Indazole, Pyrazole, and Oxazole Derivatives Targeting Nitric Oxide Synthases and Carbonic Anhydrases

Article abstract of DOI:10.1002/cmdc.201600204

Nitric oxide (NO) is an essential endogenous mediator with a physiological role in the central nervous system as neurotransmitter and neuromodulator. A growing number of studies have demonstrated that abnormal nitrergic signaling is a crucial event in the development of neurodegeneration. In particular, the uncontrolled production of NO by neuronal nitric oxide synthase (nNOS) is observed in several neurodegenerative diseases. Moreover, it is well recognized that specific isoforms of human carbonic anhydrase (hCA) physiologically modulate crucial pathways of signal processing and that low expression of CA affects cognition, leading to mental retardation, Alzheimer′s disease, and aging-related cognitive impairments. In light of this, dual agents that are able to target both NOS (inhibition) and CA (activation) could be useful drug candidates for the treatment of Alzheimer′s disease, aging, and other neurodegenerative diseases. In the present work, we show the design, synthesis, and in vitro biological evaluation of new nitrogen-based heterocyclic compounds. Among the tested molecules, 2-amino-3-(4-hydroxyphenyl)-N-(1H-indazol-5-yl)propanamide hydrochloride (10 b) was revealed to be a potent dual agent, able to act as a selective nNOS inhibitor and activator of the hCA I isoform.

Full text of DOI:10.1002/cmdc.201600204

DOI: 10.1002/cmdc.201600204
Communications
Indazole, Pyrazole, and Oxazole Derivatives Targeting
Nitric Oxide Synthases and Carbonic Anhydrases
Cristina Maccallini,*[a] Mauro Di Matteo,[a] Daniela Vullo,[b] Alessandra Ammazzalorso,[a]
Simone Carradori,[a] Barbara De Filippis,[a] Marialuigia Fantacuzzi,[a] Letizia Giampietro,[a]
Assunta Pandolfi,[c] Claudiu T. Supuran,[d] and Rosa Amoroso*[a]
Nitric oxide (NO) is an essential endogenous mediator with
a physiological role in the central nervous system as neuro-
transmitter and neuromodulator. A growing number of studies
have demonstrated that abnormal nitrergic signaling is a crucial
event in the development of neurodegeneration. In particular,
the uncontrolled production of NO by neuronal nitric oxide
synthase (nNOS) is observed in several neurodegenerative dis-
eases. Moreover, it is well recognized that specific isoforms of
human carbonic anhydrase (hCA) physiologically modulate cru-
cial pathways of signal processing and that low expression of
CA affects cognition, leading to mental retardation, Alzheimer’s
disease, and aging-related cognitive impairments. In light of
this, dual agents that are able to target both NOS (inhibition)
and CA (activation) could be useful drug candidates for the
treatment of Alzheimer’s disease, aging, and other neurodege-
nerative diseases. In the present work, we show the design,
synthesis, and in vitro biological evaluation of new nitrogen-
based heterocyclic compounds. Among the tested molecules,
2-amino-3-(4-hydroxyphenyl)-N-(1H-indazol-5-yl)propanamide
hydrochloride (10b) was revealed to be a potent dual agent,
able to act as a selective nNOS inhibitor and activator of the
hCA I isoform.
rodegeneration depend on many factors, such as protein mis-
folding, fibril formation, mitochondrial dysfunction, and altered
signaling cascades.[1] An important role is also played by oxida-
tive and nitrosative stress.[2] In particular, a crucial event in neu-
rodegeneration is the upregulation of the neuronal isoform of
the nitric oxide synthase enzyme family (nNOS), which is re-
sponsible for the biosynthesis of nitric oxide (NO) in the CNS.[3]
NO is a diffusible, lipophilic free radical implicated in a number
of physiological processes. However, under excitotoxic condi-
tions, after an increase in Ca2+ influx into neuronal cells via the
N-methyl-d-aspartate receptor (NMDAR), and coupling with
the PSD95 protein, nNOS is overstimulated, and NO is exces-
sively generated.[4] This leads to the generation of reactive
oxygen and nitrogen species (ROS and RNS), responsible for
DNA and lipid damage, and for Snitrosylation or tyrosine nitra-
tion in proteins. The resulting excitotoxicity contributes to the
genesis and development of neurodegenerative diseases such
as multiple sclerosis and Alzheimer’s and Parkinson’s disease.[5]
Dysregulation of NO signaling also mediates neuronal death in
cerebrovascular stroke.[6] Therefore, the selective inhibition of
nNOS is an emerging strategy in the therapy of neurodegener-
ative diseases.[7]
Beyond the neuronal isoform, the NOS family also includes
a constitutively expressed endothelial isoform (eNOS) and an
inducible one (iNOS). All the three isoforms have different
tissue localizations and separate roles: basically, iNOS is ubiqui-
tously expressed during the immune response, eNOS activity is
predominant in the cardiovascular system, where it maintains
vasculature homeostasis, whereas nNOS is primarily expressed
in the CNS, and is involved in neuronal signaling.[8] Therefore,
adequate isoform selectivity is an essential feature for a NOS
inhibitor, and several bioactive nNOS inhibitors have been re-
ported so far. In particular, heterocyclic inhibitors including 2-
aminopyridine, indole, imidazole, and indazole derivatives have
been developed.[7,9]
Neurodegeneration is a general term, which encompasses sev-
eral diseases that cause the progressive and irreversible loss of
the integrity of the central nervous system (CNS). It is currently
well accepted that the pathogenesis and development of neu-
[a] Dr. C. Maccallini, Dr. M. Di Matteo, Dr. A. Ammazzalorso, Dr. S. Carradori,
Dr. B. De Filippis, Dr. M. Fantacuzzi, Dr. L. Giampietro, Prof. R. Amoroso
Department of Pharmacy,
University of Chieti “G. d’Annunzio”, 66100 Chieti (Italy)
E-mail: cmaccallini@unich.it
ramoroso@unich.it
[b] Dr. D. Vullo
Laboratorio di Chimica Bioinorganica, Universitꢀ degli Studi di Firenze,
Via della Lastruccia 3, 50019 Sesto Fiorentino, Florence (Italy)
It is important to note that conversion of one of the most
important RNS, that is the peroxynitrite ion (ONOOꢀ), in power-
[c] Prof. A. Pandolfi
[10]
C
ful oxidants (NO2, OH ) is proton dependent, and that acido-
Department of Medical, Oral and Biotecnological Sciences,
University “G. d’Annunzio”, Aging Research Center,
“G. d’Annunzio” University Foundation, 66100 Chieti (Italy)
sis can occur in different neurological pathologies.[11] One of
the functions of carbonic anhydrase (CA) is to maintain the
acid–base balance in tissues; extracellular membrane-associat-
ed CAs catalyze the interconversion of H+ +HCO3ꢀ$CO2 +H2O
at the cell surface, which would tend to promote dissipation of
pH gradients.[12] Specific isoforms are present in oligodendro-
cytes, choroid plexus epithelium, GABAergic neurons and as-
trocytes, but they usually decline with aging. The consequent
[d] Prof. C. T. Supuran
Neurofarba Department,
Section of Pharmaceutical and Nutriceutical Sciences,
Universitꢀ degli Studi di Firenze,
Via U. Schiff 6, 50019 Sesto Fiorentino, Florence (Italy)
Supporting information for this article can be found under http://
dx.doi.org/10.1002/cmdc.201600204.
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impairment of pH buffering could enhance cellular nitrosative
stress that occurs in neurodegeneration, both by activating the
Ca2+ influx through acid-sensing ion channels (ASICs),[11] and
by promoting decomposition of ONOOꢀ (Figure 1).
and several bioactive derivatives have been published to
date.[20] In particular, 7-nitroindazole (7-NI) is widely used as an
nNOS inhibitor, both in vitro and in vivo, being centrally active
when peripherally administered to rats.[21] Moreover, in a previ-
ous work, some of us found that a series of substituted azoles
could act as CA activators due to their capacity to activate the
proton transfer process into the enzyme active site, and pyra-
zole derivatives proved to be quite potent compounds.[22] In
light of this, we decided to adopt 1H-indazole and 1H-pyrazole
nuclei to target both the nNOS and CAs binding sites. More-
over, because the oxazole ring is a bioisostere of pyrazole and
considering that its basicity is similar to that of indazole and
pyrazole, this heterocycle was also included in our molecular
design (Figure 2, compounds 8–12). The selected nitrogen-con-
Figure 1. Hypothetical mechanistic scheme of nNOS and CA involvement in
neurodegenerative conditions. Intracellular Ca2+ concentration is increased
through influx via N-methyl-d-aspartate receptors (NMDAR) and acid-sensing
ion channels (ASICs). The overexpressed nNOS is calcium activated, and the
resulting overproduction of nitric oxide causes excitotoxic lesions due to mi-
tochondrial stress, protein nitrosation and nitrosylation, and generation of
ROS and RNS. Moreover, decreased CA levels could contribute to nitro-oxida-
tive stress due to low intra- and extracellular pH buffering. Indeed, the im-
paired pH dissipation could promote intracellular generation of ROS and the
activation of membrane ASICs. Therefore, compounds able to inhibit nNOS
and activate CAs could be valuable therapeutic agents.
Figure 2. Structures of target compounds.
taining heterocycles were linked to specific amino acids, with
the aim of obtaining selective compounds. Indeed, compounds
with ionizable groups able to interact with the NOS substrate
access channel show high isoform selectivities and at the same
time could confer CA isoform specificity.[23] Alanine (Ala), tyro-
sine (Tyr), and glutamic acid (Glu) were preliminarily selected
owing to their side chain differences in terms of lipophilicity
and interacting groups, changing from the Ala methyl to the
Glu carboxylate group, and to the Tyr p-hydroxybenzyl group.
As for the syntheses, a preliminary reduction of 1H-indazole-
6-carbonitrile and 4-nitropyrazole was performed according to
published procedures[24,25] to obtain the corresponding (1H-in-
dazol-6-yl)methanamine (1) and 1H-pyrazol-4-amine (2), re-
spectively (Schemes 1 and 2). Then, as shown in Scheme 3, the
appropriate heterocycle was coupled with the fully protected
amino acids Boc-l-Ala, Boc-l-Tyr(OtBu), and Boc-l-Glu(OtBu) in
Moreover, CAs physiologically modulate crucial pathways of
signal processing, long-term synaptic transformation, oligoden-
drocyte processes, proper neuronal communication, and
memory storage. As a consequence, their dysfunction or low
expression affects cognition, leading to mental retardation, Alz-
heimer’s disease, and age-related cognitive impairments.[13]
Indeed, CA levels are significantly decreased in the brain tissue
of patients suffering from Alzheimer’s disease, demonstrating
a pivotal involvement of various human CA isozymes (hCA I, II,
IV, and VII) in cognitive and learning functions.[14] For this
reason, CA activators (CAAs) have been widely studied and
proposed as potential pharmacological agents,[15] according to
their structure–activity relationships and catalytic mechanism,
as well as crystallographic studies of reported enzyme–activa-
tor adducts. Among the plethora of published compounds, the
most significant are nitrogen-based scaffolds derived from
structures such as histamine,[16] histidine,[17] tryptophan,[18] and
carnosine, as well as oligopeptides, showing CA activation pro-
files in the nanomolar range, with interesting isoform specifici-
ty.[19]
Because the concurrent yet independent dysregulation of
both nNOS- and hCA-related pathways is involved in the pro-
gression of neurodegeneration, we hypothesized that com-
pounds endowed with pharmacophoric elements that are able
to selectively inhibit nNOS and activate CAs could represent
a new multitarget approach in treating age-related neurode-
generation (Figure 1).
Scheme 1. Reduction of 1H-indazole-6-carbonitrile.[24] Reagents and condi-
tions: 2m LiAlH4, dry THF, 08C!reflux, N2.
Scheme 2. Reduction of 4-nitropyrazole.[25] Reagents and conditions: H2
(3.5 bar), Pd/C, EtOH, RT, N2.
Among the known molecular scaffolds responsible for nNOS
inhibition, indazoles and pyrazoles have been extensively used,
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Scheme 3. Synthesis of target molecules 8–12. Reagents and conditions: a) Boc-l-Ala or Boc-l-Tyr(OtBu) or Boc-l-Glu(OtBu), iBuOCOCl, NMM, dry DMF,
ꢀ158C!RT, N2; b) Boc-l-Ala or Boc-l-Tyr(OtBu) or Boc-l-Glu(OtBu), EDC, DMAP, 08C!RT, dry DMF, N2; c) 4n HCl, 1,4-dioxane, RT.
the presence of iBuOCOCl and N-methylmorpholine (NMM) to
Table 1. Inhibition of nNOS, iNOS, and eNOS by compounds 8–12.
obtain Boc-protected 3–6, or EDC and DMAP for protected
Compd
Inhibition [%]
iNOS[a]
products 7. All these intermediates were finally deprotected
with 4n HCl in 1,4-dioxane to give the desired products.
The synthesized compounds were evaluated for their in vitro
NOS inhibitory activity by measuring the conversion of l-argi-
nine to l-citrulline using a validated HPLC method with fluo-
rescence detection, as previously reported.[26] In a preliminary
evaluation, percent nNOS and iNOS inhibition values were de-
termined at 1 mm for each compound, whereas eNOS inhibi-
tion was evaluated at 10 mm. The results are listed in Table 1.
The indazole 6-amino or methylenamino derivatives 8a–c and
9a–c did not reveal useful nNOS inhibitors; indeed these com-
pounds gave only weak nNOS inhibition, and the best result
was 32.77% nNOS inhibition. On the other hand, compounds
9a–c gave an interesting iNOS inhibition profile, and in partic-
ular, the 6-glutamylmethylenaminoindazole 9c was found to
completely and selectively inhibit iNOS at 1 mm. These results,
together with the promising selectivity that molecules 9a–
c demonstrated over eNOS, suggest that the indazole-6-meth-
ylenaminic core could be a useful scaffold to generate new se-
lective iNOS inhibitors.
nNOS[a]
eNOS[b]
8a
8b
8c
20.31ꢁ1.24
32.77ꢁ1.80
5.31ꢁ0.74
55.81ꢁ4.27
0.52ꢁ0.23
29.94ꢁ1.36
0.07ꢁ0.005
0.01ꢁ0.001
0.54ꢁ0.02
9a
9b
9c
0.28ꢁ0.52
0.32ꢁ1.73
25.44ꢁ2.21
77.25ꢁ2.81
49.86ꢁ2.54
99.58ꢁ5.86
0.15ꢁ0.01
0.09ꢁ0.007
0.16ꢁ0.02
10a
10b
10c
62.43ꢁ3.27
98.16ꢁ1.74
61.83ꢁ4.21
0.45ꢁ0.0.3
14.24ꢁ0.81
0.15ꢁ0.01
0.29ꢁ0.01
0.18ꢁ0.01
0.35ꢁ0.03
11 a
11 b
11 c
57.24ꢁ2.81
24.76ꢁ1.95
40.41ꢁ4.23
86.44ꢁ6.47
34.78ꢁ1.14
12.46ꢁ0.82
0.20ꢁ0.06
0.47ꢁ0.02
0.11ꢁ0.01
12a
12b
12c
82.49ꢁ3.94
60.31ꢁ3.58
52.44ꢁ3.39
12.79ꢁ0.55
0.08ꢁ0.02
0.25ꢁ0.08
42.23ꢁ2.65
2.36ꢁ0.15
6.97ꢁ0.01
[a] Percent NOS inhibition at 1 mm compound concentration. [b] Percent
eNOS inhibition at 10 mm compound concentration. Values are the mean
ꢁSD of experiments performed in triplicate.
More interesting results on nNOS were obtained when the
amino acid tail was moved to the indazole 5-position: com-
pounds 10a–c gave >60% nNOS inhibition, and 10b, bearing
a tyrosine, remarkably inhibited the enzyme almost completely
(98.16%), without affecting eNOS and poorly modifying iNOS
activity (14.24%). Considering these results, we were prompted
to evaluate 10a–c IC50 values against NOSs, and the results are
listed in Table 2. As expected, these compounds revealed to be
quite potent nNOS inhibitors, and 10b gave the best results,
showing not only high potency (IC50 =0.174 mm), but also ex-
cellent in vitro selectivity with respect to eNOS (327-fold).
In contrast, with pyrazole as the heterocycle (compounds
11 a–c), only moderate nNOS inhibition was observed, with
57.24% being the best result, observed for 11 a (Table 1). This
compound was also revealed to be an interesting iNOS inhibi-
tor (86.44%). Indeed, the IC50 value for 11 a (Table 2) was found
to be 1.089 mm against nNOS, and 0.681 mm against iNOS,
whereas it did not affect eNOS activity (IC50 >100 mm).
Finally, the oxazoles 12 a–c demonstrated a good profile of
nNOS inhibition at 1 mm (Table 1), with the alanyl derivative
giving the best result (82.49%). However, 12a also significantly
inhibited eNOS at 10 mm, resulting in poor selectivity. There-
fore, only 12b and 12c were selected for evaluation of IC50
values (Table 2), which were 1.023 and 1.256 mm, respectively,
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results were obtained in the analysis of the activa-
tion data of hCA I, with low nanomolar values. The
1H-indazole series seems to be preferred, with com-
pound 9b being the best activator (KA =9 nm)
within this scaffold. Compound 10b (KA =15 nm),
which displayed the best percentage nNOS inhibi-
tion, could be classified as a dual agent (nNOS inhib-
itor and selective hCA I activator) for the treatment
of neurodegenerative disease. In addition, the pres-
ence of different R substituents on the lateral chain
of the nitrogen-based core was also found to modu-
late biological activity.
Table 2. Inhibition of nNOS, iNOS, and eNOS by selected compounds.
Compd
IC50 [mm][a]
Selectivity
i/n e/n
nNOS
iNOS
eNOS
10a
10b
10c
0.723ꢁ0.048 44.13ꢁ2.40
0.174ꢁ0.014 27.58ꢁ1.12
0.945ꢁ0.033 36.31ꢁ1.24
74.13ꢁ1.24
56.89ꢁ0.81
61
158
38
102
327
>100
>100
11 a
12b
12c
1.089ꢁ0.027
0.681ꢁ0.024
>100
–
53
50
>100
84
1.023ꢁ0.019 54.14ꢁ2.52
1.256ꢁ0.031 62.31ꢁ2.91
86.23ꢁ3.71
91.13ꢁ3.41
72
7-NI[27]
0.71ꢁ0.01
5.8ꢁ0.4
0.78ꢁ0.2
8.1
–
[a] Values are the mean ꢁSD of experiments performed in triplicate at seven different
Due to the promising in vitro biological profile,
the chemical and enzymatic stability of 10b was in-
vestigated by dissolving 1 mg of this compound in
1 mL phosphate buffer (pH 7.4), HCl solution
concentrations.
against nNOS, with good selectivity with respect to iNOS and
eNOS.
(pH 2.0), NaOH solution (pH 9.0), and human plasma. Immedi-
ately after dissolution, and at appropriate time intervals, 5 mL
of each solution was withdrawn and injected into an HPLC ap-
paratus (Waters, Milford, USA), equipped with a Polarity C18
column (Waters), eluted using a 40:60 mixture of CH3OH and
carbonate buffer (pH 11), and detected by photodiode array.
Solutions were kept at 378C and monitored for 24 h. While
10b was found to be chemically stable, as no loss of product
was observed within the considered time period, a half-life of
3 h in human plasma was measured. This should be carefully
considered for future pharmacokinetic assessments on this
compound.
In vitro activation data of isozymes hCA I, II, IV, and VII with
the newly synthesized derivatives as well as standard activa-
tors, are listed in Table 3. The CA activation data shows signifi-
cant differences among the four investigated isozymes. Collec-
tively, our compounds displayed a slight activation of isoforms
II and IV in the micromolar range (KA values ranging from 4.0
to 43.2 mm for hCA II and from 7.1 to 48.6 mm for hCA IV) simi-
lar to the two reference compounds (l- and d-histidine). Some
of them were found to be potent activators of hCA VII in the
high nanomolar range (9b: KA =0.69 mm, 10a: KA =0.59 mm,
and 10c: KA =0.51 mm), but without any robust correlation be-
tween chemical structure and biological activity. Better affinity
In conclusion, new indazole-, pyrazole-, and oxazole-based
compounds were synthesized in this study. Among these com-
pounds, 5-substitued indazole derivatives were found to inhibit
nNOS with high potency, and remarkably, high selectivity with
respect to iNOS and eNOS. Different molecules also behave as
effective CA activators against all four isozymes investigated
herein, probably due to the presence of specific moieties that
are able to act as proton shuttles or by intervening in the cata-
lytic cycle of CA, leading to the formation of enzyme–activator
complexes. Compound 10b emerged as a dual agent able to
effect selective nNOS inhibition and hCA I activation; it is
therefore a promising drug candidate in the therapy of neuro-
degeneration.
Table 3. Activation data for compounds 8–12 toward hCA I, II, IV, and VII.
Compd
KA [mm][a]
hCA II
hCA I
hCA IV
hCA VII
8a
8b
8c
0.54ꢁ0.02
0.70ꢁ0.05
0.092ꢁ0.001
26.4ꢁ1.3
15.7ꢁ0.8
29.6ꢁ2.0
8.4ꢁ0.6
12.3ꢁ0.9
39.7ꢁ2.4
1.38ꢁ0.05
7.25ꢁ0.14
16.5ꢁ1.2
9a
9b
9c
0.39ꢁ0.03
0.009ꢁ0.001
1.25ꢁ0.10
24.5ꢁ2.1
37.9ꢁ1.7
35.5ꢁ3.0
15.0ꢁ1.1
47.8ꢁ3.5
9.1ꢁ0.2
5.10ꢁ0.27
0.69ꢁ0.04
5.91ꢁ0.17
10a
10b
10c
6.39ꢁ0.21
0.015ꢁ0.002
4.12ꢁ0.14
12.2ꢁ0.6
33.0ꢁ2.5
20.6ꢁ1.9
11.5ꢁ0.8
21.6ꢁ1.7
30.7ꢁ2.5
0.59ꢁ0.03
10.8ꢁ0.92
0.51ꢁ0.05
Experimental Section
The synthesis of target compounds as shown in Schemes 1–3, to-
gether with their spectral properties, procedures for in vitro NOS
and CA activity assays, and chemical and enzymatic stability evalu-
ations for compound 10b are described in detail in the Supporting
Information.
11 a
11 b
11 c
0.97ꢁ0.04
0.11ꢁ0.006
0.43ꢁ0.02
13.1ꢁ0.8
7.2ꢁ0.5
4.0ꢁ0.2
10.0ꢁ0.3
13.7ꢁ1.1
17.1ꢁ0.4
18.3ꢁ0.96
0.81ꢁ0.04
1.02ꢁ0.09
12a
12b
12c
2.47ꢁ0.11
2.51ꢁ0.09
0.082ꢁ0.003
43.2ꢁ2.7
40.3ꢁ3.1
22.4ꢁ1.4
15.3ꢁ1.2
7.1ꢁ0.3
48.6ꢁ3.3
3.16ꢁ0.25
8.04ꢁ0.72
1.78ꢁ0.15
Acknowledgements
l-His[b]
d-His[b]
0.030ꢁ0.001
0.090ꢁ0.008
10.9ꢁ0.7
43.5ꢁ3.6
7.3ꢁ0.2
0.92ꢁ0.03
0.71ꢁ0.04
12.3ꢁ1.1
The Ministero dell’Istruzione, dell’Universitꢀ e della Ricerca (MIUR)
is acknowledged for financial support. Work in the research
group of C.T.S. was supported by two European Union 7th Frame-
work Programme (7FP) grants (Dynano and Gums & Joints).
[a] KA =activation constant, determined by a stopped-flow carbonic anhy-
drase assay;[28] values are the mean ꢁSD of experiments performed in
triplicate. [b] l-His and d-His were used as reference compounds.
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Received: April 14, 2016
Revised: May 30, 2016
Published online on && &&, 0000
ChemMedChem 2016, 11, 1 – 6
www.chemmedchem.org
5
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
These are not the final page numbers! ÞÞ

COMMUNICATIONS
C. Maccallini,* M. Di Matteo, D. Vullo,
A. Ammazzalorso, S. Carradori,
B. De Filippis, M. Fantacuzzi,
L. Giampietro, A. Pandolfi, C. T. Supuran,
R. Amoroso*
Double agent! This study involved the
design, synthesis, and in vitro biological
evaluation of a cluster of new nitrogen-
based heterocyclic compounds. Com-
pound 10b was revealed to be a potent
dual agent, able to act as a selective
neuronal nitric oxide synthase inhibitor
and activator of the human carbonic an-
hydrase I isoform. It is a promising lead
for the design of therapies for neurolog-
ical diseases.
&& – &&
Indazole, Pyrazole, and Oxazole
Derivatives Targeting Nitric Oxide
Synthases and Carbonic Anhydrases
&
ChemMedChem 2016, 11, 1 – 6
www.chemmedchem.org
6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!