Synthesis of Some Phenylpyrazolo Benzimidazolo Quinoxaline Derivatives as Potent Antihistaminic Agents

2,3-Diphenyl quinoxaline (NI) was fused with benzimidazole (NII) by a methylene bridge, which was then allowed for acetylation. The acetylated product (NIV) was made to react with different aromatic aldehydes to give chalcones (NV1-NV5). Chalcones refluxed with substituted acid hydrazides to afford different phenyl pyrazolo benzimidazole quinoxaline derivatives (NVI 1-NVI 15). The structure of chalcones and phenyl pyrazolo benzimidazole quinoxaline derivatives were confirmed by m.p, TLC and spectral data. All the synthesized compounds were screened for their antihistaminic activity. Compounds NVI-3, NVI-12, NVI-13, NVI-14 and NVI-15 were shown good % protection of antihistamic activity.


Introduction
Benzimidazole moiety plays an important role in heterocyclic chemistry largely due to its wide range of biological activities [1][2][3][4] such as antimicrobial, antitubercular, anti-inflammatory, anticancer etc. Quinoxaline derivatives have been reported to possess a wide variety of biological activities [5][6][7] .Notable among these are antioxidant, anti-inflammatory antimicrobial, anticancer and antihistamic activities.Drugs having pyrazoline ring system [8][9][10] are well known for their anti-inflammatory, antioxidant, antihistamic, antimicrobial, antidepressant, hypoglycemic, hypotensive, anticarcenogenic activities etc.In view of the above facts, it was contemplated to design and synthesize some phenyl pyrazolo benzimidazolo quinoxaline derivatives (Scheme 1) by condensing benzimidazole quinoxaline chalcones with different aromatic acid hydrazides.All the synthesized compounds were screened for their antihistaminic activity.The structure of chalcones and phenyl pyrazolo benzimidazolo quinoxaline derivatives were confirmed by m.p, TLC, and spectral data.

Experimental
The melting point of the compounds were determined on a Thoshniwal electric melting point apparatus and the values were uncorrected.IR spectra of the compounds were recorded on a Thermo Nicolet Nexus670-FTIR, IICT, Hyderabad using KBr disc method. 1 H NMR spectra were recorded onAvance-300, IICT, Hyderabad using CDCl 3 as solvent.Mass spectra were recorded on HITACHI RMU GL, IICT, Hyderabad.All the solvents used were of analytical grade.

General procedure for synthesis of (Z)-4-phenyl-1-(5-((2,3-diphenylquinoxalin-6yl)methyl)-1H-benzo[d]imidazol-1-yl)but-3-en-2-one (NV1-NV5) 10
Method of aldol condensation was followed.A solution of NaOH / KOH (8 mL, 10% in water) was added drop wise to a well-stirred solution of NIV (0.01 M) and (0.01 M) of appropriate aldehyde in 20 mL ethanol.The reaction mixture was stirred for 24 h.at cold conditions.Then diluted with ice water and acidified with con.HCl.Filtered the product and recrystallized with aqueous ethanol.The purity of the compound was checked by TLC and melting point.

Pharmacological evaluation Antihistaminic activity 15 Histamine chamber method
In this method, thirty two healthy adult guinea pigs of either sex divided into group of 2 animals each weighing around 400 g, fasted overnight, were kept in histamine chamber, and exposed to histamine aerosol (0.5% aqueous solution of histamine acid phosphate in a Nebulizer) until they collapse.Those that collapse within 2 minutes were revived with fresh air and used for this test.Twelve hours later, the animals were given an oral dose of test compound suspended in 1% acacia solution and after 1 h for absorption; the guinea pigs were again exposed to the same concentration of histamine aerosol.Those that do not collapse within 6 minutes are deemed protected.Percentage protection has been measured by using the following formula: [1-T 1 / T 2 ] x 100 Where T1 was the mean of control preconvultion time in vehicle treated group and T 2 was the mean of control preconvultion time in drug treated group.The results are shown in Table 2.

Table 1 .
All the synthesized compounds were screened for their Antihistaminic activity.