Dihalosubstituted Quinazolin-4'(3’h)-onomethylene]- 1",3",4"-oxadiazol-2"-yl}-4,5-dihydroimidazolines as Potential Antihypertensive Agents

‘Twelve new 2{2"-carbomyl 5" [3’-amino-2' – methylmono / dihalosubstituted quinazolin4' (3’H) onomethylene] – 1",3",4" oxadiazol-2"-yl} -4, 5dihydroimidazolines were prepared and evaluated for their cardiovascular activity. The most active compound of this series is 2-{2"carbomyl-5"-[3'-amino-2'-methyl-6-bromoquinazolin-4'(3’H)-onomethylene]-”,3",4"-oxadiazol-2"yl}-4,5-dihydroimidazolines i.e. compound VIc.

moieties, plays a pivotal role in delineating the cardiovascular activity [7][8] .Moreover, quinazolinones [9][10] and oxadiazoles [11][12] have also been reported to possess potent antihypotensive activity.With an aim to develop better hypotensive agents, it was thought worthwhile to synthesize a new series of 2-substituted imidazoline derivatives bearing oxadiazolyl and quinazolinonyl moieties.All the newly synthesized compounds (synthetic route is given in scheme) were evaluated for their cardiovascular activity and acute toxicity studies.Moreover structures of all the compounds were delineated by spectral analysis.

Chemistry
All melting points are uncorrected.The purity of the compounds were checked by TLC on silica gel-G plates and spots were located by iodine.IR spectra were recorded on Beckman-Acculab-10spectrophotometer ( max in cm -1 ) 1 H-NMR spectra was recorded on Bruker-400-FT instrument.Mass spectra were recorded on Jeol-JMS D-300 spectrophotometer.

Biological activities
The present study was carried out on adult normotensive mongrel dogs (10-20 kg) or on cats (3-4 kg) and charles foster albino mice (18-25gm).The dogs/cats were divided into two groups of 5 animal each.One of the groups was treated as control group while another group was treated as test group.Dogs/cats were anaesthetized with ±chloralose (80 mg/kg i.p.) injected intravenously and maintained on positive pressure artificial respiration by cannulation of the trachea in order to avoid reflex change in respiration.The right femoral vein was cannulated in each case with on indevelling polyethene tube.The blood pressure was recorded either from the left common carotid artery by means of a mercury manometer on smoked Kymography paper or from femoral artery on one channel of "Encardiorite" (India) polygraph using stathus P23 transducer.Electrocardiogram (Lead II) was recorded on one channel of "Encardiorite" (India) polygraph in some of the experiments.The heart rate was calculated from the pressure pulse tracing in all the experiments.The newly synthesized compounds (test drugs) were administered intravenously through an indevelling polyethylene cannula by dissolving them in propylene glycol and the effect on blood pressure (B.P.), heart rate (H.R.) and pressor responses evoked either by carotid occlusion (CO) or intravenous noradrenaline (NA) 1-2 mg/kg injection was studied.0.25 ml of propyleneglycol was injected as vehicle to see the effect of vehicle on the parameters in the control group of animals.Injection of 0.25ml of propylene glycol induced a mild and transient decrease of 5 mmHg in blood pressure without affecting the CO and NA responses.The toxicity study was carried out on mice of either sex.Approximate 50% lethal dose (ALDso) of the all the compounds was determined in albino mice.The mice of either sex weighing between 18-25 gm were used for the study.The drugs were injected by intraperitonial (i.p.) route at different dose levels in separate groups of animals.From the data obtained ALD 5 o was calculated according to the method 14 .The results were analysed by using student's t-test.

Toxicity Studies: ALD 50
Approximate ALD 50 values of all the compounds were determined by observing 50% mortality after 24 hours.

RESULTS
Hypotensive activity was determined according to the reported method 15 .Cardiovascular activities of these compounds are presented in table (2, 3, & 4).All the four 2-amino-5-(3'-amino-2'memylmono/ dihalosubstitutedquinazolin-4' (3'H)onomethylene]-l,3,4-oxadiazoles (IVa-IVd; table 2) exhibited mild hypotensive activity of varying degree (10-30 mmHg) and duration (10-22 minutes) without affecting the carotid occlusion (CO) and noradrenaline (NA) pressor responses.Compound Ic i.e. 2-amino-5-(3'-amino-2'-methyl-6'-bromoquinazolin-4'(3'H)-onomethylene]-l,3,4-oxadiazole showed an immediate fall in blood pressure of l0mmHg followed by a delayed fall of 30 mmHg.The hypotensive activity of this compound lasted for 22 minutes.As these compounds IVa-IVd did not affect the CO and NA responses and had very short duration of action, therefore, they appear to be acting on the smooth muscles of blood vessels (direct vasodilators).Compounds (Va-Vd; table 3) of stage II exhibited better cardiovascular activity than their parent compounds (IVa-IVd; table-2).These compounds exhibited hypotensive activity of varying degree (20-70 mmHg) of duration (20-30 minutes) without affecting CO and NA responses and heart rate.Compound Vc showed an immediate fall in blood pressure 70 mmHg followed by a delayed fall of 30mmHg.The hypotensive activity of this compound lasted for 20 minutes without affecting the pressor responses (CO and NA) and heart rate (HR).Further, the cyclization of these above2-aminochloroacetyl-5-(2-methylmono/ d i h a l o s u b s t i t u t e d -q u i n a z o l i n -4 ( 3 H )onomethylene)-l,3,4-oxadiazoles into their corresponding carbomyl (CONH) imidazolines i.e. 5-membered ring structure (Vla-VId; table-4) exhibited potent cardiovascular activity of varying degree (10-60 mmHg) of duration (30-50 minutes).All these compounds Vla-VId showed more' potent cardiovascular activity than their parent compounds (Va-Vd; table-3) due to the presence of imidazoline ring.Compound VIc i.e. when quinazolinone was substituted with Br at 6-position, showed an

DISCUSSION
It is interesting to point out that compounds of third stage have shown different pharmacological profile (clonidine like centrally acting as compound VIa, VIb & VIc, secondly a purely peripheral adrenergic blocking type as compound VId.Furthermore, all the compounds i.e.Vla-VId of stage third exhibited the more potent antihypertensive activity than their parent compounds (IVa-IVd and Va-Vd).On the contrary, all the compounds of stage first (IVa-IVd) and stage second (Va-Vd) did not affect the CO and NA responses and had short duration of action.They appear to be acting directly on the smooth muscles of the blood vessels (direct vasodilators).Moreover, it is also evident from the results that presence of imidazoline ring with oxadiazolyl and quinazolinonyl moieties is beneficial for cardiovascular activity.Moreover, the cyclisation of compound Va-Vd to Vla-VId i.e. imidazolines increases the cardiovascular activity in terms of magnitude as well as duration.

Table 4 : Cardiovascular activity of 2-{2"-carbomyl-5"-[3'-amino-2'-methylmono/ dihalosubstitutedquinazolin- 4'(3lH)-onomethylene]-1",3",4"-oxadiazol-2"-yl}-4,5-dihydroimidazolines S. X Dose Change in mean blood pressure mmHg Change in Effect on Pressor ALD 50 .
The results of the cardiovascular activity are mentioned in table(4).Compound VId has also exhibited a potent hypotensive fall of 50 mmHg.The hypotensive activity of this compound lasted for 30 minutes with inhibition of both CO and NA.Such cardiovascular profile is suggestive of peripheral site of action of this compound.Compound VIa exhibited an immediate fall of blood pressure 40 mmHg followed by a delayed fall of 30mmHg.The hypotensive activity of compound VIa was lasted for 35 minutes with potentiation of CO without affecting the NA response, which might be suggestive of central site of action of this compound.