Sulphonamide and sulphonyl-hydrazone cyclic imide derivatives: Antinociceptive activity, molecular modeling and in Silico ADMET screening

Article abstract of DOI:10.1007/s12272-012-1002-1

In this paper, we describe the antinociceptive activity, molecular modeling and in silico ADMET screening of a series of sulphonyl-hydrazone and sulphonamide imidobenzene derivatives. Among these compounds, the sulphonyl-hydrazones 9 and 11 showed the mos

Full text of DOI:10.1007/s12272-012-1002-1

Arch Pharm Res Vol 35, No 10, 1713-1722, 2012
DOI 10.1007/s12272-012-1002-1
Sulphonamide and Sulphonyl-hydrazone Cyclic Imide Derivatives:
Antinociceptive Activity, Molecular Modeling and In Silico ADMET
Screening
Kely N. de Oliveira1, Márcia M. Souza3, Plínio Cunha Sathler2, Uiaran O. Magalhães4, Carlos R. Rodrigues4,
Helena C. Castro2, Patrícia R. Palm6, Maicon Sarda6, Pablo E. Perotto6, Sabrina Cezar6, Monique A. de Brito5,
Ariane S. S. R. Ferreira2, Lúcio Mendes Cabral4, Clodoaldo Machado5, and Ricardo J. Nunes1
1Departamento de Química, Universidade Federal de Santa Catarina (UFSC), Florianópolis, SC, Brazil, CEP 88040-900,
2Laboratório de Antibióticos, Bioquímica e Modelagem Molecular (LABioMol), Instituto de Biologia (IB), Departamento
3
de Biologia Celular e Molecular, Universidade Federal Fluminense (UFF), Niterói, RJ, Brazil, CEP 24001-970, Núcleo de
Investigações Químico Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí, UNIVALI, Itajaí, SC, Brazil, CEP 88302-
4
202, ModMolQSAR, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ, Brazil,
5
CEP 21941-590, Laboratório de Química Medicinal Computacional, Departamento de Farmácia e Administração Far-
macêutica, Faculdade de Farmácia, Universidade Federal Fluminense (UFF), Niterói, RJ, Brazil, CEP 24241-000, and
6Departamento de Química, Universidade Regional de Blumenau (FURB), Blumenau, SC, Brazil, CEP 89010971
(Received January 19, 2012/Revised May 7, 2012/Accepted June 11, 2012)
In this paper, we describe the antinociceptive activity, molecular modeling and in silico
ADMET screening of a series of sulphonyl-hydrazone and sulphonamide imidobenzene deriv-
atives. Among these compounds, the sulphonyl-hydrazones
analgesic activity (ID50 = 5.1 and 6.8
uated in this study have a better analgesic profile than the control drugs, acetyl salicylic acid
and acetaminophen. Derivative was the most promising compound; with a level of activity
9
and 11 showed the most potent
µ
mol/kg, respectively). Interestingly, all derivatives eval-
9
that was 24 times higher than the control drugs. Our SAR study showed a relationship among
the distribution of the frontier orbital HOMO coefficients, HOMO-LUMO energy gap of these
molecules and their reactivity. The best analgesic compounds (including 6, 9, 10, 11 and 12)
fulfilled the Lipinski “rule-of-five”, which is theoretically important for good drug absorption
and permeation.
Key words: Sulphonylhydrazones, Sulphonamides, Analgesic activity, SAR, ADMET
with advanced cancer will experience pain. Tragically,
Selected by Editors
cancer pain frequently goes untreated, and when it is
treated, relief is often inadequate. In fact, more than
half of cancer patients suffer unrelieved pain due to
inadequate treatment (Plante and VanItallie, 2010;
INTRODUCTION
Pain is a fundamental event that is normally asso- Portenoy, 2011).
ciated with some kind of health problems, e.g. the mani-
The traditional pain treatments (e.g., those based on
festation of inflammatory dysfunctions (Lima et al., the use of nonsteroidal anti-inflammatory drugs -
2000). However, pain becomes a problem when it occurs NSAIDs, and opioid analgesics) exhibit several side
often and severely. More than two thirds of patients effects. Thus, in the past 20 years, it has increased the
interest in the area of the so-called ‘adjuvant analgesics’
or drugs that have primary indications other than
pain, but may be analgesics in selected circumstances
(Portenoy, 2000; Mitra and Jones, 2011).
In this context, particularly regarding the therapy of
chronically debilitating pain, the search for new analgesic
Correspondence to: Helena C. Castro, Universidade Federal
Fluminense, Instituto de Biologia, Departamento de Biologia
Celular e Molecular, 24020-150 Niterói, RJ, Brazil
Tel: 55-21-2629-2294, Fax: 55-21-2629-2284
E-mail: hcastrorangel@vm.uff.br and hcastrorangel@yahoo.com.br
1713

1714
K. N. de Oliveira et al.
agents that are potent, selective and with reduced toxicity
is of extreme importance.
MATERIALS AND METHODS
The therapeutic potential of cyclic imides has been
known for several decades, and they have been used
Chemistry
The sulphonamides and the sulphonyl-hydrazones
in treating several different pathologies (Hargreaves were synthesized in 3-4 reaction steps. The first step
et al., 1970; Filho et al., 1998; Abdel-Aziz et al., 2011). was the Diels-Alder reaction between the -( -chloro-
N
p
These organic compounds are described as presenting sulphonyl)phenylmalemide and two dienes: furan or
several pharmacological activities, including antibac- 2-methylfuran. The reactions of furan and 2-methyl-
terial, antitumor, diuretic and antiviral profiles, similar furan were carried out at room temperature in diethyl
to sulphonamides and sulphonyl-hydrazones (Lima et al., ether, by stirring for 10 days. The sulphonamides (
3-
1999; Betz et al., 2002; Rollas et al., 2002; Bhattacharya
6) were obtained by condensation of the Diels-Alder
et al., 2004; Sondhi et al., 2006; Hu et al., 2007; adducts with different amines in methanol, at approxi-
Nishimori et al., 2007; Frlan et al., 2008). Moreover, mately 0oC. For the synthesis of the sulphonyl-hydra-
the literature has reported some N-substituted malei- zones (
9-14), adducts were condensed with hydrazine
mides as inhibiting cyclooxygenase (COX), similar to hydrate, followed by reaction with different benzalde-
some NSAIDs, acetyl salicylic acid, indomethacin, and hydes (Fig. 2), as described by our research group
ibuprofen (Kalgutkar et al., 1996).
In a previous publication, we reported the synthesis were acquired from Sigma-Aldrich and Merck. All the
of imidobenzenesulphonyl compounds (
and
), which compounds were characterized by 1H-NMR, 13C-NMR,
(Oliveira and Nunes, 2006). The solvents and reagents
1
2
showed promising analgesic profile in the acetic acid- IR, and elemental analysis. The purity of these com-
induced mice writhing test (Fig. 1). Acetic acid injected pounds was determined by TLC, using several solvent
intraperitonially induces the release of several inflam- systems of different polarity. Infrared spectra were de-
matory mediators, including prostaglandins (Dray, 1995; termined with a Perkin Elmer 16PC spectrophotometer
1
Filho et al., 1996). Compound
2
was the most effec- (Perkin Elmer). H-NMR and 13C-NMR spectra were
tive, being 13 times better than acetyl salicylic acid, recorded with a Bruker AC-200F spectrometer at 400
possibly due to additional non-covalent interactions MHz and 100 MHz, respectively. CDCl3 and DMSO
with the COX active site (Walter et al., 2004).
In this paper, we described the analgesic potential of as the internal standard; chemical shifts (
were used as solvents with tetramethylsilane (TMS),
) were in parts
δ
sulphonamide and sulphonyl-hydrazones cyclic imide per million. For the CHN analysis, a CHN elemental
derivatives, using the writhing test in mice and the eval- analyzer PERKIN ELMER 2400 was used. In the thin
uation of their theoretical, chemical and toxicological layer chromatography, aluminium sheets with silica
properties, by using a molecular modelling approach.
gel 60 F-254 and 0.2 mm thickness were used.
Fig. 1. Maleimide (1) and sulphonamide cyclic imide derivative (2) with analgesic profile.
Fig. 2. (a b) EtOH, r.t., 1 h, benzaldehydes.
) i. furan or 2-methylfuran, Et2O, r.t; ii. amine or N2H4, MeOH, ~ 0oC, (

Antinociceptive Activity of Sulphonyl Derivatives
1715
for each compound was calculated, using the Crippen
Biological assays
The abdominal constrictions test (writhing tests) was method available in the Spartan program (Jordão et
performed, according to the procedures described pre- al., 2011).
viously (Collier et al., 1968; Souza et al., 1998; Duarte
In this work, we used the Osiris program (http://www.
et al., 2006; Morales et al., 2006). The animals were pre- organic-chemistry.org/prog/peo/) to determine the com-
treated by intraperitoneal route with the compound pound drug-likeness, which was partially based on the
administered in three doses always starting to 10 mg/ topological descriptors, fingerprints of molecular drug
kg, increasing or decreasing depending on the results likeness structure keys or other properties as clogP
obtained, with the initial dose 30 min before the injec- and molecular weights (Ghose et al., 1999). In this pro-
tion with acetic acid (0.6%, 0.45 mL/mouse, respectively. gram the occurrence frequency of each fragment is de-
The control animals received a similar volume (10 mL/ termined within the collection of the traded drugs, and
kg, i.p.) of vehicle (an aqueous solution of DMSO 2%). within the supposedly non-drug-like collection of Fluka
After the challenge, pairs of mice were placed in sepa- compounds. We also submitted the most active com-
rate boxes and the number of abdominal constrictions pounds to an in silico ADMET screening, using the
was cumulatively counted, over a 20 min period. Antino- OSIRIS program to analyze their overall drugscore
ciceptive activity was expressed as the reduction in and toxicity risks (mutagenic, irritant, tumorigenic,
the number of constrictions in mice pretreated. The and reproductive effects), compared to the available
result was compared with the positive control, the stand- drugs used for chemotherapy.
ard drugs commercially used (acetyl salicylic acid and
acetaminophen). All experiments were carried out at
23 ± 2oC. Antinociceptive activity was expressed as
the number of abdominal contractions between the
control animals and mice pre-treated with the studied
compound.
RESULTS
Abdominal constrictions test
All compounds were evaluated in acetic acid-in-
duced abdominal constrictions (writhing) tests, using
mice as described in the literature (Souza et al., 1998;
Duarte et al., 2006). This initial screening assay (10
Statistical analysis
The results are presented as the mean ± S.E.M., and mL/kg, i.p.) revealed that all compounds were more
the statistical significance between the groups was an- active than acetyl salicylic acid and acetaminophen,
alysed by the means of variance, followed by Dunnett’s the standard drugs, at this concentration (Fig. 3). In
multiple comparison test.
P values of less than 0.05 fact all compounds are more potent than these stand-
were considered as indicative of significance. The ID50 ard drugs, when comparing the ID50 (e.g. compound
9
values (concentration of the compound that reduced was about 24 times more potent than acetyl salicylic
responses by 50% with respect to control values) were acid and acetaminophen) I (Table I).
estimated by graphical interpolation from individual
experiments. ID50’s are presented as the mean values the following order of potency:
with 95% confidence interval.
Then, an overall analysis of these results revealed
10 12 13
5 > 14 > 4 > 3 > acetyl salicylic acid > acetaminophen.
9
>
6
>
>
>
>
The ID50 of compound 11 was not possible to be deter-
mined, since the pain inhibition was over 50% with
Computational details
To identify stereo-electronic parameters of the sul- the lowest dose (3 mg/kg) used in pharmacological
phonamide and sulphonyl-hydrazone cyclic imide de-
rivatives, which could be correlated with the biological
activity, we performed a molecular modeling study,
using the Spartan'08 program (Wavefunction Inc). Ini-
tially, systematic conformational analyses of the com-
pounds were performed by using increments of 30 to
30 degrees in the flexible bonds, through the Merck
Molecular Force Field (MMFF) method. The lower en-
ergy conformer of each molecule with largest CPK area
was selected for a single point calculation, using the
Density Functional Theory method and basis set 6-31-
G*. Then we calculated the HOMO and LUMO coeffici-
ents and energies of the compounds, electronic density
maps and dipole moments. Also, the lipophilicity (cLogP)
Fig. 3. Comparison of the analgesic effect (%) of sulphona-
mides and sulphonyl-hydrazone cyclic imide derivatives
with acetyl salicylic acid (AAS) and acetaminophen (ACT) at
screening concentration (10 mg/kg) in acetic acid-induced
writhing in mice.

1716
K. N. de Oliveira et al.
Table I. Comparison of the analgesic effect (ID50 in mg/kg and mmol/kg) of sulphonamides and sulphonyl-hydrazone
cyclic imide derivatives and the standard drugs (acetyl salicylic acid - AAS and acetaminophen - ACT) in acetic acid-
induced writhing in mice
Energy (eV)
LUMO
Lipinski Rule of 5
ID50
(mg/kg)
ID50
mol/kg)
Dipole
(debye)
Compound
(µ
HOMO
∆E
cLogP
HBA HBD Molecular weight
3
4
5
6
9
10
11
12
13
14
AAS
ACT
32.01
26.61
15.91
4.32
2.40
5.62
< 3
8.40
15.44
28.95
24
85.49
68.16
40.95
10.68
5.12
-6.72
-6.31
-6.57
-6.31
-6.75
-6.17
-6.41
-5.30
-6.70
-5.94
-
-1.48
-1.66
-1.54
-1.65
-3.33
-1.61
-1.81
-1.36
-2.78
-1.45
-
5.24
4.65
5.03
4.66
3.42
4.56
4.60
3.94
3.92
4.49
9.21
7.84
7.47
7.66
8.42
6.95
5.18
6.03
11.24
4.97
4.67
2.68
0.04
-0.68
0.25
-0.46
1.71
1.55
1.28
1.95
1.92
1.50
1.17
0.55
8.00 0.00
9.00 0.00
8.00 0.00
9.00 0.00
12.00 1.00
10.00 1.00
10.00 2.00
10.00 1.00
12.00 1.00
10.00 2.00
2.00 1.00
3.00 2.00
374.41
390.41
388.44
404.44
468.44
453.47
439.44
466.51
482.47
453.47
180.15
151.16
12.39
6.83
18.01
32.00
63.84
133.0
125.0
18.8
-
-
The stereoelectronic properties of these derivatives have also been shown, including HOMO and LUMO energies (eV),
energy gap ( E), Dipole moment (debye) and calculated Lipinski parameters of lipophilicity (cLogP), volume (ų), area
(Ų), molecular weight, number of hydrogen bond acceptor (HBA) and donor (HBD).
∆
Fig. 4. Effect of Suphonamides (Compounds
3-6) administered intraperitoneally against acetic acid-induced writhing
response in mice. Each column represents the mean of six to eight mice and the error bar indicates the S.E.M. Control
values C indicate the mice injected with vehicle and the asterisks denote the significance levels when compared with control
groups (one-way ANOVA followed by Newman- Keuls test): **p < 0.01, ***p < 0.001. IM = maximum inhibition.
assays. In this case, it is assumed that the ID50 is less pharmacological profile with IMs calculated of 66.19%
than 3.0 mg/kg or 6.83 mmol/kg. and 66.13%, respectively (Fig. 4). Compound showed
The results obtained with the synthesized sulphona- an antinociceptive effect in a dose-dependent manner
mides when evaluated in the acetic acid induced model with calculated IM 74.02%. However, compound was
showed that compounds and exhibited the same the most effective by inhibiting 100% of the painful
6
5
3
4

Antinociceptive Activity of Sulphonyl Derivatives
process with a dose of 30 mg/kg.
1717
In the series of sulphonamides, derivative
6
with the
The results on the effects of mice treatment with sul- morpholine group linked to the sulphonamide group,
phonyl-hydrazones (Fig. 5) showed that compounds and the methyl group linked to oxabicyclo was the
9
,
10 and 11 reduced the number of writhing induced by most active compound. Importantly, the morpholine,
acetic acid in a dose-dependent mode (IMs calculated without the methyl group, decreased the activity to
of 92.02%, 94.50% and 97.71% respectively). Particular- around one sixth of the value (Table I). The overall
ly, we observe a rather pronounced analgesic effect of replacement of morpholine with a pyrrolidine group,
compound 11 with the lowest dose used in the phar- with or without a methyl group, decreased the activity
macological experiments. This compound reduced the of the compound; probably due to weaker van der
analgesia induced by acetic acid in more than 50%. Waals interactions between the derivatives and the
The compounds 12 and 13 reduced pain response of receptor (Table I).
animals in 76.20 and 95.83%, respectively, when com-
The sulphonyl-hydrazones (
9-14) differ in terms of
pared with their respective controls groups, while the the substituent linked to the aromatic ring next to the
compound 14 was the least effective of the tested deriv- sulphonyl-hydrazone moiety, and the methyl group
ative group.
linked to the oxabicyclo system. Compound 9 with the
nitro group at the para-position of the aromatic ring
showed the best activity. However, there is no signifi-
Molecular modeling studies
Fig. 5. Effect of Sulphonyl-hydrazones (Compounds
9-14) administered intraperitoneally against acetic acid-induced
writhing response in mice. Each column represents the mean of six to eight mice and the error bar indicates the S.E.M. The
control values C indicate the mice injected with vehicle and the asterisks denote the significance levels when compared with
the control groups (one-way ANOVA followed by Newman- Keuls test): **p < 0.01, ***p < 0.001. IM = maximum inhibition.

1718
K. N. de Oliveira et al.
cant difference in the distribution of the HOMO and to penetrate the biological membranes, as determined
LUMO coefficients or the electrostatic potential in these by the Lipinski “rule-of-five” (cLogP < 5, MW > 500, HBD
derivatives (Fig. 6). Interestingly, the lowest energy < 5 and HBA < 10) (Lipinski et al., 2001). Therefore, our
gap (
for the most active derivative (
least active derivative (14), indicating that the differ-
ences in the reactivity of these molecules may affect assess the drug-likeness and drug-score of a compound,
their biological activity (Table I). some based on topological descriptors (Tetko, 2005). In
∆
EHOMO LUMO
-
) of these derivatives were obtained results suggest a good theoretical oral bioavailability
), and highest for the for most of the series (Table I).
Currently, there are many approaches available to
9
The addition of a methyl group to the oxabicyclo ring the Osiris program (http://www.organic-chemistry.org/
in the structure of the compounds led to a decrease in prog/peo/) the occurrence frequency of each fragment
the activity of compounds 13 and 14. The superposition is determined within the collection of marketed drugs,
of derivatives
series) showed a specific conformation, apparently Fluka compounds. In this study, we submitted the most
being related to the highest activities (not shown). In potent compounds ( 10 11 and 12) to in silico
fact, compounds with conformations similar to derivative ADMET screening, using the Osiris program, to analyze
showed better activity (Fig. 6). their overall drug-score and drug-likeness potential
The electrostatic potential map of the series reveal- and toxicity risks (irritant, tumorigenic, and reproduc-
6, 9, 10, 11 and 12 (most active of this and within the supposedly non-drug-like collection of
6,
9,
,
9
ed two conserved regions in all derivatives related to tive effects) (Fig. 7). In addition, we compared them to
the presence of the oxygen atoms from the pyrrolidino- acetyl salicylic acid and acetaminophen, drugs that are
dione and sulphonyl groups. These conserved regions currently used for analgesic treatment.
may be related to the biological activity observed for
the whole series. The oxabicyclo derivatives ( 14)
Interestingly, the drug-likeness values for most of
the compounds were better than those for acetyl salicylic
9-
showed an increase in the electron density of the hydra- acid and acetaminophen (not shown). The only excep-
zone system in the central portion of the molecule, tion was with the nitro group, which is described in
which apparently reduces the biological activity (Fig. the literature as a group with mutagenic and cytotoxic
9
6).
profiles in other drugs, such as antiparasitic drugs
(Collier et al., 1968; Tocher, 1997; Buschini et al., 2007).
Nevertheless, the overall potential of
9, represented by
In silico ADMET evaluation and comparison
the drug-score value, was found to be similar to salicylic
with current drugs
In the in silico evaluation, the analysis of different acid and acetaminophen (Fig. 7). This theoretical feature
descriptors of all compounds (calculated octanol/water highlights this derivative as a potential analgesic pro-
partition coefficient, molecular weight, molecular volume, totype option for further evaluation and modification
and number of hydrogen bond donor and acceptor for the improvement, as this research proceeds. The
groups) revealed that they are sufficiently hydrophobic other active compounds showed higher values than
Fig. 6. Comparison of electronic parameters, including molecular electrostatic potential map (up), HOMO (medium) and
LUMO (down) orbital coefficients distribution of sulphonamides and sulphonyl-hydrazones (
most active ( ) and the less active (14) derivatives ( ). Molecular electrostatic potential in a 0.002 eV/au³ surface and energy
range varying from -165.0 kJ/mol (deepest red) to 210.0 kJ/mol (deepest blue).
A) and Structural alignment of
9
B

Antinociceptive Activity of Sulphonyl Derivatives
1719
Fig. 7. Comparison of the in silico ADMET screening including the overall drugscore and toxicity risks (tumorigenic - black,
irritant - gray, and reproductive effects - light gray) of the most active compounds and the available drugs used on
chemotherapy - acetyl salicylic acid (AAS) and acetominophen (ACT). The scale of toxicity risk ranges from low (0-1),
medium (1-2) and high (2-3) calculated by using Osiris program (http://www.organic-chemistry.org/prog/peo).
the control drugs, also being worthy of further investi- directly by inducing the release of endogenous media-
gation.
tors, stimulating the nociceptive neurons, which are
The lower or similar theoretical tumorigenic, irritant, sensitive to nonsteroidal anti-inflammatory drugs
and reproductive effects of these more potent derivatives (NSAIDs) and opioids (Collier et al., 1968; Mogil, 2009).
compared to the control drugs suggest a low risk drug- Acetic acid induces pain by enhancing PGE2 and PGF2α
like profile for these compounds (Fig. 7). This reinforces levels (Souza et al., 1998) at the receptors of peritoneal
their promising profile for testing in a further study. cavity (Bentley et al., 1983; Ramadan, 1997). Therefore,
It is important to note that the toxicity predicted here- this infers that any active compound acts indirectly by
in is not fully reliable, nor does it guarantee that these increasing the release of endogenous mediators and
compounds are completely free of any toxic effect, but stimulating the nociceptive neurons.
rather should be used as a base to guide the selection
of compounds for future in vitro and in vivo assays.
Acetic acid induces mice writhing movements - stretch-
ing of hind limbs and bending of trunk, which is a model
of visceral pain by causing irritation to peritoneum
(Collier et al., 1968; Vasudevan et al., 2007; Fernández-
Dueñas et al., 2011). This animal pain model has long
DISCUSSION
Our group has been working with the synthesis of been used as a screening tool for the assessment of an-
sulphonamides and sulphonyl-hydrazones of cyclic algesic or anti-inflammatory properties of new agents
imides derivatives (Walter et al., 2004; Oliveira and (Syková and Vyklický, 1978; Souza et al., 1998). Regard-
Nunes, 2006; Silva et al., 2006). These compounds less of the painful stimuli, the mechanism process
have a potential biological action due to the presence generally involves sensitization of the nociceptors,
of these two important groups in the same structure. transmission of impulses to the spinal cord and to the
The cyclic imide has been long studied because of its pain center in the thalamus, followed by integration of
pharmacological effect. The sulphonyl moiety has also the sensation in the sensory cortex as pain (Colleoni
therapeutic activity, as described previously. These two and Sacerdote, 2010).
groups in the same structure allowed the development
Based on the acetic acid assays features used to
of interesting molecules with important biological evaluate our compounds, the significant inhibitory
activities, such as, analgesic (Lima et al., 2000; Walter effects, observed for these new compounds, may have
et al., 2004) and antidepressant effects (Duarte et al., involved peripheral and/or cerebral mechanisms. Thus,
2006). In this context, four sulphonamides (
sulphonyl-hydrazones ( 14) were synthesized from through either peripherally at the site of nociceptors
-( -chlorosulphonyl)phenylmalemide, to evaluate the or centrally in the spinal cord or the brain. This can
3-6) and six the antinociceptive action of our derivatives may be
9-
N
p
feasibility of this analgesic profile. In this paper the only be pinpointed by investigating the influence of the
pharmacological model used was the in vivo model of compounds on the main sensitizers of the peripheral
acetic acid induced pain.
Past studies have postulated that acetic acid acts in-
nociceptors, mainly prostaglandins (Rainsford, 2007).
By comparing the results in
mol/kg, apparently the
µ

1720
K. N. de Oliveira et al.
methyl group linked to the oxobicyclic ring was impor- we explored the analgesic profile and several chemical
tant for the activity in the sulphonamides. Both com- properties of this series of sulphonamide derivatives.
pounds
dents
5
and
and
6
were more active than the correspon- Apparently, the sulphonyl-hydrazone moiety and the
3
4, without the methyl group, in contrast nature of the substituents introduced into the R2-Ph
to sulphonyl-hydrazones. Based on this experimental ring appear to be important in determining the bio-
result, the van der Waals force between the methyl group logical activity profile. Our SAR study also showed a
and the receptor is more important in sulphonamides relationship between the frontier orbital HOMO coeffi-
than in sulphonyl-hydrazones. The sulphonyl-hydra- cient distribution of some of these molecules and their
zones have the possibility for more hydrogen bonds reactivity. Despite their chemical structural differences,
with the receptor, in their structure. For this reason, the best analgesic compounds fulfilled the Lipinski
they probably have a different interaction with the “rule-of-five,” which, theoretically, is important for good
receptor. Then, in this case, the presence of this methyl drug absorption and permeation. Although the Osiris
group could avoid the formation of the hydrogen bonds risk alerts do not provide a fully reliable toxicity pre-
between the hydrazone moiety and the receptor that diction, the theoretically obtained low-toxicity profile
seems to be important for the bioactivity. Compounds of this series reinforces their potential as lead mole-
13 and 14 with the methyl group have a reducing cules for further synthetic and biological exploration,
biological effect compared to compounds
4B).
9
-
12 (Fig. for the development of new drugs in analgesic treatment.
The significant activity and theoretical profile of the
), which sulphonyl-hydrazones and 11 were highlighted in
The HOMO-LUMO energy gap (
∆
EHOMO LUMO
-
9
is related to the reactivity in chemical reactions, is an this study as the potential molecules for further inves-
important feature concerning the ability of a molecule tigation.
to react, and constitutes an important stability index
(Burdett and Coddens, 1988; Faust, 1989; Pearson,
1989; Tuppurainen et al., 1991). In fact, a large
ACKNOWLEDGEMENTS
∆
EHOMO LUMO
-
implies high stability and low reactivity
This research was supported by grants and fellow-
in chemical reactions, the contrary occurs when the ships from CNPq (Conselho Nacional de Desenvolvi-
EHOMO LUMO is small (Galeazzi et al., 2003). In our mento Científico e Tecnológico), CAPES (Coordenação
modeling studies, compound with the lowest energy de Pessoal de Nível Superior) and FAPERJ (Fundação
gap was the most active, whereas the less active was de Amparo à Pesquisa do Estado do Rio de Janeiro).
compound with the highest energy gap. This sug- We would like to thank the Núcleo de Investigações
gested that the higher reactivity of the compound Químico Farmacêuticas (NIQFAR) for the biological
∆
-
9
3
9
allowed for more interactions between this compound tests, as well, the work group of Prof. Helena C. Castro
and the receptor. However, this relationship is not ex- for the molecular modeling.
actly in accordance for all compounds, indicating that
the energy gap is not the only important factor for this
activity.
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