Antibacterial activity of some 5-dialkylaminomethylhydantoins and related derivatives

Article abstract of DOI:10.1248/cpb.c13-00461

In connection with our studies on antibacterial compounds in the class of 5-dialkylaminomethylhydantoins against Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) strains, some molecular modifications were attempted. The antibacte

Full text of DOI:10.1248/cpb.c13-00461

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Note
Chem. Pharm. Bull. 61(10) 1090–1093 (2013)
Vol. 61, No. 10
Antibacterial Activity of Some 5-Dialkylaminomethylhydantoins and
Related Derivatives
Fumiko Fujisaki, Keiko Toyofuku, Mayu Egami, Shiori Ishida, Naho Nakamoto,
Nobuhiro Kashige, Fumio Miake, and Kunihiro Sumoto*
Faculty of Pharmaceutical Science, Fukuoka University; Nanakuma, Jonan-ku, Fukuoka 814–0180, Japan.
Received June 11, 2013; accepted July 23, 2013
In connection with our studies on antibacterial compounds in the class of 5-dialkylaminomethylhydan-
toins against Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) strains, some
molecular modifications were attempted. The antibacterial activities of all of the synthesized hydantoin de-
rivatives were evaluated. Among the hydantoin derivatives designed in this study, C2-symmetrical twin-drug
type compound (7) showed the highest level of antibacterial activity against S. aureus strain.
Key words hydantoin; antibacterial activity; C2-symmetrical twin-drug; Escherichia coli; Staphylococcus
aureus; β-aminoalanine
Since bacteria can develop resistance to generally used tural isomers of oxazolidin-2-ones as a general structure (A)3)
antibacterial agents, resulting in the generation of various or a bioisosteric replacement6) of the oxazolidinone ring in
drug-resistant bacteria strains, the development of new anti- linezolid7) by a hydantoin nucleus (B) (Fig. 1). Among previ-
bacterial agents is required. In the early invasion stage of ously synthesized target hydantoin derivatives (B), we found
bacteria such as Escherichia (E.) coli, cell surface glycans of that many 5-dialkylaminomethylhydantoin derivatives showed
bacteria recognize host cell lectin. For such recognition by a wide range of remarkable antibacterial activities (minimum
glycans, the major recognition patterns between the host and inhibitory concentration (MIC) values in a sub-micro molar
guest molecules are thought to be intermolecular hydrogen range) against both Staphylococcus (S.) aureus and E. coli
bonding interactions. This interaction process is a logical path strains. This finding encouraged us to investigate further mo-
and is thought to control biological response. We have been lecular modifications of this class of compounds. We therefore
interested in molecules that interfere with such carbohydrate carried out additional synthetic investigations of newly de-
recognition stages in order to find new antibacterial leads.
signed 5-dialkylaminomethylhydantoin derivatives.8)
In connection with our studies on antibacterial compounds,
In this article, we present results of biological evaluation
we have already reported some molecular designs, synthesis for antibacterial activity of these new 5-dialkylaminomethyl-
and biological evaluations of a few heterocyclic compounds or 3-substituted hydantoin derivatives with E. coli and S. aureus
various types of functionalized symmetrical molecules.1–5) In strains.
our previous articles on chemical modifications of linezolid,
Antibacterial Activity and Discussion Many tested hy-
we reported synthesis and antibacterial activity of new struc- dantoin derivatives showed significant antibacterial activity
Fig. 1. Structures of A, B and Linezolid
The authors declare no conflict of interest.
© 2013 The Pharmaceutical Society of Japan
*To whom correspondence should be addressed. e-mail: kunihiro@adm.fukuoka-u.ac.jp

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Table 1. Antibacterial Activities of Target Hydantoin Derivatives (3–7)
Antibacterial activity MIC (mM)
Compound
Antibacterial activity MIC (mM)
Compound
E. coli
S. aureus
E. coli
S. aureus
0.113
0.226
0.216
>0.432
>0.513
>0.344
>0.513
>0.344
0.367
>0.733
>0.332
>0.332
>0.364
0.091
0.088
0.048
0.104
0.097
0.044
>0.416
>0.366
>0.366
0.190
0.190
>0.206
0.051
0.095
0.024
a) Data were taken from ref. 6.
against both E. coli (Gram-negative) and S. aureus (Gram- tion product (5) showed a weaker antibacterial activity (MIC=
positive) at concentrations of 0.024–0.226mM. 0.367mM) only against E. coli than those of 3a and 3b (see
Among the 3-(2-chloroethyl)-substituted new hydantoin de- Table 1).
rivatives (3a,b, 4, 5) listed in Table 1, compound (3a) showed
N(1)-Unsubstituted hydantoin derivatives (3c–e) that have a
the highest antibacterial activities against both of E. coli sterically bulky aryl ring such as a biphenyl or naphthyl group
and S. aureus strains (MIC=0.113, 0.226mM, respectively), at the N(3)-position of the hydantoin ring generally showed
but the levels of its activity were lower than those of 3-p- lower levels of activity than those of 3-chlorosubstituted phe-
chlorophenyl-substituted derivatives (3f)6) reported previously. nyl derivatives (3f,g) except for compound 3e. Compound 3e
3-Chloroethyl-5-disubstituted hydantoin (4) did not show any showed notable antibacterial activity against S. aureus (MIC=
remarkable antibacterial activity against either E. coli and S. 0.091mM). Through these structural modifications by the in-
aureus strains at a concentration of 0.513mM. The deamina- troduction of a sterically bulky aromatic ring, no significant

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Vol. 61, No. 10
Chart 1. Synthesis of 5-Dialkylaminomethylhydantoins 3 and 7
potentiating effect of antibacterial activity was observed.
roethyl derivatives (3a,b) at the N(3) position of a hydantoin
Among the compounds described in this paper, it is note- ring also seem to indicate the importance of a substituent at
worthy that the introduction an N(1)-methyl group on the hy- the N(3) position in the hydantoin ring together with the na-
dantoin nucleus resulted in decreases in antibacterial against ture of substituents such as lipophilic properties.
both E. coli and S. aureus. For example, compound 3f showed
At present, we have no clear evidence that these types of
an MIC value of 0.048mM against E. coli, but the correspond- hydantoin derivatives have the same mode of antibacterial
ing N(1)-methylated derivative 3h had decreased activity action as that of linezolid. However, to obtain some identical
(MIC=0.104 mM). A similar decrease in activity to S. aureus information on the mode of antibacterial activity for the target
was also observed. This peculiarity of structure indicates molecules as well as to confirm the usefulness of this hydan-
that the N(1)-H moiety in the hydantoin ring in the molecule toin scaffold for antibacterial efficacy, further synthetic trials
plays an important role in the action for antibacterial activity. of new hydantoin derivatives including new types of C2-sym-
Compared with the structure of linezolid, we have pointed out metrical twin-drug type derivatives containing other linkers
in our previous paper that the bioisosteric hydantoin nucleus6) are being conducted. Regarding sugar recognition properties
has a characteristic functional group (N-H) for acting as a of highly bioactive twin-drug type compounds such as 7 and
hydrogen bonding donor in the 5-membered hydantoin ring 6, we are also planning to carry out calorimetric experiments
system. The results obtained for the new N(1)-methyl hydan- with sugar derivatives.
toin derivatives (3h–j) by a bioisosteric modification seem to
provide useful information regarding the importance of the
presence of a functional group acting as a hydrogen bonding
donor in the molecule for antibacterial activity.
Experimental
Synthesis of Target 5-Dialkylaminomethyl-3-substituted
Hydantoins and Related Compounds According to the
Symmetrical twin-drug type molecules,9,10) in general, are procedure reported in our previous paper,8) we prepared target
expected to produce more potent and/or selective biological 5-dialkylaminomethyl-3-aryl-hydantoins (3) by cyclization of
activities stemming from the ligand pharmacophore. The two urea intermediates (2), which are easily obtained from the
identical ligands could bind to the same receptor or enzyme reaction of β-aminoalanine ester derivatives (1) with isocya-
sites simultaneously. From this well-known conception of nates. Compound (7) was also prepared by double cyclization
identical twin-drugs, further molecular modifications of this of symmetrical intermediate (6) as shown in Chart 1. The
class of hydantoins to twin-drug type molecules seemed to be structures of these compounds have been shown in detail in
interesting in the search for new leads. We therefore attempted our previous paper. Compounds (3a,c,e, 7) were used as hy-
synthesis and antibacterial evaluation of a twin-drug type drochlorides for antibacterial activity assay.
molecule (7) having a diphenylmethane moiety as a linker (see
Assay for Antibacterial Activity We used S. aureus
Table 1). The C2-symmetrical compound 711) showed the high- ATCC6538P and E. coli NBRC14237 (NIHJ) (Gram-positive
est level of antibacterial activity (MIC=0.024mM) against S. and Gram-negative bacteria, respectively) as target organ-
aureus and also a high level antibacterial activity against E. isms. Synthesized compounds (3–7) were dissolved in di-
coli (Gram-negative) (MIC=0.095mM).
methyl sulfoxide (DMSO) to a concentration of 1.280µg/mL.
The intermediate C2-symmetrical urea derivative (6) as a The minimum inhibitory concentration (MIC) of a standard
precursor to the compound (7) also showed significant anti- strain was measured by the authentic microdilution method
bacterial activity (MIC=0.051mM) only against S. aureus.
to monitor the bacterial growth turbidity in Muller–Hinton
As structural factors for antibacterial activities in this se- broth according to the Japanese Society of Chemotherapy.12,13)
ries, the results obtained suggest not only the state of an elec- The values of MIC for target compounds determined by this
tric charge of an introduced aryl ring but also the contribution authentic MIC method, as well as those of previously reported
of a rotational isomer8) about the C–N pivot bond connecting compounds (3f,g) for comparison, are summarized in Table
the two ring systems (see 3e or 3j). The results for 2-chlo- 1. The values of MIC are expressed as molar concentrations

October 2013
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Academic Press, San Diego, 2008 and related references cited
therein.
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References and Notes
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11) The obtained compound
13C-NMR in DMSO-d6, indicating little difference with respect
to the signal assignable to substituted hydantoin rings and
7 exhibited very simple symmetrical
a
linker diphenylmethane moiety. From a stereochemical viewpoint,
however, product 7 can be considered to be a mixture of three
twin-drug type molecules, i.e., two C2-symmetrical molecules that
have the same absolute configuration (R,R or S,S) regarding two
chiral hydantoin rings in the molecules and a Cs-symmetrical meso
compound having different absolute configurations (R,S). We dis-
tinguished the presence of three predominant stereoisomers in the
free base of product 7 by an HPLC method (CHIRALPAK IA®)
with a mobile phase consisting of n-hexane–2-propanol–diethyl-
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