Studies on Novel N4-[4,6-Diaryl-2-pyrimidinyl]- 7-chloro-4-quinolinamine and their Microbicidal Efficacy

The required chalcones 1a-h were prepared by reaction of substituted acetophenone with different aryl aldehyde, which in turn treated with guanidine nitrate, yielded 4-(substituted phenyl)-6-(substituted phenyl)-2-pyrimidinamine 2a-h. Novel pyrimidine quinoline clubbed molecules 3a-h have been prepared by reaction of 2a-h with 4,7-dichloroquinoline. All the compounds were characterized by elemental analysis and spectral studies. The newly synthesized compounds were evaluated for their antibacterial and antifungal activity.


Introduction
Heterocycles are abundant in nature and are of great significance to life, because their structural subunits exist in many natural products such as vitamins, hormones, antibiotics etc 1 . Hence, they have attracted considerable attention in the design of biologically active molecules 2-3 . The classes of pyrimidines possess a broad spectrum of biological effectiveness such as antimicrobial [3][4] , calcium channel blockers 5 , antitubercular 6 , anticancer 6 , antibacterial 7 , antiinflammatory 8 and many classes of chemotherapeutic agents containing pyrimidine nucleus are in clinical uses. Apart from these, chalcones have been reported to possess various biological activities [9][10][11][12][13] . Extensive work on synthesis of chalcones has been done by various routes [14][15][16] . Quinoline derivatives are also drugs of therapeutic importance showing wide spectrum of biological activities. Some 4-substituted quinoline derivatives have been found to possess enhanced antibacterial activity [17][18][19][20] . Numerous processes for the preparation of chloroquinoline derivatives were reported in literature [21][22] . If pyrimidine and quinoline moieties clubbed into one molecule, the resultant molecule may enhance the pharmaceutical activity up to some extent. Hence, it was thought interesting to explore the study of such molecules. Thus the present paper describes the synthesis of N4-[4,6-diaryl substituted-2-pyrimidinyl]-7-chloro-4-quinolinamine derived from 2-amino-4,6-diaryl substituted pyrimidine derivatives and 4,7-dichloroquinoline. This work is shown in Scheme 1.

Preparation of 2-amino-4,6-diaryl substituted pyrimidine (2a-h)
A mixture of substituted chalcone 1a-h (0.01 mol) and guanidine nitrate (0.01 mol) was dissolved in ethanol (30 mL). Aqueous sodium hydroxide (40%, 1 mL) was added and the reaction mixture was refluxed. Further installments of sodium hydroxide (4x1 mL) were added during two hours to the refluxing solution. Refluxing was continued (10-12 h) and the completion of the reaction was monitored by TLC. The resultant mixture was cooled at room temperature, diluted with water (3 x 100 mL) and neutralized with cold dilute HCl (10%). The product thus separated was filtered out, washed with water dried and crystallized from ethanol. Following the same procedure all the compounds of this series were prepared. Their characterization data are recorded in Table 1.

Preparation of 4,7-dichloroquinoline
It was synthesized according to the method reported in the literature 22 .
General procedure for the preparation of (3a-h) To a mixture of 2-amino-4,6-diaryl substituted pyrimidine (0.01 mol) 2a-h and 4,7dichloroquinoline (0.01 mol) in THF, anhydrous K 2 CO 3 (0.11 mol) were added. The reaction mixture was refluxed. TLC [Toluene-ethyl acetate-acetone; 5:3:2] showed that reaction was complete after 8 h. The reaction mixture was poured in an ice water and the precipitate was filtered, washed with water, dried and recrystallized from ethanol. Their characterization data are recorded in Table 2.
The antimicrobial activity of 1a-h, 2a-h and 3a-h was carried out against some strain bacteria. The results show that the synthesized compounds were toxic against the bacteria. The comparison of the antibacterial and antifungal activity of these compounds with standard drugs shows that the presence of methoxy and halogen (-Cl,-Br,-F) groups in the phenyl ring increases the activity.

Biological Screening Antibacterial activities
Antibacterial activities of all the compounds were studied against gram-positive bacteria [Staphylococcus aureus (MTCC96), Streptococcus pyogenes (MTCC442)] and gram-negative bacteria [Escherichia coli (MTCC443), Pseudomonas aeruginosa (MTCC424)] at a concentration of 100 µg/mL by agar cup plate method. DMF system was used as control in this method. Under similar condition using chloramphenicol, ciprofloxacin and norfloxacin as a standard for comparison control experiment was carried out. The area of inhibition of zone measured in mm.

Conclusions
The clubbing of 2-amino-4,6-diaryl substituted pyrimidine derivatives and 4,7dichloroquinoline has been done successfully into one molecule. Both the moieties have important applications in medicinal use; the synthesized compounds may act as good biological compounds.