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Mass Spectral and Antimicrobial Studies of the Benzofuran Analog of Chloramphenicol.

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162
Bevinakarti and Badiger
Arch. Pharm.
3 V.I. Kuznetsov, J. Gen. Chem. USSR 9,2263 (1939); C.A. 34,5052 (1940); J. Gen. Chem. USSR
16, 187 (1946); C.A. 41, 443 (1947).
4 L.M.Venzani, J. Chem. SOC.1958, 719.
5 E.D. Thorsett und F.R. Stermitz, J. Heterocycl. Chem. 10, 243 (1973).
6 H . Schmid und P. Karrer. Helv. Chim. Acta 32, 960 (1949).
7 J. Knabe, Pharmazie 20, 741 (1965).
8 J. Knabe und A. Ecker, Arch. Pharm. (Weinheim) 312, 273 (1979).
9 F.H.Case, J. Am. Chem. SOC.68, 2574 (1946).
[Ph 2561
Arch. Pharm. (Weinheim) 314, 162-167 (1981)
Mass Spectral and Antimicrobial Studies of the
Benzofuran Analog*)of Chloramphenicol**
Hanamanthsa S. Bevinakatti and Virupax V. Badiger’
Department of Chemistry, Karnatak University, Dharwad-580003, India
Eingegangen am 8. April 1980
1-(2-Benzofuranyl)-2-(dichloroacetamido)propane-l,3-dio11)breaks down in a well-defined manner
upon electron impact. The principal ions formed are characterised and the most plausible mechanism
of their formation is discussed. The results of in vitro antibacterial and antifungal screening of the
benzofuran analog of chloramphenicol as well as its two precursors are reported.
MS- und antimilrrobielle Untersuchungen des Benzofuran-Analogen des Chloramphenicols
2-Dichloracetamido-l-(Z-benzofuranyl)propan-l
,3-dio11)fragmentiert unter ElektronenstoS in definierter Weise. Die Hauptionen werden charakterisiert und ihr Bildungsmechanismus wird diskutiert.
Die Ergebnisse der antibakteriellen und fungistatischen in vitro Testung des Benzofuran- Analogen des
Chloramphenicols und seiner 2 Vorstufen werden mitgeteilt.
Although the mass spectrum of the parent antibiotic chloramphenicol has been reported in the
literature*) , its detailed mass spectral fragmentation pattern remains unexplored. In view of this, our
interest was aroused to study in detail, the mass spectrum of the benzofuran analog of
chloramphenicol prepared by us”.
The electron impact fragmentation of 2-dichloroacetamido-l-(2-benzofuranyl)propane-1,3-diol becomes an interesting subject of study by virtue of the number and variety of
fragments formed. Because of the branching as well as the larger size of the side-chain, it is
possible to have several modes of fragmentation, which can be well explained by different
* * Part of the thesis submitted by H.S.Bevinakaiti to Karnatak University, Dharwad-3, India
1980.
0365-6233/81/02M-0162S M M/O
0 Vcrlag Chcmie, GmbH, Weinheim 1981
Benzofuran Analog of Chloramphenicol
314181
163
schemes as described below. In addition, the observation of the corresponding peaks in the
mass spectrum of chloramphenico12) , confirms the fragmentation pattern suggested
here.
Results and Discussions
Unlike the mass spectrum of chloramphenico12),the molecular ion (M:)peakinthemass
spectrum of the benzofuran analog of chloramphenicol appeared at an ionising potential of
70eV. However, this peak at m/e 317 has a relatively lower abundance (2 % of the base
peak). The (M+ 1) peak at m/e 318, with an equal abundance as that of the molecular ion,
also was found.
Scheme A : The principal fragmentation occurs according to the known method of fragmentation of
secondary alcohols to expel the largest substituted fragment most readily, thus giving the most
abundant (100 %) even electron ion In, which constitutes the base peak at m/e 147. The stability of the
ion I, is due to its various resonating structures like In, Ib, Ic etc, which can be seen in the other
schemes also.
The side-chain fragment 11, appears at a relatively lower abundance at d e 170. This olefinic ion, in
turn, can lose a molecule of C12C=C=0 by the cleavage of the amide bond with the hydrogen
transfer, to give another odd electron ion IU, which forms an interesting peak at d e 60.
Scheme A
l+*
P
NH-C-CHC~,
@ ( $ & H - C OH
H,OH
'
M+'m/e 317
E
Q
C
H
+AH
Ia m / e 147
+/y'
HSq-CCl'
HC,
CHzOH
I I m / e 170
-EH-CH,OH
+NH,
-CCIPGO
IIIm/e 60
Scheme B: The "new bond formation" McLafferty type rearrangements leading to a loss of the smaller
fragments like H,O, HCI etc, even without the involvement of any double bond in the rearrangement
are quite common in the mass spectrometry of organic molecules" . A rearrangement of this type may
take place in the molecular ion by the homolytic cleavage of three bonds, combined with the loss of
one molecule water, thus resulting in the two fragments IV and V. The olefin IV thus obtained by a
new n-bondformation, competes with the other fragment V for the positive charge.')Thisolefinicodd
electron ion, on homolytic cleavage of the C-C bond, results into two even electron ions VI and Vn.
The ion VU, due to the isotopic characters of two chlorine atoms, constitutes three peaks at m/e 83.85
and 87 at the known ratio of 9 :6 : 1.
164
Bevinakacti and Badiger
Arch. Pharm.
The other odd electron ion V,obtained after rearrangement, forms a peak of high intensity (62 % of
the base peak) at m/e 146. Once this ion is formed, the peaks at m/e 145,118,117,90,89 and 63 can be
readily explained by the fragmentation pattern which is already known.4) .
Scheme C: The possibilities of a McLafferty rearrangement') involving the transfer of a hydrogen from
the methylene group to the n-bond of the aromatic furan ring are also present in the molecular ion,
thus leading to the odd electron ion XIVs.The ion XIVa may either lose a H-radical to give Ib or it
may produce the odd electron ion XV by losing carbon monoxide through its resonating structure
XI-. The ion XV undergoes further fragmentations according to the known splitting pattern 4, to
yield the ions XVI, XVII, XVIU,XIX and XX.
Scheme B
l+*
Mt'
I
-Hi0
I V m / e 153, 155
V m / e 146
VII
m / e 83, 85, 87
FCH-NH-C=O+
H2
1
a
'
+
*
-"/
V I I I m / e 145
X
m / e 118
-CHKH
X I U m / e 63
XI1 m / e 89
Scheme D: Production of the odd electron ion XIV, which has been seen in scheme C, can also be
explained by another type of hydrogen rearrangement which is likely to occur. This rearrangement
involves the migration of the hydrogen from the same methylene group (as that seen in scheme C), but
314181
Benrofuran Analog of Chloramphenicol
165
this time to the oxygen of the furan ring with concurrent elimination of the neutral olefin and thus
resulting in the formation of the radical ion which rearranges to give the odd electron ion MVc which
is the resonance structure of XIVn and X I M ? )
Scheme C
l+*
AH
M+'
Ib m / e 147
XIVa m / e 148
XIVb
-H'
f--
6H
Ic m / e 1 4 7
XIVc m / e 148
166
Arch. Pharm.
Bevinakatti and Badiger
Experimental
The mass specrrurn was recorded on a CEC 21-ll0B mass spectrometer at an ionising potential of
70eV. using a direct inlet system at 150”.
100
-
90 -
80 70 w
60
-
c
m
:
50
n
a
“0
W
m
-
30 20 10 -
0-
1-1
,1
I
50
70
I
90
1
i
110
L
130
150
170
190 210
m /e
230 250
270
290
310
Antimicrobial studies
The following compounds were tested for their antibacterial and antifungal activities.
Dichloroacetamidomethyl2-benzofuranylketone (l),2-dichloroacetamido-3-hydroxy-l-(2-benzofurany1)-1-propanone (2) and D~-threo-2-dichloroacetamido-1-(2-benzofuranyl)-propane-1,3-diol(benzofuran analog of chloramphenicol) (3).
~ C O - C H ~ - N H C O C H C 1 2
NHCOCHCI,
m C d H - C H 2 0 H
1
2
NHCOCHClz
~ C H O H - A H - C H ~ O H
3
In vitro bacterial inhibition studies were carried on the above cited three compounds using the
following oragnisms: Bacillus subtilis, Sarcina lutea, Staphylococcus aureus, Aerobacter aerogenes,
Escherichia coli, Klebsiella pneumoniae, Proteus vulgaris, Pseudomonas aeruginosa and Salmonella
entiritidis. The tests were carried out according to the cup-plate method, the diameter of each cup
being 10mm. To each cup, 0.1 ml (50pg) of the drug solution (in dimethylformamide) was added.
314181
167
Benzofuran Analog of Chloramphenicol
After 24 h. the diameter of the zone of inhibition was measured. Chloramphenicol was used as a
standard. The results are summarized in Table 1. All three compounds have shown activity against all
nine micro-organisms used. Especially against E. coli and P. aeroginosa, they are as active as
chloramphenicol.
Table 1: In vitro antibacterial activity
~
~~
~
Diameter of zone of inhibition after 24 hrs (mm)
Comp.
Nr.
1
2
3
Stand.
E
B
S
S
A
subtilis
lutea
aureus
aerogenes coli
24
24
26
35
26
25
21
47
12
19
21
37
20
17
17
42
34
34
34
36
K
P
pneuvulmoniae garis
19
19
21
50
23
22
26
40
P
S
aeruginosa
entiritidis
24
22
21
18
12
16
20
25
The in vitro antifungal tests of 1,2 and 3, were carried out by using Candida albicans and Aspergillus
niger, according to the turbidity method. The drug concentration was the same as that used for
antibacterial testing, and after 48 h, the extent of inhibition was determined by measuring the decrease
in turbidity in terms of percent transmission at 660nm. The Sabouraud's medium was used as an
organism-free control and the inoculated medium with no drug was used as a drug-free control.
The compound 1 showed better activities against both the fungi (percent transmission, 50-75) than the
other two compounds 2 and 3 (percent transmission, 25-50).
One of us (H.S.B) is grateful to the Council of Scientific and Industrial Research, New Delhi, for a
research fellowship. Thanks are also due to Dr. B.G. Pujar for his help in carrying out the
antibacterial testings.
References
1 H.S. Bevinakatti and V.V. Badiger, J. Heterocycl. Chem. 17,613 (1980).
2 C. Brunnee, G. Kappus and K.H. Maurer, Z. Anal. Chem. 232, 17 (1967).
3 F. W. McLafferty, Interpretation of Mass Spectra, 2nd Ed., p. 57-74, W. A. Benjamin, Inc.,
London 1973.
4 B. Willhalm, A.F. Thomas and F. Gautschi, Tetrahedron 20, 1185 (1964).
5 K. Heyns, R. Stute and H. Scharmann, Tetrahedron 22, 2223 (1966).
[Ph 2571
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