Download Azetidinone : A bioactive moiety

Mrunmayee Toraskar et al. / Journal of Pharmacy Research 2010, 3(1),169-173
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Azetidinone : A bioactive moiety
Mrunmayee Toraskar*1, Vithal Kulkarni2, Vilasrao Kadam1
Bharati Vidyapeeth’s College of Pharmacy,Department of Pharmaceutical Chemistry,
Sec-8,C.B.D. Belapur, Navi Mumbai 400614,India
2
poona College of Pharmacy, Erandwane, Pune-38,India
Received on: 20-09-2009; Revised on: 14-10-2009; Accepted on:18-12-2009
1
ABSTRACT
2-Azetidinone is a ß-lactam cyclic amide with four atoms in a ring. Traditionally ß-lactam is a part of structure of broad spectrum antibiotic
class of drugs – penicillins and cephalosporins .The ring ultimately is proven to be a generic descriptor for penicillin family. These molecules
operate by forming a covalent adducts with membrane bound bacterial transpeptidases which are also known as penicillin binding proteins
(PBPs), involved in the biosynthesis of cell walls.Cycloaddition of monochloracetylchloride with imine (Schiff base) result in formation of 2azetidinone(ß-lactam).Present work is an attempt to review chemistry, synthesis, spectral studies and applications of 2-azetidinones.
Keywords: 2-Azetidinone, ß-lactam, Cyclic amide, Antibacterial
INTRODUCTION
The chemistry of ß-lactams has taken an important place in
organic chemistry since the discovery of Penicillin by Sir 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 type1. There is a need for functionalized
ß- lactams or for new active principles in ß- lactam series. Apart from
antibiotic activity ß- lactam also possess cholesterol inhibition,
antithrombotic, antiviral and antifungal activities.The 2-azetitinone
(ß- lactams) ring is a common structural feature of a number of broad
spectrum ß-lactam antibiotics including penicillins, cephalosporins,
carbapenems, nocardicin and monobactams which have been widely
used as chemotherapeutic agents to treat bacterial infection and microbial diseases.2,3 These molecules operate by forming a covalent
adduct with membrane bound bacterial transpeptidases which are
also known as penicillin binding proteins (PBPs) involved in the biosynthesis of cell wall.4 These mechanism based inhibitors prevent the
construction of cell wall and eventually lead to cell lysis and death.
Moreover due to their ß- lactamase inhibitory action 2-azetidinones
based heterocycles represent an attractive target of contemporary
organic synthesis.5 It has been reported that introduction of different
substituents to four membered ß-lactam nucleus tend to exert profound influence in conferring promising biological activities.We have
recently reported synthesis and antimicrobial screening of 2-(1Hbenzotriazol-1-yl)-N-[3-chloro-2-(substituted phenyl)-4-oxoazetidin1-yl] acetamide6.
Ezetimibe, 1-(4-fluorophenyl)-3(R)-(3-(4-fluorophenyl) 3(S)hydroxypropyl)-4(S)-(4-hydroxyphenyl)-2-azetidinone, is a selective
cholesterol absorption inhibitor that effectively blocks intestinal absorption of cholesterol. Such drugs prevent the absorption of cholesterol, by inhibiting the passage of dietary and biliary cholesterol across
the intestinal wall. These drugs represent a new class of pharmaceutical agents that can be used to treat patients with hypercholesterolemia. Ezetimibe alone, or in combination with statins, effectively
reduce LDL-C concentrations. It also increases high-density lipoprotein cholesterol (HDL-C), and may reduce elevated triglyceride (TG)
concentrations.
CHEMISTRY OFAZETIDINONES
The name lactam is given to cyclic amides.In older nomenclature second carbon in an aliphatic carboxylic acid was designated
as α ,the third as ß and so on.Thus a ß- lactam is a cyclic amide with
four atoms in its ring.The contemporary name for this ring system is
azetidinone. ß- lactam came to be a generic descriptor for penicillin
family.The ring ultimately proved to be the main component of the
pharmacophore. So the term possesses medicinal as well as chemical
significance.
N
O
H
SPECTROSCOPIC STUDIES
*Corresponding author.
Mrunmayee Toraskar
Bharati Vidyapeeth’s College of Pharmacy,Department of Pharmaceutical
Chemistry,Sec-8,C.B.D. Belapur, Navi Mumbai 400614,India
Tel.: + 91-9867715334
E-mail:. [email protected];[email protected]
I.R.Study
The carbonyl C=O group shows a strong stretching absorption in the region of 1870-1640 cm-1. High intensity and freedom from
Journal of Pharmacy Research Vol.3.Issue 1.January 2010
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Mrunmayee Toraskar et al. / Journal of Pharmacy Research 2010, 3(1),169-173
interfering bands make it the easiest band to recognize in IR spectra.
Also, the position is affected by factors such as electronic and mass
effect of neighbouring substituents, conjugation, hydrogen bonding
and ring strain.7
N.M.R.Study
The chemical shift of the protons at C3 and C4 explains the effect of
the substituents which are attached to these carbons. Electronegative substituents, such as chloro and azido attached to C3 reduce the
electron density around the proton attached to C3 resulting in strong
deshielding effect on this proton. The greater the electronegativity of
the substituent, the more it deshields the proton adjacent to it, and
hence, the greater the chemical shift of this proton8.
2. Wasserman Cyclization
Roger Joyeau et al10 studied the stability of 2-azetidinones to enzymatic ring opening by ß-lactamases. They suggested that a halogen
ß- to the carbonyl would increase the IR absorption of the C=O, one
of the criteria of the reactivity of the ß-lactam in this aspect. Fluorine
substitution, which will not introduce a large steric hindrance, is particularly interesting for a possible biological effect and possible stability towards ß -lactamase. ß -Bromopropionamide derivative (2) was
prepared, which can be cyclized by wasserman procedure using sodium hydride to give the N-(3-carboxy-6-methylphenyl) 3- difluoro-2azetidinone (3).
F
SF4
BrCH2CF2COOEt
BrCH2COCOOEt
ClSO3H
Br
H2NAr
F
Cl
SYNTHETIC METHODS OFAZETIDINONES
O
F
The recent and the advanced increase in both the spectrum of ß –
lactam antibiotics and the number of the known producing organisms
is due to the development of new and more sensitive screening techniques. Further progress had been added by continuous synthetic
derivatization to those monocyclic ß -lactam compounds. Many methods had been reported in the literature. Some of those methods were
listed in this study.
Br
F
F
N
CH3
NaH
F
O
CH3
H
N
O
3
2
HOOC
HOOC
Scheme 2
1. Ketene-imine Cycloaddition
3. Synthesis of ß-Lactams from Imidates
The ketene-imine cycloaddition was reported by Staudinger9 to be a
smooth well-documented route to the synthesis of substituted ß lactam derivatives. In an effort to investigate a suitably substituted
monocyclic ß -lactam as a minimum requirement for biological activity, many scientists reported the trans stereoselective synthesis of
butadienyl azetidinones and their Diels-Alder cycloaddition. This
included the preparation of a series of Schiff’s bases and their reaction with dienylketene to produce a trans azetidinone .This involved
the in situ formation of the ketene and its subsequent addition to the
imine.
Cardellini and his group11 reported the synthesis of alkoxy ß -lactams
via acid chloride imine route. Imidates (4) such as substituted Nphenyl formimidate, were reacted with acid chlorides to produce ß lactam (6). The major feature of this synthesis is its high
stereoselectivity, only trans -4-alkoxy- ß -lactams were formed.
H
TEA
RO-CH=N-C6H5
+
H
OR
X
X-CH2-COCl
N
CH2Cl2
O
4
R
R
O
O
TEA
Cl
+
CH2Cl2
H
H
R1
Scheme 1
6
N
N
R1
Scheme 3
4. ß -Lactam Formation Using Microwave Irradiation
Formation of 2-azetidinones by the reaction of an acid chloride, Schiff’s
base and a triethylamine seems to involve multiple pathways, some
of which are very fast at higher temperatures. When it is conducted in
open vessels in unmodified domestic microwave ovens, high level
irradiation leads to preferential formation of trans ß -lactams in several cases when the Schiff’s base is derived from an aryl aldehyde
rather than glyceraldehydes acetonide.12
MW
PhCH2O-CH2COCl
+
PhCH2O
PhCH=N-CH2Ph
N
Chlorobenzene
O
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Ph
PhCH2O
+
CH2Ph
Ph
N
O
169-173
CH2Ph
Mrunmayee Toraskar et al. / Journal of Pharmacy Research 2010, 3(1),169-173
5. Acid Chloride Addition Reaction
Bose et al13has applied a method to prepare ß-lactams which involved
the reaction between benzylideneaniline and few selected acid .
carbohydrazide with chloroacetyl chloride and triethylamine.The compounds were screened in-vitro for their antimicrobial activity against
S.aureus,P.aeruginosa, A.niger and C.albicans.15
R2
R1
R3
XCH
CHR
2
C H 2X
CH R
R
Cl
NAr
CO Cl
O C
NA r
H
N
O
N
N
O
Cl
O
X
H C
CH R
O C
NAr
E t3 N
H 2C
CH R
O C
NAr
Cl
X
Cl
3.Anand K.Halve,Deepti Bhadauria and Rakesh Dubey studied synthesis and antimicrobial activity of 3 chloro-4-(3-methoxy-4-acetyl
oxyphenyl)-1-[3-oxo-3-(phenylamino) propanamido] azetidin 2-ones
and 3 chloro–4-[2-hydroxy-5- ( nitro substituted phenylazo) phenyl ]16
1- phenylazetidin 2- ones.
X
R2
Cl
H C
CH R
O C
N
X
Ar
CH
O
C H 2R
2
O C
N
O
O
Ar
NH
O
NH N
N
R
Scheme 5
H H Cl
BIOLOGICALACTIVITIES OFAZETIDINONES
H3C
Antibacterial activity.
H H Cl
N N
O
O
O2N
1. Ameya A.Chavan , and Nandini R. Pai reported synthesis of 2{2-[3-chloro-2-(aryl)-4- oxoazetidin-1-ylamino] acetylamino}
benzothiazole-6-carboxylic acid. 2- amino aminobenzothiazole -6
carboxylic acid
on condensation with chloroacetyl chloride
yielded 2- ( 2-chloroacetyl amino) benzothiazole-6- carboxylic acid
which on amination with hydrazine hydrate gave 2- ( 2hydrazinoacetyl amino) benzothiazole-6- carboxylic acid.These
subjected to Schiff reaction in presence of glacial acetic acid
with various aromatic aldehydes.The Schiff’s bases obtained
,upondehydrative annulation in presence of chloroacetyl chloride and triethylamine yielded 2-{2-[3-chloro-2-(aryl)-4- oxo
azetidin-1-ylamino] acetylamino} benzothiazole-6-carboxylic acid.
The compounds were screened for antibacterial activity against
S.aureus, B.subtilis, P.aeruginosa and E.coli14.
O
NH
HOOC
N
N
H
Cl
O
Cl
H
O N N
N
NH
Ar
O
Cl
O
N
4. N.C Desai , M.D Shah & A.M Bhavsar prepared N- ( 3-Chloro-2oxo-4 arylazetidinyl) {4-[5 oxo-2 phenyl- 4- ( phenylmethylene) ( 2imidazolinyl] phenyl} carboxamides and N (3-chloro-2-oxo-4arylazetidin-1-yl)-2-(4-chlorophenyl) acetamides and evaluated for
their antibacterial activity against E.coli and S. aureus in terms of
minimum inhibitory concentration.Also QSAR studies for the compounds were done for structural and physicochemical parameters.17
R
H
Ar
O
O
S
Cl
N
2.Gundibasappa K. Nagaraja,Gowdara K. Prakash,Marlingaplara N.
Kumaraswamy,Vijayavittala P.Vaidya and Kittappa M. Mahadevan
have synthesized N-[3- chloro-2- (2- chloroquinolin-3-yl)-4
oxoazetidin-1-yl] naphtho [2, 1-b] furan -2-carboxamide as antimicrobial agents by reacting Schiff’s bases of naphtho [2,1-b] furan–
N
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Mrunmayee Toraskar et al. / Journal of Pharmacy Research 2010, 3(1),169-173
5.N.C Desai,Dipika Dave,M.D. Shah and G. D Vyas have investigated
the synthesis and antibacterial activity of Methyl 2-{2-[3-chloro-4-oxo1-(4-nitrophenylcarbonylamino)azetidin-2yl]phenoxy}-acetate against
S.aureus and Salmonella typhi.18
O
O
S
Cl
N
O
N
N
R
O
9. (15) K.M Thakar , V.V Kachhadia and H.S Joshi have synthesized
4-Aryl-3-chloro-1-(3’,5’-dichloro-2’benzo (b) thio phenoylamino)-2azetidinones and evaluated their antimicrobial activity against
E.coli, S.aureus, P.vulgaris and A.niger .Also the compounds were
tested for their antitubercular activity against M.tuberculosis H37Rv.22
O
O
O
Ar
N N
H
Cl
Cl
Cl
O
O
N
S
N
Cl
R
Cl
H
O
Anticonvulsant activity
10. S.K Srivastava, S.Srivatsava & S.D Srivastava synthesized 1- [5’(N9- Carbazolylmethyl) - 1’, 3’, 4’- thiadiazole- 2-yl)]- 4-substituted -3
chloro-2 oxo- azetidines.The compounds were screened for their anticonvulsant activity and anti-inflammatory activity at 50 mg/kg 23
R
O
H
N N
H
S
6. 4,4’-Bis(3-chloro-4-(4-methyl phenyl)-2-oxo-azetidin-1-yl)diphenyl
sulphone have been synthesized and screened for in-vitro antifungal and antitubercular activity by P.D.Mehta, N.P.S.Sengar et al 19
R
O
Cl
O
O
O
N
N
Antitubercular activity
Ar
N
S
7.4 Aryl-3-chloro-1- (benzimidazole-2yl-benzamido)-2- azetidinones were
studied by Preeti Kaythara, Tejas Upadhayay, Rajeev Doshi and H.H
Parel and tested in-vitro for their antitubercular activity against
M.tuberculosisH37Rv.20
N
O
Cl
Anticancer activity
11.Robert M. Adlington, Jack E. Baldwin, Gerald W. Becker, Beining
Chen, Leifeng Cheng, Stephen L. Cooper, Robert B. Hermann, Trevor
J. Howe, William McCoull, Ann M. McNulty, Blake L. Neubauer, and
Gareth J. Pritchard synthesized and studied prostate specific antigen
inhibiting activity of 2-azetidinones.24
N
N
H
O
R
N
H
O
N
Cl
8. Khyati A Parikh, Paresh S.Oza , SB Bhatt and A.R Parikh studied
synthesis of 4- aryl -1-(4’-a-methoxyimino-carbmethoxy methyl
thiazol-2’-yl)-3-chloro- 2- azetidinones and evaluated the compounds
for their antitubercular activity against M. tuberculosisH37Rv.21
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Antiviral activity
12. Alan D. Borthwick, Gordon Weingarten, Terry M. Haley, Mirek
Tomaszewski , Wei Wang , Zhouhan Hu Jean Bedard , Haloun Jin ,
Leonard Yuen , Tarek S. Mansour studied design and synthesis of
monocyclic ß-lactams as mechanism based inhibitors of human cytomegalovirus protease which have been shown to acylate the viral
enzyme in a time dependant manner.25
R1
8.
9.
10.
11.
12.
OAc
R2
7.
13.
N
NHR4
O
14.
O
15.
C.N.S.Activity
16.
13.Rajesh K Goel, Amanpreet Singh, Pattipati S Naidu, Mohinder P
Mahajan, Shrinivas K Kulkarni studied some azetidin-2-ones as C.N.S
modulating agents which were previously synthesized and evaluated for hypolipidemic and antihyperglycemic activity based on the
predictions made by the computer software “Prediction of Activity
Spectra for Substances (PASS)”.26
17.
18.
CONCLUSION
19.
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 diverse biological activities such as antimicrobial, antiviral, anticancer,
cholesterol absorption inhibition and enzyme inhibition. 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.
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Source of support: Nil, Conflict of interest: None Declared
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