Introduction

Sciff bases are condensation products of primary amines and aromatic aldehydes. They are known to exhibit potent antibacterial , anticonvulsant, anti inflammatory activities₁. In addition some Schiff bases show pharmacologically useful activities like anticancer₂, anti hypertensive and hypnotic₃ activities. Heterocyclic compounds like 1,8-naphthyridines arouse great interest due to diverse type of biological activity associated with it, viz. antimalarial, anticancer, anticonvulsant,₄ antibacterial and diuretic.

Combination of two or more moieties into one is a common procedure for manipulation in medicinal chemistry and this can possibly result in augmenting the activity, removal of untoward side effects and particularly prevent the development of resistance by infectious micro organisms.

In view of these facts, synthesis of certain Schiff bases containing 1,8-naphthyridine moiety has been under taken in the hope of getting better bioactive agents. For the synthesis of such compounds, 2-amino nicotinaldehyde was treated with ethyl cyano acetate to get 2-hydroxy -3-cyano-1,8-naphtyridine. (I). This upon treatment with 10% NaoH solution gave 2-hydroxy-1,8-naphthyridine-3-carboxylic acid. (II). Compound II on treatment with phosphorus oxy chloride gave 2-chloro-1,8-naphthyridine-3-carboxylic acid.(III). The intermediate (III) upon treatment with hydrazine hydrate in ethanol gave 2-hydrzido-1,8-naphthyridine-3-carboxylic acid. (V). The constitution of all compounds synthesized was established by elemental analysis, UV, IR and NMR and mass spectral study. Selected compounds were evaluated for antibacterial and antifungal activites.

Experimental

Melting points were determined by open capillary tube method and are uncorrected. TLC was run on Silica gel G-plates using Benzene-Methanol as developing solvent. FTIR (cm1 and PMR spectra chemical shift in delta ppm downfield from TMS) were recorded on Jasco FTIR 410 spectrophotometer and AMX-400 MHz spectrophotometers respectively.

Synthesis Of 3-Cyano-2-Hydroxy-1,8-Naphthyridine- (I)

A mixture of 2-amino nicotinaldehyde₇ (0.01mole ) and ethyl cyano acetate (0.01)was refluxed in ethanol containing a few drops piperidine for a period of six hours,cooled, the solid separated was separated was filtered and recrystallised from ethyl acetate-acetone solvent pair.

Synthesis Of 2-Hydroxy-1,8-Naphthyridin-3-Carboxylic Acid-(Ii)

A mixture of 2-hydroxy-3-cyano-1,8-naphthyridin (0.01mole),50 ml of 10% sodium hydroxide solution and 10 ml of alcohol was refluxed for one and a half hours. The solution was boiled in the open flask for a few minutes. The solution was cooled and conc. hydrochloric acid was added, till the precipitation was complete. The product was filtered and washed with water and recrystallised from methanol.

Synthesis Of 2-Chloro-1,8-Naphthyridin-3-Carboxylic Acid- (Iii)

2-Hydroxy-1,8-naphthyridin-3-carboxylic acid (0.01 mole) was refluxed in 10 ml

of phosphorus oxy chloride for half and hour. The resulting mixture was poured into crushed ice and sodium carbonate solution. The resultant precipitate was fltered, washed with water and recrystallized from methanol.

Synthesis of 2-hydrazido -1,8-naphthyridin-3-carboxylic acid-.(iv)

A mixture of 2-chloro-1,8-naphthyridin-3-carboxylic acid (0.01mole) and hydrazine hydrate ( 0.015mole) was refluxed in 30 ml of ethanol for 10 hours. The reaction mixture was concentrated to one third of it,s volume and coleed. The resulting solid product was filtered and recrystallized from methanol.

Synthesis of 2-arylidene hydrazido -1,8-naphthyridin-3-carboxylic acid.-(v)

A mixture of 2-hydrazido-1,8-naphthyridin-3-carboxylic acid(0.01mole) and the appropriate aldehydde(0.01mole) was refluxed in 30 ml of methanol for 3 hours. The reaction mixture was concentrated, cooled, the solid was separated, filtered and recrystallised from methanol . The other target compounds of the series Va-d were prepared following the above procedure.

Figure 1

Figure 2

Figure 2: Continuation Of Scheme

Results

Figure 3

Table 1: CHARACTERISATION DATA OF COMPOUNDS SYNTHESIZED

Figure 4

Table 2: SPECTRAL DATA OF SYNTHESIZED COMPOUNDS

Anti Bacterial Activity

Antifungal Activity

The antifungal activity of the compounds were evaluated against Candida Albicans and Aspergillus Niger by diffusion method using Clotrimazole 10μg/disc.₆.No compounds exhibited activity against Candida Albicans and Asperigillus Niger.

Figure 5

Figure 3: FIGURE SHOWING ZONE OF INHIBITION AGAINST

The centre disc is Ofloxacin(10μgm/ml) and other discs are arranged clockwise with blank(DMF), Compounds VIa, VIc and VId

Figure 6

Figure 4: FIGURE SHOWING ZONE OF INHIBITION AGAINST

The discs are arranged clockwise

Disc with maximum zone of inhibition Ofloxacin(10μgm/ml-standard),other compounds are VIc,blank(DMF) VId and VIa and VIb.

Figure 7

TABLE 3: SHOWING ZONE OF INHIBITION OF COMPOUNDS AGAINST MICRO ORGANISMS

Discussion And Conclusion

Four compounds which are schiff’s bases of 1,8-naphthyridines were prepared and screened for antibacterial and antifungal activities. The compounds are various derivatives of 2-arylidene hydrazido-1,8-naphthyridine-3-carboxylic acids. The reactions were monitored using TLC and melting points were determined. The structures of the prototypes were confirmed by IR and NMR spectras.

Three compounds exhibited moderate activity against Staphylococcus Aureus at a concentration of 100 micrograms. Four compounds exhibited mild activity against Escherichia Coli.

The antibacterial activity exhibited by the compounds can be attributed to the presence of 1,8-naphthyridine moiety₈ as well as the Schiff base linkage present in them₉. 1,8-naphthyridin moiety is present in the well known antibacterial compound Nalidixic acid.₁₀ Further, attachment of the schiff’s base linkage can greatly enhances the anti bacterial activity of the compounds. During schiff’s base formation the primary amino group condenses with aromatic aldehydes. The nature and position of the substituents of the aromatic aldehydes greatly influences the antibacterial activity of the Schiff’s bases.₁₁ Generally the substituents that causes activity are 2-hydroxy, 4-hydroxy, 2-nitro and 4-nitro groups in the aromatic ring. It is significant that successful antibacterial agents like Chloramphenicol posess 4-nitro group in the aromatic ring.

Regarding anti fungal activity none of the compounds exhibited antifungal activity. This is because of the lack of structural requirements for satisfactory antifungal activity.

To conclude, the schiff’s bases formulated from the heterocyclic moiety 1,8-naphthyridine have given satisfactory results for its antibacterial activity. Schiff’s bases can be converted in to moities like azetidinones and thiazolidinones and it is expected that further works in this direction may yield compounds that are succesful antibacterial agents.

Correspondence to

B.Vinod, M.Pharm, Assistant Professor, Pushpagiri College of Pharmacy, Tiruvalla Kerala, India Vino604@yahoo.com