Synthesis and antimicrobial activity of some isoindolin-1-ones derivatives

Article abstract of DOI:10.1016/S0960-894X(00)00306-1

A range of N-substituted isoindolin-1-ones was prepared and their potential as novel antimicrobial agents was investigated. MIC values for active compounds were determined and reported. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0960-894X(00)00306-1

Bioorganic & Medicinal Chemistry Letters 10 (2000) 1629±1631
Synthesis and Antimicrobial Activity of Some Isoindolin-1-ones
Derivatives
Jaco C. Breytenbach,a Sandra van Dyk,a,* Ilse van den Heever,a Steven M. Allin,b
Claire C. Hodkinson,c Christopher J. North®eldc and Micheal I. Pagec
aSchool of Pharmacy, Potchefstroom University, Potchefstroom 2520, Republic of South Africa
bDepartment of Chemistry, Loughborough University, Loughborough, Leicestershire, LE11 3TU, UK
cDepartment of Chemical and Biological Sciences, The University of Hudders®eld,
Queensgate, Hudders®eld, HD1 3DH, UK
Received 13 March 2000; accepted 17 April 2000
AbstractÐA range of N-substituted isoindolin-1-ones was prepared and their potential as novel antimicrobial agents was investigated.
MIC values for active compounds were determined and reported. # 2000 Published by Elsevier Science Ltd.
N-Substituted isoindolin-1-one derivatives have generated
considerable interest lately as they have been reported
as having diverse biological activity. Compound 1, for
instance, is an inhibitor of thromboxane A2-induced
vasoconstriction,1 and compound 2 is a potential anti-
psychotic agent due to its action as an antagonist of
dopamine D2 and serotonin 5-HT2 receptors.2 Other
examples of biologically active isoindolinones include
anxiolytics and reverse transcriptase inhibitors.3,4
As we recognised the g-lactam functionality contained
within the N-substituted isoindolin-1-ones, it was inter-
esting to note the report on lactivicin (3), a monocyclic
g-lactam isolated from Empedobacter lactamgenus and
Lysobacter albus, as having b-lactam-like biological
activity. Lactivicin is moderately active against Gram
negative bacteria, highly active against Gram positive
bacteria, but inactive against fungi.5
In addition two bicyclic g-lactams (4a and 4b) derived
from penems were found to have low but demonstrable
activity against a wide range of Gram positive and
Gram negative bacteria.6
In this communication we wish to report the synthesis
We wished to further explore the diverse biological activity
of the N-substituted isoindolin-1-ones and as there have
been reports of g-lactams having antimicrobial activity5,6
(vide infra), a range of N-substituted isoindolin-1-ones
were synthesised and subjected to antimicrobial testing.
and antimicrobial activity, expressed as minimum inhibi-
tory concentrations (MIC values) of N-substituted iso-
indolin-1-one derivatives 5, 6, 7 and 8 and present them as
a novel class of bicyclic aromatic g-lactam antibacterial
compounds.
Compounds 5a±j (Table 1) were prepared by re¯uxing
the corresponding amino acid with o-phthalaldehyde in
*Corresponding author. Tel.: +27-18-299-2267; fax.: +27-18-299-
2284; e-mail: fchsvd@puknet.puk.ac.za
0960-894X/00/$ - see front matter # 2000 Published by Elsevier Science Ltd.
PII: S0960-894X(00)00306-1

1630
J. C. Breytenbach et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1629±1631
acetonitrile. After 12 h the hot reaction mixture was ®l-
tered to remove unreacted amino acid and on cooling the
desired isoindolin-1-one crystallised and could be iso-
lated simply by ®ltration. Yields ranged from 33±87%.7
Table 2. Structures of inactive compounds
Compound
R
Con®guration
6a
(S)
6b
6c
8a
8b
8c
(R,S)
(3R)
(3S)
Compounds 6a±c (Table 2) were prepared by combining
the corresponding amino acid with o-phthalaldehyde in
either acetonitrile, chloroform or diethyl ether with cataly-
tic amounts of acetic acid at temperatures ranging from
0±80 ꢀC. Yields of 70±78% were obtained.8
Compound 7 (Table 1) was prepared by adding the
corresponding primary amine to phthalaldehyde acid
Table 1. MIC values (mg/mL) of N-substituted isoindolin-1-ones
Compound
R
Con®guration
B.s.a
M.r.b
S.a.c
E.c.d
P.a.e
5a
5b
5c
(S)
(R)
(S)
0.729
0.328
0.729
1.62
2.61
2.61
1.62
1.62
3.6
1.62
3.6
3.6
3.6
3.6
1.62
5d
5e
(S)
(S)
0.147
1.62
2.61
1.62
3.6
3.6
0.729
1.62
1.62
3.6
5f
(R)
1.62
1.62
3.6
3.6
3.6
3.6
3.6
3.6
3.6
5g
(R,S)
0.729
5h
5i
(R,S)
(S)
0.729
0.529
1.175
0.729
3.6
1.62
1.62
3.6
3.6
Zero growth
inhibition
5j
(S)
1.175
2.61
1.62
Zero growth
inhibition
Zero growth
inhibition
3.6
3.6
3.6
7
(R,S)
Zero growth
inhibition
2.61
DMSO controls
Zero growth
inhibition
Zero growth
inhibition
Zero growth
inhibition
Zero growth
inhibition
Zero growth
inhibition
aB.s.=Bacillus subtilis.
bM.r.=Micrococcus roseus.
cS.a.=Staphylococcus aureus.
dE.c.=Escherichia coli.
eP.a.=Pseudomonas aeruginosa.

J. C. Breytenbach et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1629±1631
1631
chloride and triethylamine in chloroform. The reaction
mixture was left overnight at room temperature and then
extracted with dilute hydrochloric acid. The chloroform
solution was dried over anhydrous potassium carbonate
and concentrated. Puri®cation was achieved by recrys-
tallisation from chloroform±ether mixtures. Yields of
45±50% were obtained.9
showed no antibacterial activity in the initial screening
test.
Compounds 5a±j and 7 exhibited antimicrobial activity
similar to b-lactam antibiotics (MIC values for ampicillin
and amoxycillin ranges from 0.02.0 mg/mL) and other
g-lactams such as the monocyclic lactivicin5 and the
bicyclic penems (4a and b).6 Lactivicin and the bicyclic
penems (4a and b) had activity against Gram positive
and Gram negative bacteria but not against fungi. This
corresponds well with the results obtained with the N-
substituted isoindolin-1-one compounds tested in this
study.
Compounds 8a±c (Table 2) were prepared by re¯uxing
the corresponding amino alcohol and 2-formylbenzoic
acid under Dean±Stark conditions in toluene for 12 h.
Puri®cation was achieved by ¯ash chromatography with
diethyl ether/light petroleum ether mixtures as eluents.
Yields of 70±72% were obtained.10
In conclusion, we report that N-substituted isoindolin-1-
ones derived from available amino acids constitute a novel
class of bicyclic aromatic g-lactam antibacterial agents,
with the carboxylic acid derivatives displaying the greatest
activity.
Compounds 5±8 were subjected to in vitro microbiological
testing and determination of MIC values.
Antimicrobial activity was determined by using the direct
agar plate technique.11 A range of Gram positive and
negative bacteria, an Aspergillus sp and Candida albicans
were used in the initial screen. Substances 5a±j and 7 were
found to be active against Gram positive as well as Gram
negative bacteria with only substance 8a having activity
against the Aspergillus sp. and Candida albicans. Structures
of inactive compounds are given in Table 2.
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The COOH functional group present in compounds
5a±j seems to be necessary for antibacterial activity for
that speci®c series as compounds 6a±c lacking this
group but similar in structure to compounds 5a±j