Adamantane-pyrido[2,3-d]pyrimidine Derivatives; Synthesis, Characterization and Investigation of Antimicrobial Study

Target molecules based on Adamantane-pyrido[2,3-d]pyrimidine derivatives were prepared. Adamantane-pyrido[2,3-d]pyrimidine series using N -(hydroxyadamantan-1-yl)-5-(2,4-substitutedphenyl)-2-Methyl-4-Oxo-7-(2-oxo-2 H -Chromen-3-yl)pyrido[2,3-d]Pyrimidine-3(4 H ) carboxamide (6a-j) was synthesized by reaction between 3-(2-chloroacetyl)-5-(2,4-substitutedphenyl)- 2-Methyl-7-(2-Oxo-2 H -Chromen-3-yl) pyrido[2,3-d]pyrimidin-4(3 H )-one (5a-j) and 3-aminoadamantan-1-ol. These derivatives of Adamantane-pyrido[2,3-d]Pyrimidine were investigated In vitro for their biological characteristics against the strains which were isolated clinically and confirmation of their structure was done by FTIR, 1 H-NMR, 13 C NMR and LCMS. The newly synthesized derivatives gave promising antimicrobial activity.


INTRODUCTION
The research on biochemical importance of pyrimidines and pyrimidine derivatives have centered great importance because of the pyrimidines represent the main backbone in alkaloids and nucleic bases as well as their interesting powerful biological activities.Pyrimidine derivatives contain diversified applications as pharmaceuticals and occupy a unique place in heterocyclic and medicinal chemistry also [1][2][3] .Combination of coumarin derivatives and pyrimidine derivatives has received considerable attention by researchers because of possessing so many biological important application and pharmacological activities [4][5][6][7] .Various pyrimidine derivatives show very broad range of biological activities viz.antimicrobial activity 8 , anti-inflammatory 9 , anticancer 10 , antiviral 11 , antitubercular 12 , antihypertensive [13][14] , anticonvulsant 15 , H1-antihistamines 16 , 4-phosphodiester inhibitors [17][18] and antimalarial [19][20] .

MATERIALS AND METHODS
The synthesis was carried out using A R Grade reagents and solvents and were used without further purification.Open capillary method was used to take melting points and are uncorrected.TLC (thin layer chromatography) was used check the progress of reactions using silica gel plates GF254 (E.Merck).The solvent system comprised of methanol and toluene; the chromatograms visualized using source of UV light (254nm).FTIR spectra were recorded making use of KBr on pallets Perkin Elmer 1600 FTIR. 1 H NMR and 13 C NMR spectra were obtained using Bruker 500 MHz, DMSO-d 6 as the solvent and TMS (tetra methyl silane) as internal standard.LCMS was used to carry out LC-MS.

Preparation of various substituted chalcone derivatives (2a-k)
B a s e c a t a l y ze d C l a i s e n -S c h m i d t condensation reaction was used to synthesize various chalcone derivatives of the appropriate substituted aldehydes and substituted acetophenone by reported literature method 21 .
3-Acetyl-2H-chromen-2-one (0.01mole) (1)  and substituted benzaldehyde (0.01mole) dissolved in 10 mL ethanol in RBF using a magnetic stirrer.Water bath was used to maintain the temperature of reaction at 20-25 o C. 1 g NaOH in 10 mL dist.H 2 O was taken and this NaOH solution was drop wise added into to the reaction mixture for 30 min with continuous stirring.On completion of addition, solution was stirred further for 4-5 h and kept at RT for 12 hours.The final solution was dumped into chilled H 2 O and neutralized using 0.1-0.2NHClwhereby solid obtained.The product was filtered & then dried in air.The crude was recrystallized by rectified spirit.Further purification was done by used ethyl acetate and n-hexane.

RESULTS AND DISCUSSION
3-Acetyl-2H-Chromen-2-one resulted by the reaction of Ethylacetoacetate (EAA) & Salicylaldehyde.(DEA) Diethyl Aniline then was mixed with continuous stirring dropwise at RT to obtain solid.Various chalcone compounds were prepared using Claisen-Schmidt (base catalyzed) condensation reaction of selected substituted aldehyde and substituted acetophenone by known literature method 19 .Substituted benzaldehyde and 3-Acetyl-2H-Chromen-2-one was mixed in ethanol using magnetic stirrer.Water bath was used to maintain the reaction temperature between 20-25 o C on the magnetic stirrer. 1 g NaOH was added to 10 mL distilled water and the resulted aqueous NaOH solution was dropwise added into the to the reaction mixture and when addition was completed this solution was stirred further for 4-5 h and kept for 12 hours.The mixture was made neutral with 0.1-0.2NHCl till the solidification obtained.The resulted mixture was filtered then dried in air finally recrystallized using rectified spirit.Further carried out from purification was Ethyl Acetate & n-Hexane.Chalcone derivatives (2a-k), malononitrile and anhydrous ammonium acetate were taken in RBF and absolute ethanol was used as solvent.This mixture was refluxed for 7-8 hours.Then cooled to RT.As solution attained RT, solid was obtained.Filtration & washing was done with dist.H 2 O thoroughly, recrystallization from Ethanol to yielded compounds (3a-k) 23 .
Compound (3a-k) and excess of glacial CH 3 COOH were mixed and then refluxed condition for 7-8 hours.Glacial acetic acid was self-solvent.After the completion of reaction, solution was cooled to RT. Solid thus obtained, was filtered, then washed thoroughly with cold dist.H 2 O several times, dried, Dioxane was used for recrystallization to give compounds (4a-k).
When addition was completed, this reaction mixture was heated at 80 o C for 1.5 h & this solution was stirred at RT for 12 h which gave compounds (5a-k).
The compounds were confirmed by study of FT-IR spectra, using KBr discs.on Perkin-Elmer 1600 FTIR, 1 H NMR and 13 C NMR spectra were measured on Bruker 500 MHz in DMSO-d 6 as solvent was used and TMS-tetra methyl silane was internal standard respectively.LC-MS were carried out on LCMS.According to NMR data presence of methyl group showed value of d near 2.92-3.09,proton of the secondary of NH group showed value of d near 6.76-7.35,-OH group pf adamantane showed value of d near 3.43-3.47,-OCH 3 showed value of d near 3.79-3.90and 5H of coumarin showed value of d 6.75-8.59.Fig. 1 to 4 shows 1 H NMR spectra of the compounds TT 1 , TT 3 , TT 5 and TT 8 respectively.Fig. 5 shows 13 C NMR spectra of the compound TT 1 .Fig. 6 and 7 shows IR spectra of the compounds TT 1 and TT 3 respectively.Fig. 8 represents LCMS spectra of the compounds TT 1 and TT 3 respectively.

biological activity
Antibacterial activity: Table 3