Quaternary ammonium N,N-dichloroamines as topical, antimicrobial agents

Article abstract of DOI:10.1016/j.bmcl.2009.03.120

A series of backbone modified and sulfonic acid replacement analogs of our topical, clinical candidate (iii) were synthesized. Their antimicrobial activities and aqueous stabilities at pH 4 and pH 7 were determined, and has led us to identify quaternary ammonium N,N-dichloroamines as a new class of topical antimicrobial agents.

Full text of DOI:10.1016/j.bmcl.2009.03.120

Bioorganic & Medicinal Chemistry Letters 19 (2009) 2731–2734
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Quaternary ammonium N,N-dichloroamines as topical, antimicrobial agents
Charles Francavilla, Eddy Low, Satheesh Nair, Bum Kim, Timothy P. Shiau, Dmitri Debabov, Chris Celeri,
*
Nichole Alvarez, Ashley Houchin, Ping Xu, Ron Najafi, Rakesh Jain
NovaBay Pharmaceuticals Inc., 5980 Horton St. Suite 550, Emeryville, CA 94608, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of backbone modified and sulfonic acid replacement analogs of our topical, clinical candidate (iii)
were synthesized. Their antimicrobial activities and aqueous stabilities at pH 4 and pH 7 were deter-
mined, and has led us to identify quaternary ammonium N,N-dichloroamines as a new class of topical
antimicrobial agents.
Received 23 February 2009
Revised 20 March 2009
Accepted 25 March 2009
Available online 28 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
N-Chloroamaines
Antimicrobial agents
Taurine
Minimum bactericidal concentration
Quaternary ammonium
The problem of the growing resistance to current antibiotics has
led pharmaceutical programs to identify new classes of therapeutic
agents, instead of improving the potency or spectrum of existing
classes. This change in direction was driven by the increasing prob-
lem of multi-drug resistant pathogens. Therefore, there is an ur-
gent need for antimicrobial agents that function with unique
mechanism-of-actions, which do not show cross resistance with
existing antibacterials.
properties. This first study suggested that a dimethyl substitution
on the carbon linked to the dichloroamino group was critical for
aqueous stability of this class of compounds, but surprisingly, lar-
ger alkyl, heteroalkyl, cycloalkyl and heterocycloalkyl groups re-
sulted in poor stability. This second study suggested that an
ethyl spacer between the N,N-dichloroamino and sulfonic acid
groups was optimal in the taurine series. Therefore, we have
turned our focus towards modifications to the backbone and
replacement of the sulfonic acid to identify drug-like molecules
in this series to address the key issue—aqueous stability—for these
compounds.
We expected that our initial lead could be further optimized for
aqueous stability, topical antimicrobial potency and in vivo effi-
cacy by suitable structural modifications. Our earlier study4 sug-
gested that the ester modification in the backbone looked
promising and maintained antimicrobial activity (Fig. 1).
H H
N
H H
Me Me
N
Cl
SO3Na
Cl
SO3Na
Cl
SO3Na
N
Cl
Cl
H
i
iii
ii
Nagl and co-workers1 had extensively studied the bactericidal,
fungicidal, and virucidal activity as well as the clinical safety of
N-chlorotaurine (i). Since this class of compounds has a non-spe-
cific mechanism of action, there is a low potential for the develop-
ment of resistance. 2-Dichloroamino-2-methyl-propane-1-sulfonic
acid sodium salt (iii),2 a stable derivative of endogenous 2-chloroa-
mino-ethane-1-sulfonic acid sodium salt (i) and 2-dichloroamino-
ethane-1-sulfonic acid sodium salt (ii), has been identified and is
currently under development as a topical, broad-spectrum antimi-
crobial agent.
In this Letter, we report the design, synthesis, stability and bio-
logical activity of a series of backbone modified and sulfonic acid
replacement analogs (Fig. 2) of compound iii. Various syntheses
for the preparation of these compounds are outlined in Schemes
1–7. This paper describes the structure–activity relationship and
In our earlier studies in this class, a limited number of analogs
with b-substitutions3 and backbone modifications4 were prepared.
The structure stability/activity relationships (SSR/SAR) were evalu-
ated to identify therapeutic agents with altered physiochemical
O
H
N
Cl
O
Cl
SO3H Cl
SO3H
SO3H
N
Cl
N
Cl
N
Cl
O
O
iv
1/2 = 2.5 h
*Stability was performed in water (pH 4) at 40 ºC
v
vi
12 h
t
t1/2
=
t1/2 = >95 days
* Corresponding author. Tel.: +1 510 899 8871; fax: +1 510 740 3469.
E-mail address: rjain@novabaypharma.com (R. Jain).
Figure 1. Previous SSR in backbone modification.
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.03.120

2732
C. Francavilla et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2731–2734
X
Cl
( )m
( )n
N
Cl
W
Figure 2. SSR/SAR in N,N-dichloroamine series.
structure–stability relationship of backbone modification (X) and
sulfonic acid replacement (W) in N,N-dichloroamine series.
The syntheses of the amide and ester analogs of the N,N-dichlo-
roamines began with the commercially available 3,3-dimethylac-
rylic acid 1 (Scheme 1). This acrylate was used in a conjugate
addition to give a previously synthesized azide.5 Hydrogenation
of the azide yielded the amine,6 followed by Cbz-protection to give
the common intermediate (2). The Cbz-protected 3-amino-3-
methylbutanoic acid was reacted with carbonyldiimidazole to give
an imidazolide intermediate, which was treated with either an
amine or alcohol.7 Treatment with 2-aminoethanol and 2-(methyl-
amino)ethanol, followed by a Mitsunobu esterification reaction8
with thioacetic acid gave amides 3 and 4. Treatment of the imi-
dazolide intermediate with N,N,N’-trimethylethylenediamine, fol-
lowed by methylation gave the ammonium salt 5; while
treatment with 1-(2-hydroxyethyl)piperidine and methyl iodide
gave the ester 6. The oxidation of thioacetates 3 and 4 to the sul-
fonic acids9 followed by N-deprotection and N,N-dichlorination
with t-butyl hypochlorite10 provided A and B, respectively. The re-
moval of N-Cbz group from amines 5 and 6 with HBr, halogen ex-
change with silver(I) oxide and aqueous HCl, followed by N,N-
dichlorination with t-butyl hypochlorite yielded C and D.
Synthesis of the ammonium sulfonic acid E (Scheme 2) was
accomplished under Mannich conditions11 with commercially
available 2-nitropropane, formaldehyde and 2-(methylamino)eth-
anol in the presence of base. The nitro aminoalcohol was converted
to the thioacetate, via the mesylate. N-Methylation of nitro amino
thioacetate with methyl iodide, followed by oxidation with perfor-
mic acid, provided nitro methylammonium sulfonic acid 8. Hydro-
genation of the nitro group in the presence of Raney nickel at 500
psi,11 followed by chloride exchange and N,N-dichlorination, gave
compound E.
N+
I-
8
f,g,h
a,b,c,d,e
13%
Cl
N+
O2N
SO3H
Cl-
N
SO3H
NO2
33%
Cl
7
E
Scheme 2. Reagents and conditions: (a) 37% aq formaldehyde, 2-(methyl-
amino)ethanol, 5 N NaOH, 10–50 °C, 2 h; (b) MeSO2Cl, CH2Cl2, Et3N, 0–20 °C, 2 h;
(c) KSAc, DMF, 50 °C, 4 h; (d) MeI, EtOH, 45 °C, 72 h; (e) HCO2H, 30% H2O2, 50 °C,
2 h; (f) Raney Ni, H2 (500 psi), EtOH; (g) Ag2O, water, 0.5 h; then aq HCl; (h) MeOH,
t-BuOCl, 0–20 °C, 1 h.
R
CO2Et
N
O
N
N
N
O
N
N
N
N
Cbz
a,b
56%
h,i,j
Cbz
Cbz
Cbz
N
N
H
OH
O
N
H
N
H
O
9
11 R=H 67%
2
c,k,l
c,d
12 R=Me 55%
72%
SAc
R
N
N
Cbz
Cl
N
O
N
H
SAc
N
H
10
24%
13 R=H 42%
e,f,g
e,m,n,g
14
R=Me 71%
SO3H
R
N
N
Cl
N
O
N
N
SO3H
Cl
Cl
F
G R=H 7%
H
R=Me 5%
Scheme 3. Reagents and conditions: (a) Ethyl 2-amino-2-(hydroxyimino)acetate,
DMF, CDI, 20 °C, 16 h; (b) xylene, 140 °C, 5 h; (c) EtOH, NaBH4, 0–5 °C, 1 h; (d) AcSH,
PPh3, DIAD, THF, À5 to 20 °C, 16 h; (e) HCO2H, 30% H2O2, 20 °C, 16 h; (f) 10% Pd-
BaSO4, H2, MeOH, 20 °C, 4 h; (g) MeOH, t-BuOCl, 0–20 °C, 0.5 h; (h) NH4Cl, CDI, DIEA,
THF, 20 °C, 16 h; (i) N,N-dimethylformamide dimethyl acetal (for 11) or N,N-
dimethylacetamide dimethyl acetal (for 12), 120 °C, 2 h; (j) ethyl hydrazinoacetate
hydrochloride, 90 °C, 2 h; (k) MsCl, Et3N, THF, 20 °C, 1 h; (l) KSAc, DMF, 90 °C, 0.5 h;
(m) HBr, AcOH, 20 °C, 2 h; (n) Ag2O, water, 0.5 h; then aq HCl.
hydrazinoacetate hydrochloride provided the desired triazoles 11
and 12. Reduction of the ester to the alcohol, followed by Mitsun-
obu esterification reaction with thioacetic acid,7 gave thioacetates
10, 13 and 14. Compounds F, G, and H were prepared from the
respective thioacetates via a similar set of reaction sequences as
described for the synthesis of A from 3 in Scheme 1.
Syntheses of two 1,2,3-triazoles I and J from N-Boc protected al-
kyne 16 required a copper-mediated cycloaddition reaction utiliz-
ing Click chemistry (Scheme 4).12 This was accomplished by the
reaction of 16 with ethyl azidoacetate to provide an intermediate
triazole compound. Reduction of the ethyl ester, followed by reac-
tion with methanesulfonyl chloride, gave mesylate 17. Nucleo-
philic displacement of the mesylate with potassium thioacetate,
The synthesis of heterocyclic modifications F, G, and H in back-
bone began with a common intermediate, N-Cbz-3-amino-3-meth-
ylbutanoic acid (2), as shown in Scheme 3. The imidazolide, formed
from 2 and CDI, was reacted with ethyl 2-amino-2-(hydroxyimi-
no)acetate, to give a 1,2,4-oxadiazole 9. N-Cbz amide prepared
from 2 and ammonium chloride under CDI coupling conditions
was heated with either N,N-dimethylformamide dimethyl acetal
or N,N-dimethylacetamide dimethyl acetal to generate intermedi-
ate acylamidines. The cyclization of the acylamidines with ethyl
O
O
O
f,b,g
SAc
Cl
SO3H
OH
CbzHN
N
N
N
R1
1
R1
Cl
1
A: R1=H 77%
3
4
: R =H 71%
: R =Me 58%
1
a,b,c
B: R1=Me 65%
H2N
66%
O
d,e
d,h
15
N
Boc
Boc
Cl
N
N
H
N
N
O
e,f,g,h
6%
O
i,j,g
N
Cl
N+
N
a
N
N+
92%
Cl
N
Cbz
SO3H
N
N
H
N
I-
CbzHN
OH
b,c,d
i
17%
Cl-
I
17
18
20%
d,k
O
O
Cl
46%
59%
O
2
5
C
S
Boc
N
H
46%
Cl
N
g,h
N
O
O
N
16
i,j,g
Cl
N+
O
N+
N
N
Cl
Cbz
35%
N
H
N
N
N
H
O
I-
40%
Cl-
N+
N
Cl
Cl-
J
6
D
Br
-
N+
Scheme 1. Reagents and conditions: (a) NaN3, AcOH, H2O, 95 °C, 48 h; (b) 10% Pd-C,
MeOH, H2, 20 °C, 16 h; (c) THF, Cbz-OSu, 20 °C, 16 h; (d) CDI, DMF, 20 °C, 1 h; then,
2-aminoethanol (for 3) or 2-(methylamino)ethanol (for 4) or N,N,N’-trimethylethy-
lenediamine (for 5) or 1-(2-hydroxyethyl)piperidine (for 6), 20–60 °C, 16 h; (e)
AcSH, PPh3, DIAD, THF, À5 to 20 °C, 16 h; (f) 30% H2O2, HCO2H, 16 h, 20 °C; (g)
MeOH, t-BuOCl, 0–20 °C, 1 h; (h) MeI, EtOH, 20 °C, 16 h; (i) 33% HBr-AcOH, 20 °C,
1 h; (j) Ag2O, water, 0.5 h; then aq HCl; (k) MeI, CH2Cl2, 20 °C, 16 h.
Scheme 4. Reagents and conditions: (a) di-t-butyl dicarbonate, THF, 20 °C, 16 h; (b)
ethyl azidoacetate, DIEA, CuI, THF, 20 °C, 2 h; (c) EtOH, NaBH4, 20 °C, 1 h; (d)
MeSO2Cl, CH2Cl2, Et3N, 20 °C, 2 h; (e) KSAc, DMF, 90 °C, 0.5 h; (f) HCO2H, 30% H2O2,
20 °C, 2 h; (g) 4 M HCl/dioxane, 20 °C, 2 h; (h) MeOH, t-BuOCl, 0–20 °C, 2 h; (i) (2-
azidoethyl)trimethylammonium bromide (prepared from (2-bromoethyl)trimethy-
lammonium bromide, NaN3, DMF, 20 °C, 16 h), DIEA, MeOH, CuI, 20 °C, 16 h.

C. Francavilla et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2731–2734
2733
I-
Cl-
S+
e,f,g
followed by oxidation, deprotection and N,N-dichlorination, gave
a,b,c,d
41%
S+
Cl
Cbz
Cbz
OH
N
N
H
N
H
54%
the sulfonic acid I. Similarly, a cycloaddition of 16 and (2-azidoeth-
yl)trimethylammonium bromide furnished triazole 18. The re-
moval of N-Boc with HCl, followed by N,N-dichlorination gave
trimethylammonium compound J.
Cl
28
27
Q
j,k,l,g
13%
h,i
44%
Cl
Boc
16
N
Cl-
N+
N
H
Substitution of the sulfonic acid with other water solubilizing
groups, without the backbone modification, were also explored
(Scheme 5 and 6). The syntheses of analogsK, L, and M started with
reactions with the appropriate amines, formaldehyde and 2-nitro-
propane under Mannich conditions13 to give tertiary amines 19, 20
and 21. A common reaction sequence (methylation, nitro reduc-
tion, anion exchange and N,N-dichlorination) was used for the
preparation of K (from 19) and L (from 20) as described earlier
for the synthesis of E. The methylation of 21, unlike previous ana-
logs, failed to give the desired ammonium product. The dichloro-
amine M was obtained through an alternate sequence (nitro
reduction, Cbz protection, methylation, anion exchange and N,N-
dichlorination) in low yield. Compound N was synthesized from
commercially available 2-methyl-1-morpholinopropan-2-amine
22 with di-t-butyl dicarbonate in THF, followed by methylation
with methyl iodide and halide exchange as described earlier, to
provide the quaternary ammonium 23. The removal of N-Boc
group with HCl, followed by N,N-dichlorination, resulted in the for-
mation of the desired N,N-dichloroamino compound N.
Compounds O and P (Scheme 6) were synthesized from the
Cbz-protected 3-amino-3-methylbutanoic acid 2. Coupling of 2
with ammonium chloride under CDI conditions gave the corre-
sponding amide 24. Reaction of 24 with N,N-dimethylformamide
dimethyl acetal or N,N-dimethylacetamide dimethyl acetal,14 fol-
lowed by treatment with methyl hydrazine, gave compounds 25
and 26. Methylation of 25 and 26 with methyl iodide, N-deprotec-
tion under acidic conditions and N,N-dichlorination provided N,N-
dichloro triazole compounds O and P, respectively.
Cl
N
29
R
Scheme 7. Reagents and conditions: (a) AcSH, PPh3, DIAD, THF, À5 to 20 °C, 16 h;
(b) MeOH, 5 N NaOH, 20 °C, 0.5 h; (c) MeOH, MeI, TEA, 20 °C, 16 h; (d) EtOH, MeI,
20 °C, 72 h; (e) AcOH, Ag2O, 0.5 h; 6 N HCl; (f) 10% Pd-C, H2, 0.2% aq HCl, 20 °C, 20 h;
(g) MeOH, t-BuOCl, 20 °C, 1 h; (h) 4-bromopyridine, THF, DIEA, Pd(dppf)Cl2, 20 °C,
16 h; (i) 10% Pd-C, EtOH, 20 °C, 16 h; (j) MeI, 80 °C, 2 h; (k) Ag2O,water, 0.5 h; (l) 4 M
HCl/dioxane, 20 °C, 16 h.
dimethylsulfonium salt 28 was obtained by Mitsunobu esterifica-
tion of 27 with thioacetic acid, followed by de-S-acetylation, S-
methylation to the methyl sulfide, and a second S-methylation to
the dimethylsulfonium iodide.15 The iodide was exchanged for
chloride, with acetic acid added to prevent demethylation. Re-
moval of the Cbz group by hydrogenation under acidic conditions
(to prevent methyl transfer from sulfur to nitrogen), followed by
N,N-dichlorination, gave sulfonium compound Q. The methyl
pyridinium salt R was synthesized from Boc-protected 2-methyl-
3-butyn-2-amine 16. The cross-coupling of 16 with 4-bromopyri-
dine under Sonogashira conditions16 followed by hydrogenation17
furnished compound 29. Conversion of 29 to N-methylpyridium
compound R was accomplished by N-methylation of the pyridine
ring, halide exchange, Boc-deprotection, and N,N-dichlorination.
All compounds were purified by silica gel flash chromatography
or preparative HPLC and their structures were confirmed by 1H
NMR spectroscopy and LC/MS analysis.
Table 1 summarizes antimicrobial assay results and aqueous
solution stabilities for compounds A–R. Both parameters are criti-
cal in assessing the potential of this class of compounds as topical
antimicrobial agents. The minimum bactericidal concentration
(MBC) or minimum fungicidal concentration (MFC) for each com-
pound was evaluated as described previously.4 The biological eval-
uation was carried out for all analogs with sufficient aqueous
solution stability (>24 h at 40 °C). All analogs except M were active
against all organisms tested; there were no significant differences
between the in vitro activities for Gram-positive versus Gram-neg-
ative organisms. Some compounds with either a triazole function-
ality (I, J, O, and P) or an oxadiazole moiety (F) had the same or
better activity against Candida albicans than iii.
The dimethylsulfonium compound Q was synthesized from N-
Cbz-protected amino alcohol 27 (Scheme 7). N-Cbz-protected
Cl
N+
Cl-
b,c,d,e
N
N
O2N
63%
Cl
K
L
19
a
61%
Cl-
b,c,d,e
46%
f
Cl
Cl
N+
NO2
N
20
N
O2N
O2N
98%
Cl
g
7
NAc
O
NAc
N+
c,k,b,l,d,e
6%
Cl-
N+
81%
N
21
N
M
Cl
O
O
Analogs with backbone modifications A–D, F–J were prepared
as ester replacement analogs of vi, which was more stable than
most of the compounds reported in Ref. 4. It became apparent that
a backbone modification containing an ester (D) had good stability
at pH 4; however, it was less stable at pH 7, possibly due to sapon-
ification of the ester functionality.
j,e
h,i,d
78%
N+
Boc
N
Cl
H2N
N
N
Cl-
Cl-
11%
22
H
23
Cl
N
Scheme 5. Reagents and conditions: (a) aq dimethylamine, 37% aq formaldehyde,
50 °C, 1 h; (b) MeI, MeOH, 20 °C, 48 h; (c) Raney Ni, H2 (500 psi), MeOH–H2O, 20 °C,
72 h; (d) Ag2O, water, 0.5 h; then aq HCl; (e) MeOH, t-BuOCl, 0–10 °C, 1 h; (f)
piperidine, 37% aq formaldehyde, 10–50 °C, 1 h; (g) 1-(piperazin-1-yl)ethanone,
37% aq formaldehyde, 10–50 °C, 1 h; (h) di-t-butyl dicarbonate, THF, 20 °C, 16 h; (i)
MeI, 20 °C, 18 h; (j) 4 M HCl/dioxane, 20 °C, 2 h; (k) THF, Cbz-OSu, 20 °C, 16 h; (l)
33% HBr-AcOH, 20 °C, 1 h.
Dimethylammonium salt E and quaternary ammonium salts (K
and L) showed exceptional and surprising stability. They were the
first series of analogs whose stabilities were comparable to com-
pound iii. Most important, the stability of compound K at pH 7 has
been spectacular, and has shown little degradation at elevated tem-
peratures for over a year. Compounds L–N demonstrated, however,
that there are still many factors which can influence compound sta-
bility distal to the dichloroamine. Substitution of the terminal sul-
fonic acid group in the backbone-extended analogs (comparison of
B with C, vi with D, and I with J) with the trialkylammonium group
looked promising in this series of molecules. Triazolium salts (O
and P), dimethylsulfonium salt Q, and pyridinium salt R were pre-
pared as variations on the theme of the trimethylammonium deriv-
ative K. While many of these were promising for acidic solutions,
they lacked the exceptional pH 7 stability of derivative K.
R
R
Cl-
N+
N
N
N
O
b,c
d,e,f
a
Cl
N
2
Cbz
N
Cbz
N
N
H
N
H
NH2
73%
Cl
24
O
25 R=H 22%
R=H 15%
26
P R=Me 2%
R=Me 41%
Scheme 6. Reagents and conditions: (a) CDI, DIEA, NH4Cl, DMF, 20 °C, 16 h; (b) N,N-
dimethylformamide dimethyl acetal (for 25) or N,N-dimethylacetamide dimethyl
acetal (for 26), 120 °C, 2 h; (c) Methyl hydrazine, acetic acid, 90 °C, 2 h; (d) MeI,
MeOH, 70 °C, 16 h; (e) 33% HBr-AcOH, 20 °C, 2 h; (f) Ag2O, water, 0.5 h; then aq HCl;
(g) MeOH–H2O (9:1; v/v), t-BuOCl, 20 °C, 1 h.

2734
C. Francavilla et al. / Bioorg. Med. Chem. Lett. 19 (2009) 2731–2734
Table 1
Compounds
MBC or MFCa(
lg/mL)
t
pH 4 (saline)
t pH 7 (phosphate)
½
½
(days)
(days)
m
X
n
W
S. aureus ATCC
E. coli ATCC
C. albicans ATCC
29213
25922
10231
iii
A
B
C
D
E
1
1
1
1
1
1
1
n/a
CONH
CONMe
CONMe
CO2
0
2
2
2
2
2
1
SO3H
SO3H
SO3H
NMe3
Me-piperdinium
SO3H
SO3H
2
8
2
16
4
2
2
1
2
2
16
4
32
64
32
32
n/a
128
16
>730
33
1
>300
36b
1
6
7
4
>72
>180
106
NMe2
1,2,4-
64
2
19
17
F
Oxadiazole
1,2,4-Triazole
3-Me-1,2,4-
Triazole
1,2,3-Triazole
1,2,3-Triazole
n/a
G
H
1
1
2
2
SO3H
SO3H
4
4
2
4
64
64
21
46
23
50
I
J
K
L
M
0
0
1
1
1
2
2
0
0
0
SO3H
NMe3
NMe3
Me-piperdinium
Me-piperazinium-
Ac
8
8
16
16
64
4
4
8
8
32
32
128
64
>1024
10
52
>325
>122
37
5
23
>396
100
6b
n/a
n/a
16
N
O
P
1
1
1
n/a
n/a
n/a
0
0
0
Morpholinium
1,2,4-triazolium
3-Me-1,2,4-
triazolium
n/a
4
8
n/a
2
4
n/a
16
32
<1
67
61
<1
5
4
Q
R
1
1
n/a
n/a
0
1
Dimethylsulfonium
Me-pyridinium
8
8
4
2
128
1024
>67
>60
1
20b
a
Minimum bactericidal concentration (MBC) was determined using a modified standard method described in CLSI M26-A whereby isotonic saline at pH 4 is substituted for
Mueller–Hinton broth (MHB) to compensate for the reactivity of chlorine to certain components of MHB. Due to the rapid cidal nature of chlorinated derivatives, the assay
was shortened from 16–20 h at 35 °C to1 h at room temperature.
b
In 0.6% borate buffer pH 7.
Antimicrob. Chemother 1999, 43, 805; (i) Nagl, M.; Miller, B.; Daxecker, F.;
Gottardi, W. J. Ocul. Pharmacol. Ther. 1998, 14, 283; (j) Nagl, M.; Larcher, C.;
Gottardi, W. Antiviral Res. 1998, 38, 25; (k) Nagl, M.; Gottardi, W. Hyg. Med
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SSR/SAR suggested that the trimethylammonium group is a privi-
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unique replacement for a sulfonic acid in terms of stability and
activity. In this report, we have identified quaternary ammonium
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