Synthesis , Structure Activity Relationship Studies and Pharmacological Evaluation of 2-Phenyl-3-( Substituted Phenyl )-3 H-Quinazolin-4-ones as Serotonin 5-HT 2 Antagonists

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Melting points of the synthesized compounds were determined by open capillary method and are uncorrected.Thin layer chromatography of synthesized compounds was performed on precoated silica gel G 254 plates and visualized in iodine or UV.The IR spectra of synthesized compounds were recorded on Perkin-Elmer FTIR in potassium bromide discs.The proton nuclear magnetic resonance ( 1 H NMR) was recorded in NMR Varian Mercury 300 MHz.The solvents used were DMSO-d 6 and acetone.Chemical shifts are reported in δ ppm, downÞ eld from tetramethylsilane (δ 0.00).Splitting patterns are designated as singlet (s), doublet (d) and multiplet (m).The electrospray mass spectra (ESMS) were recorded on a Micromass Quattro II triple quadrupole mass spectrometer.Elemental analysis was performed (C, H and N).All the target compounds and the reference olanzapine were orally administered (5-HTP was intraperitoneally administered).All protocols of animal experiments have been approved by Institutional Animal Ethics Committee.Antagonism of serotonin (5-HT 2 ) receptor was studied by inhibition of L-5-hydroxytryptophan induced head twitches behaviour [16] .
Group of six male Wistar rats (180-280 g) was used in this test procedure.Sixty minutes prior to scoring head twitch behaviour, L-5-hydroxy tryptophan (5-HTP) was administered intraperitoneally at dosage of 10 mg/kg.Thirty minutes following the injection, test compounds were administered orally.Control group were administered the appropriate vehicle.Sixty minutes post 5-HTP administration; each animal was individually placed in a clear plastic cage and observed for head twitch response [16] .The number of head twitches per animal was recorded over a 10 m interval and the total summed for each group.The percentage change from control for each group was then calculated.ED 50 values were calculated by sigmoidal dose-response curve analysis using the program PRISM (Graph pad Software).P-value less than 0.05 (P<0.05) was considered statistically signiÞ cant.
Compound 1 showed IR absorption at 1764 cm -1 corresponding to carbonyl group stretching in lactones. 1H NMR spectral studies showed multiplets in the regions 7.2-7.3δ and 7.8-8.01δ, assigned respectively to protons of phenyl ring at C 2 and the protons at C 5 , C 6 , C 7 and C 8 .The ESMS of the compound 1 showed its (M+H) + peak at 224.

Scheme 1: Synthesis of 2-phenyl-3-(substituted phenyl)-3hquinazolin-4-ones
The IR spectra of the title compounds 2a-2f showed characteristic absorption peaks in the range 1665-1680 cm -1 , assigned to carbonyl stretching in δ lactams.The 1 H NMR spectral studies showed multiplets in the range 6.91-7.09,7.13-7.19and 7.73-8.1δ,assigned respectively to phenyl at C 3 , phenyl at C 2 and the protons at C 5 , C 6 , C 7 and C 8 .The ES MS of title compounds showed their respective (M+H) + peaks.All these observations confirmed the structures of the title compounds 2a-2f.Characterization data of the synthesized compounds is given in Table 1.The propensity of title compounds to antagonize 5-HTP induced head twitch was evaluated and their respective ED 50 values are reported in the Table 3.Our synthetic efforts in the series of compounds synthesized were directed to find the effect of electronic character of the substituent in phenyl ring on the afÞ nity for 5-HT 2 receptor.
As is evident from Table 3, the efficacy of the compounds to antagonize the head twitch depended greatly on the nature of substituent.Of the synthesized compounds, not all were able to antagonize the head twitches induced by 5-HTP.The presence of electron withdrawing groups (Cl and F) at ortho-and para-positions lead to potent derivatives 2b and 2c.Substitution of the orthohydrogen by electron donating group (-OCH 3 ) decreased the potency; however it was more potent than the unsubstituted compound 2a.Di-substitution with methyl at 2, 4 and 2, 6 positions yielded the least potent members of the series, i.e the compounds 2d and 2e.The most potent compound in the series was 3-(2-chlorophenyl)-2-phenyl-3Hquinazolin-4-one (compound 2b).Thus, the series synthesized afforded compounds having varying degree of afÞ nity for the 5-HT 2 receptor and offers interesting series of molecules to be worked upon for reÞ nement of biological activity.

TABLE 1 : CHARACTERIZATION DATA OF THE TITLE COMPOUNDS
Elemental analyses results were within ± 0.4% of the calculated values, b Melting points are expressed in ûC and are uncorrected, c Solvent for recrystallization is alcohol, d Yields are not optimized, e Mobile phase is 20 % EtOAc-benzene a

TABLE 2 : SPECTRAL CHARACTERIZATION DATA OF THE TITLE COMPOUNDS
a KBr pellet was used for determination, b Solvent used was dueterated acetone

TABLE 3 : INHIBITION OF HEAD TWITCHES AFTER ADMINISTRATION OF TEST AND REFERENCE COMPOUND
a ED 50 was calculated by sigmoidal dose response curve analysis using the program PRISM (Graphpad Software) after oral administration of drug.P-value less than 0.05 (P<0.05) was considered statistically signiÞ cant.