.6 ± 0.974
9	5 mg	86.3 ± 0.785	87.5 ± 0.724	88.8 ± 0.674	90.0 ± 1.126	91.2 ± 1.158	91.3 ± 0.811
14	5 mg	90.1 ± 1.024	90.2 ± 0.816	89.6 ± 0.811	90.5 ± 0.916	89.9 ± 1.307	91.0 ± 0.749
15	5 mg	92.3 ± 0.688	91.9 ± 0.617	91.5 ± 0.517	92.4 ± 0.506	91.5 ± 0.861	89.7 ± 0.912
19	5 mg	87.4 ± 0.993	88.2 ± 0.998	89.0 ± 1.153	90.3 ± 1.168	89.6 ± 0.894*	91.0 ± 0.759
20	5 mg	85.6 ± 1.763*	89.3 ± 0.684	88.6 ± 1.160	91.3 ± 0.812	91.4 ± 0.840	91.7 ± 0.915
Diazoxide	5 mg	86.9 ± 2.058	98.1 ± 0.708**	112.0 ± 0.566**	116.5 ± 0.317**	119.1 ± 0.438**	121.0 ± 0.706**

All values were expressed as Mean ± SEM (*p ≤ 0.05), each group comprised 6 animals (i.e. n = 6).

*p < 0.05, **p > 0.01 signification from control animals.