INTRODUCTION:
The chemistry of ß-lactams have taken an important
place inorganic chemistry since the discovery of Penicillin by Alexander
Fleming in 1928 and shortly thereafter Cephalosporin which were both used as
successful antibiotics. Even now the research in this area is stimulated
because of development of bacterial resistance to widely used antibiotics of
this type. 2-Azetidines have been extensively investigated by the
organic chemists due to their close association with various types of
biological activities. Azetidine-2-ones also have great importance because of
the use of ß-lactam derivatives as an antibacterial agent. The antibiotic
activity is closely related to the substituted ß-lactam ring
structure1.
2-Azetidinone is a ß-lactam cyclic amide with four
atoms in a ring. It is evident that in azomethine derivatives the C=N linkage
is an essential structural requirement for biological activity. These compounds
are readily hydrolyzed under acidic conditions leading to active aldehydes
which can act as alkylating agents2. Besides, several azomethines
have been reported to possess remarkable antibacterial3-7,
antifungal7-9, anticancer9-11, and diuretic activities12.
Traditionally ß-lactam is a part of structure of broad spectrum antibiotic
class of drugs – penicillins and cephalosporins. 2-Azetidines have been
extensively investigated by the organic chemists due to their close association
with various types of biological activities12-15.
Azetidine-2-ones also have great importance because of the
use of β-lactam derivatives as an antibacterial agent16. The
antibiotic activity is closely related to the substituted β-lactam ring
structure17-25.
More
particularly and recently these types of compounds have been found in the
treatment of T.B. and other chemotherapeutic diseases. Hence it was thought
interesting to synthesize novel azetidinone derivatives. The present paper
comprises the synthesis, characterization and evaluation of some azetidinone
derivatives.
MATERIAL
AND METHODS:
Experiment:
Melting points were recorded on electrothermal
apparatus and are uncorrected. The synthesized compounds were characterized by
IR spectroscopy, thin layer chromatography was performed on silica gel layer
and spots were visualized by exposing the developed spots and dry plates to
Iodine vapours. The IR spectra were recorded in KBr pellets on a Perkin-Elmer
spectrophotometer.
Synthesis of schiff’s bases:
Step-1:
(Synthesis of 2- hydroxyl benzaldehyde derivatives)
0.05
Mole of aniline (4.65gm or 4.65ml) (or) 4-amino phenol (5.45 gm) (or)
4-aminobenzoic acid (6.85mg or 7.1 ml) was dissolved in minimum quantity of
absolute alcohol in a round bottom flask. To this add the alcoholic solution of
2-hydroxy benzaldehyde 0.05 mol (5.3ml or 6.1 gm) drop by drop and it was reflux
for 2 hours. Then it was cooled and added in to ice cold water. A colored
compound was obtained which was separated by filtration and washed with cooled
water, dried and recrystallized with a mixture of ethanol and water.
Step-2:
(Synthesis of benzaldehyde derivatives):
0.05
Mole of aniline (4.65 gm or 4.65ml) (or) 4-amino phenol (5.45 gm) (or)
4-aminobenzoic acid (6.85mg or 7.1 ml ) were dissolved in minimum quantity of
absolute alcohol in a round bottom flask. To this alcoholic solution of
benzaldehyde 0.05 mol (5.3ml or 6.1 gm) drop by drop was added and reflux for 2
hours, cooled and added in to ice cold water. A colored compound was obtained
which was separated by filtration and washed with cooled water, dried and
recrystallized with a mixture of ethanol and water.
Synthesis
of 2-azetidinone derivatives:
The
schiff base (0.001 mol) was treated with triethylamine (0.003 mol) and
dissolved in 2,4-dioxane (25 ml). To this chloroacetyl chloride (0.0012 mol)
was added as drop wise. The reaction mixture was stirred for 14 hr at room
temperature and excess solvent was removed by distillation. The residue was
poured over crushed ice, solid separated was filtered, washed with water and
crystallized from dichloromethane.
Antibacterial activity:26
Antibacterial activity is carried out by agar cup-plate
method; Nutrient agar medium was used for the study. After sterilization the
nutrient agar medium was melted, cooled and inoculated with Staphylococcus
aureus and Escherichia coli organism and poured into sterile Petri dish to
get a uniform thickness of 6 mm. Cups were made out in the other plate using
sterile cork borer (6 mm dia). The standard antibacterial agent Sparfloxacin
(100 μgL-1), solvent control (DMF) and the synthesized compounds in a
concentration of 100 μg L-1 were added with the sterile micro pipette into
each cup. The plates were then incubated at 37ºC for 24 h and the diameter of
zone of inhibition were measured s for antibacterial activity. The potency of
the synthesized compounds was determined against standard drug Sparfloxacin
and measured the zone of inhibition and the result was given in the table.4.
RESULT:
The
physical data of the synthesized compounds such as color, percentage yield,
melting point and molecular weight obtained are presented in table.1.
The
IR spectral data obtained for each synthesized compounds are tabulated in the
following table 2.
CONCLUSION:
From
the table-4, it reveals that the test compounds E and F exhibit good activity
and remaining compounds shows moderate anti-bacterial activity when compared to
the standard drug Sparfloxacin. ß-lactams are still the most prescribed
antibiotics in medicine. The activity of famous antibiotics such as penicillin,
cephalosporins and carbapenems are attributed to the presence of 2-azetidinone
ring in them. The literature confirms that the 2-azetidinone moiety have
antimicrobial activity. The importance and structural diversity of biologically
active ß-lactam led to the development of many synthetic methods for the
construction of the appropriately substituted 2-azetidinones.Therefore it can
be concluded that derivatives of 2- azetidinones have a great potential to
develop into a bioactive molecule. Further study needed for the similar line of
newer derivatives and their biological screening towards the various
pharmacological activities.
REFERENCES:
1) Mrunmayee Toraskar, Vithal Kulkarni,
Vilasrao Kadam. Azetidinone : A bioactive moiety. Journal of Pharmacy Research
2001; 3(1):169-173
2)
Ross WCJ, Warwick GP. Aryl
(2-haloalkyl) amines. The rates of reduction of substituted N, N-bis
(2-chloroethyl)-4-phenylazoaniline by stannous chloride, hydrazine, and the
xanthine oxidase-xanthine system. J Chem Soc 1956; 18: 1724-1732.
3)
More SV, Dongarkhadekar DV, Chavan
RN, Jadhav WN, Bhusare SR, Pawar RP. Synthesis and antibacterial activity of
new Schiff bases, 4-thiazolidinones and 2-azetidinones. J Indian Chem Soc 2002;
79: 768-769.
4)
Bhendkar AK, Vijay K, Raut AW.
Synthesis of some novel Schiff bases of 2-aminopyrimidine and their
antimicrobial activity. Acta Ciencia Indica Chem 2004; 30: 29-32.
5) Vaghasiya YK, Nair RS, Baluja M, Chanda SS. Synthesis
structural determination and antibacterial activity of compounds derived from
vanillin and 4-aminoantipyrine. J Serb Chem Soc 2004; 69: 991-998.
6) Vashi K, Naik HB. Synthesis of novel Schiff base and
azetidinone derivatives and their antibacterial activity. Eur J Chem 2004; 1:
272-276.
7) Rhodes RC, Hall H, Beesley SR, Jenkins JE, Collins DC,
Zheng P. Therapeutic Potentiation of the immune system by costimulatory Schiff
base-forming drugs. Nature 1995; 377: 71-75.
8) Safwat HM, Ragab FA, Eid NM, Abdel GM. Synthesis
anti-tumor and antimicrobial activities of 3-chloro-9-(p-N-substituted
sulfamoyl phenyl amino ethylene) acridines. Egyptian J Pharm Sc 1988; 29: 99-110.
9) Mtrei R, Yadawe M, Patil SA. Synthesis of biologically
active p-bis(amino-5-mercapto-1,2,4- triazol-3-yl)benzene and its Schiff base:
a new class of bis-triazole. Orient J Chem 1996; 12: 101- 102.
10) Hossain, ME, Allam MN, Begum J, Akbar MA, Uddin MN,
Smith FE, Hynes RC. The preparation, characterization, crystal structure and
biological activities of some Cu(II) complexes of the 2-benzoyl pyridine Schiff
bases of S-methyl-and S-benzyldithiocarbazate. Inorg Chim Acta 1996; 249:
207-213.
11) Sharma KP, Jolly VS, Phatak P. Schiff bases and their
derivatives as potential anticancer agents. Ultra Scient Phys Sci 1998; 10:
263-266.
12) Shingare MS, Ingle DB. Synthesis of pyrimidine Schiff
bases as anticancer agents. J Indian Chem Soc 1976; 53: 1036-1037.
13) Shkawat DR, Sabnis SS, Deliwala CV. Potential
anticancer agents, Schiff bases from p-(3- azaspiro [5,5] undec 3 yl)
benzaldehydes. Bull Haffkine Inst 1973; 1: 35-39.
14) CT Barboiu M , Luca C , Pop E , Brewster ME, Dinculescu
A. Carbonic anhydrase activators. Part 14. Syntheses of mono and bis pyridinium
salt derivatives of 2-amino-5-(2- aminoethyl)- and
2-amino-5-(3-aminopropyl)-1,3,4-thiadiazole and their interaction with
isoenzymeII Supuran. Eur J Med Chem 1996; 31: 597-606.
15) Rao JS, Srenivasulu B and Mogilaiah K. Indian J. Chem.
1995; 34B: 734.
16) Kidwai M, Bala R and Kumar K. Synthesis of new
4-thiazolidinones and 2-azitidiones with their vitro biological activities. Indian
J Pharm Sci 1995; 57: 252-259.
17) Hartmann H, Czerney P, Liebscher. J Chem Abstr 1984,
101, 7145.
18) Amjid Iqbal, Hamid Latif Siddiqui, CM Ashraf, Matloob
Ahmad, George W Weaver. Synthesis, Characterization and antibacterial activity
of azomethine derivatives derived from 2-Formylphenoxyacetic acid. Molecules 2007; 12: 245-254.
19) Rajasekaran A, Periasamy M Venkatesan S. Synthesis,
characterization and biological activity of some novel azetidinones. Journal of Developmental Biology and Tissue
Engineering. 2010; 2: 5-13.
20) Stacey GL and Keen NT. Plant-microbe interactions.
Chapman and Hall, New York.1996.
21) Patwardhan B, Hopper M. Ayurveda and future drug
development. Int J alternative complement med. 1992; 10: 9-11.
22) Grabley S, Thiericke R, Bioactive agents from natural
sources: Trends in discovery and application. Adv. Biochem Eng Biotechnol 1999;
64: 101-154.
23) Kalsi R, Pande K, Bhall TN, Barthwal J P, Gupta P S .
Anti inflammatory activity of Qunazolino Formazone. J Pharm Sci 1990; 79:
517-520.
24) Shukla JS, Fadayan M. Synthesis of 2- Methyl/Phenyl
-3(4- substituted benzylidine amino phenyl) 6, 3 substituted – 1, 3 quinazolin
– 4(3H) – ones as potential anthelmintic agents. Asian J Chem 1989; 1: 208.
25) Akers M. J. Bently’s text book of Pharmaceutics. Eighth
Edition, Bailliere Tindall, London. 1992.
26) Michael J. Pelczar,
E.C.S.Chan, Noel R Kreig. Microbiology - Concepts and Applications, Mc. Graw
Hil Inc., New York. 1993.
), 1553.34
(Mono substituted aromatic ring).
).