Importance of the thiomorpholine introduction in new pyrrole derivatives as antimycobacterial agents analogues of BM 212

Article abstract of DOI:10.1016/S0968-0896(02)00455-8

During the course of our investigations in the field of azole antimicrobial agents, we have identified BM 212, a pyrrole derivative with good in vitro activity against mycobacteria and candidae. These findings prompted us to prepare new pyrrole derivative

Full text of DOI:10.1016/S0968-0896(02)00455-8

Bioorganic & Medicinal Chemistry 11 (2003) 515–520
Importance of the Thiomorpholine Introduction in
New Pyrrole Derivatives as Antimycobacterial
Agents Analogues of BM 212
Mariangela Biava,a,* Giulio Cesare Porretta,a Delia Deidda,b Raffaello Pompei,b
Andrea Tafic and Fabrizio Manettic
a
`
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Universita ‘La Sapienza’,
P.le A Moro 5, 00185 Rome, Italy
b
`
`
Cattedra di Microbiologia Applicata, Facolta di Scienze Matematiche Fisiche Naturali, Universita degli Studi di Cagliari,
Via Porcell 4, 09124 Cagliari, Italy
`
Dipartimento Farmaco Chimico Tecnologico, Universita degli Studi di Siena, Via Aldo Moro snc, 53100 Siena, Italy
c
Received 31 May 2002; accepted 19 September 2002
Abstract—During the course of our investigations in the field of azole antimicrobial agents, we have identified BM 212, a pyrrole
derivative with good in vitro activity against mycobacteria and candidae. These findings prompted us to prepare new pyrrole
derivatives 1–10 in the hope of increasing the activity. The microbiological data showed interesting in vitro activity against
Mycobacterium tuberculosis and atypical mycobacteria.
# 2002 Elsevier Science Ltd. All rights reserved.
Introduction
Most of the synthesized compounds showed interesting
antifungal and antimycobacterial activities, but, among
them, BM 212 proved the most active, and it appeared
to be endowed with particularly potent and selective
antimycobacterial and antifungal properties.
The resurgence of tuberculosis (TB) is by now sadly
remarkable. Moreover, the drug-resistant TB has
become a serious concern as increasing numbers of TB
cases are reported to be caused by strains of Myco-
bacterium tuberculosis resistant to one or more anti-
tuberculosis drugs.1À3 An urgent need exists for the
development of new antimycobacterial agents with a
unique mechanism of action that, endowed with differ-
ent mode of action, look like a possible solution of this
problem. Moreover, since in immunocompromised
patients, tubercular pathology is very often accom-
pained by mycotic infections caused by Candida albi-
cans, Candida sp. and Cryptococcus neoformans, this
concomitance has suggested a search for new substances
able to act both as antifungals and antimycobacterials.
It was also active against drug resistant mycobacteria of
clinical origin, including strains resistant to Etham-
butol, Isoniazid, Amikacin, Streptomycin, Rifampin
and Rifabutin, and against intracellular mycobacteria,
residing in the U937 human histiocytic lymphoma cell
line, after 7 days of contact.4
Then, since BM 212 was also active against C.albicans
and Candida sp., we considered BM 212 a promising
lead for the discovery of more potent agents with both
antifungal and antimycobacterial activities.
Previously, we have reported on the synthesis of both
antimycobacterial and antifungal activities of some
pyrrole derivatives,4À6 and it was the first report
regarding pyrrole compounds on this topic.
Consequently, we pursued a program to systematically
modify structure BM 212 but the first modifications
have not increased its activity,5 nevertheless they
allowed us to point out the importance of substituents
in C5 and N1. As a consequence, we synthesized other
derivatives,6 in which we alternatively introduced
N-methylpiperazine or thiomorpholine at C3 of the
pyrrole and introduced a phenyl ring in N1 and C5 of
the pyrrole ring unsubstituted or substituted with a
*Corresponding author. Tel.: +39-06-4991-3812; fax: +39-06-4991-
3133; e-mail: mariangela.biava@uniroma1.it
0968-0896/03/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(02)00455-8

516
M.Biava et al./ Bioorg.Med.Chem.11 (2003) 515–520
chlorine atom. The choice to employ the thiomorpho-
line has been done on the basis of what was observed by
Barbachyn,7 while the introduction of the phenyl rings
was on the basis of what was previously observed by us.
As a consequence, the pharmacophore model has been
applied to rationalize the structure–activity relationship
data of the new compounds described in this paper.
New compounds exhibited good in vitro activity
against both M.tuberculosis and non tuberculosis
species of mycobacteria and a similar behavior for
both thiomorpholine and N-methylpiperazine deriva-
tives; moreover the presence of the chlorine atom at
C5 in the phenyl moiety seemed to be an important
parameter for the activity against atypical myco-
bacteria.
Chemistry
Compounds 1–10 were prepared as illustrated in
Scheme 1, from the appropriate 1,4-diketone, obtained
by reacting levulinic acid and chorobenzene in the pres-
ence of AlCl3. The Mannich bases were obtained by a
procedure previously described by us.5
All new compounds were identified by elemental
analyses and NMR data are reported in the Experi-
mental only for compounds 1 and 2 as representative
of N-methylpiperazine and thiomorpholine derivatives,
respectively.
In any case, none of them was found to be more active
than the lead compound BM 212.
The above findings suggest further studies directed
towards improving the inhibitory activities and reducing
the cytotoxicity of BM 212.
Physicochemical data for compounds 1–10 are shown in
the References section.
In this paper, we report the synthesis of new compounds
1–10 alternatively introducing N-methylpiperazine or
thiomorpholine at C3 of the pyrrole and substituting
para position of the phenyl ring in N1 and/or C5 of the
pyrrole ring with Cl or F atoms.
Results
The in vitro activities of compounds 1–10 against M.
tuberculosis 103471, M.gordonae 6427, M.smegmatis
103599, M.marinum 6423 and M.avium 103317 are
listed in Tables 1 and 2. The Cytotoxicity and Protection
As reported in the Experimental we carried out the same
biological screening previously performed to better
compare the activity of new compounds with those pre-
viously tested. BM 212 was obviously employed as the
reference compound.
Moreover, we previously built and optimized a four-
feature pharmacophore model for antitubercular com-
pounds with different structures, and consisting of a
hydrophobic, a hydrogen bond acceptor group and two
aromatic ring pharmacophore features.8
A preliminay superimposition between the most active
compound of this series and the model evidenced that
2 possessed appropriate structural elements to interact
with all the features of the pharmacophore model itself.
This finding led to the suggestion that the new com-
pounds 1–10 were characterized by chemical functions
similar (in physicochemical properties and three-
dimensional arrangement) to those of the antitubercular
compounds used to generate the pharmacophore model
and, thus, they all can share the same receptor binding site.
Scheme 1.

M.Biava et al./ Bioorg.Med.Chem.11 (2003) 515–520
517
Index (PI) were also evaluated for all synthesized com-
pounds and data are reported in Table 1. None of the
investigated compounds was found to be active against
C.albicans , Candida sp., C.neoformans , Gram-positive
or Gram-negative bacteria, viruses and isolates of
pathogenic plant fungi (data not shown).
2 proved to be the most active compound, and both its
activity and PI are comparable to those of reference
compounds. These findings confirm what was reported
about the introduction of the fluorine atom in a struc-
ture, regarding better activity and lower toxicity.
As 2 is an analogue of BM 212, we also tested it against
intracellular and resistant mycobacteria, and data are
reported in Tables 3 and 4. All of the tested strains were
inhibited by compound 2, and it exerts bactericidal
activity also on intracellular mycobacteria. The MIC is
comparable to that of Rifampin, even though it is
higher than BM 212. This result is very important
because mycobacteria can reside for years inside lym-
phoid cells and macrophages, and traditional drugs are
not able to get through it. One other important aspect is
the high selectivity of derivatives 2, 4, 6, 8 and 10
against mycobacteria. In fact, these compounds are very
active only against M.tuberculosis , while they are com-
pletely inactive against atypical mycobacteria, with the
exception of 2 that is also active against M.avium (see
Table 2).
Discussion
Antimycobacterial activity
Interesting results were obtained from data regarding
antimycobacterial activity. In fact, compounds 2, 4, 6, 8
and 10 not only show a remarkable in vitro activity against
M.tuberculosis , but they were also only slightly toxic. In
particular, compounds 2 and 4 were the most active.
It is important to point out that compound 2, besides
being more active than the lead compound BM 212,
shows a very good Protection Index (PI). In particular,
Table 1. Cytotoxicity, in vitro activity against M.tuberculosis and
Protection Index (PI) of compounds BM 212, 1–10, Isoniazid, Strep-
tomycin and Rifampin
In conclusion, compound 2 is the most potent pyrrole
derivative studied so far, more potent, less toxic and
more selective than BM 212, the lead compound for this
class of antimycobacterial agent, that shows, differently
from 2, also anticandida activity. A chloro atom simul-
taneously in the para position at both N1 and C5 of
the pyrrole seems to be essential for the antimycotic
activity.
Compound
MIC (mg/mL)
Protection
Index (PI)
MTD50
VERO cells
M.tuberculosis
103471
BM 212
1
2
3
4
4
16
8
4
4
0.70
16
0.4
16
0.5
5.6
1
20
0.25
8
Computational investigations
5
6
7
8
9
10
8
8
16
8
16
8
32
>64
64
16
2
16
1
2
1
0.25
0.5
4
1
8
8
Considering biological data, it is possible to observe
that activity of compounds 1–10 is markedly affected by
replacement of the N-methylpiperazine moiety with a
thiomorpholine group, with compounds 2 and 4 show-
ing the best values of in vitro activity toward M.tuber-
culosis (0.4 and 0.5 mg/mL, respectively). Moreover, in
the thiomorpholino series, monofluoro derivatives 2 and
4 are more active than the corresponding dihalogenated
counterparts 6, 8, and 10.
8
Isoniazid
Streptomycin
Rifampin
128
128
213
0.50
0.3
Table 2. In vitro activity against M.smegmatis , M.marinum , M.
gordonae and M.avium of compounds BM 212, 1–10, Isoniazid,
Streptomycin and Rifampin
To further analyze the relationships between the struc-
tural properties of compounds 1–10 and their relative
activity data, we have applied a pharmacophore model
recently built8 and optimized9 by our research group
starting from compounds belonging to different struc-
tural classes of known antitubercular agents.
Compound
MIC (mg/mL)
M.smegmatis M.marinum
103599
M.gordonae M.avium
6427 103317
6423
BM 212
1
2
3
4
5
6
7
8
25
100
>100
0.4
>16
2
16
16
>16
>16
>16
16
The aim of the current computational study was the
investigation of the structural features of compounds
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
64
>16
>16
16
>16
>16
>16
>16
16
8
>16
16
32
0.6
>16
>16
>16
>16
16
>16
>16
>16
>16
16
Table 3. Inhibition of intramacrophagic M.tuberculosis
compound 2 and Rifampin
of
Compound
MIC (mg/mL)
Inhibition of
intramacrophagic mycobacteria
9
10
>16
16
32
2
3
1
3
Isoniazid
Streptomycin
Rifampin
32
16
0.6
BM 212
Rifampin
8
32
8
0.3

518
M.Biava et al./ Bioorg.Med.Chem.11 (2003) 515–520
Table 4. Sensitivity of different strains of M.tuberculosis resistant to different inhibitors
Strains resistant N.
Streptomycin
Isoniazid
Rifampicin
Ethambutol
BM 212
2
M.tuberculosis 15
M.tuberculosis 150
M.tuberculosis 585
M.tuberculosis 535
M.tuberculosis 541
Sensitive
Sensitive
Sensitive
Sensitive
Resistant
Sensitive
Sensitive
Resistant
Sensitive
Resistant
Resistant
Resistant
Resistant
Sensitive
Sensitive
Sensitive
Sensitive
Sensitive
Resistant
Sensitive
Sensitive
Sensitive
Sensitive
Sensitive
Sensitive
Sensitive
Sensitive
Sensitive
Sensitive
Sensitive
1–10 responsible for antitubercular activity toward M.
tuberculosis, with a view to contributing to the under-
standing of the interaction of all these compounds with
the corresponding putative receptor. In this context, we
have assumed that all these compounds bind in the
same way to the receptor itself.
such compounds, the N1 nitrogen atom fulfills the HBA
feature.
Analysis of the fitting properties of the studied com-
pounds to the pharmacophore model allowed additional
considerations. In fact, within the thiomorpholino sub-
set, compound 4 showed a very similar orientation with
respect to 2, the fluorine atom occupying the hydro-
phobic feature and the pyrrole nucleus simply reversing
its orientation of 180ꢀ. Similarly, compounds 8 and 10
possess a fluorine atom (bound to the phenyl ring
attached to the pyrrole nitrogen) mapping HY. On the
contrary, the best orientation of 6 showed the chlorine
substituent matching HY and the fluorine atom lying in
an empty region of space adjacent to RA2.
Moreover, because no experimental data on the biolo-
gically relevant conformations of the selected com-
pounds are available, we resorted to a molecular
mechanics approach (the 2D–3D sketcher of Catalyst)10
to build the conformational models to be used in the
fitting procedure to the pharmacophore.
Evaluation of how well derivatives 1–10 are able to fit
the pharmacophore model highlighted that the chemical
functionalities of the model are all matched by the
chemical groups of 2 (Fig. 1), the most active compound
of the whole set, taken as a representative example of all
pyrrole derivatives. In particular, while the fluorine
atom occupies the hydrophobic feature (HY) of the
model, RA1 is matched by the phenyl ring bound to the
nitrogen of the pyrrole nucleus. Moreover, the second
aromatic ring feature (RA2) is mapped by the phenyl
ring at the 2-position of the pyrrole, and the sulfur atom
of the thiomorpholine ring is located inside the hydro-
gen bond acceptor feature, HBA. The last finding is
worthy of further consideration. Particularly, the loca-
tion of the sulfur atom allows the rationalization of the
best activity generally associated with the thiomorpho-
lino derivatives with respect to the corresponding
N-methylpiperazine analogues. In fact, for compounds
1, 3, 5, 7, and 9 we were unable to find a similar con-
formation characterized by the piperazine N4 nitrogen
atom as the hydrogen bond acceptor. Accordingly, for
In summary, the pharmacophore model was able to
rationalize two major structure–activity relationships
for these compounds. In particular, structures with a
thiomorpholine ring were found to better fit the model
with respect to the corresponding N-methylpiperazine
derivatives, in agreement with in vitro activity data
toward M.tuberculosis . Finally, a fluorine atom lying in
the region of HY was shown as a well-suited substituent
to allow a good fit of such compounds into the pharma-
cophore model and enhance their antitubercular activity.
Experimental
Melting points were uncorrected and taken on a
Fischer-Jones apparatus. Infrared spectra (Nujol mulls)
were run on a 297 Perkin-Elmer spectrophotometer.
NMR spectra were recorded for all the synthesized
compounds on a 200 Brucker spectrometer using deu-
terochloroform as solvent and TMS as internal stan-
dard. Microanalyses of compounds 1–10 were performed
by the Servizio di Microanalisi dell’Area di Ricerca di
Roma del CNR (Dr. F. Tarli, Dr. Petrilli and Mr. Dia-
netti). Carlo Erba aluminum oxide (activity II–III,
according to Brockmann) was used for chromatographic
purifications. Fluka Stratocrom aluminum oxide plates
with fluorescent indicator were used for thin-layer chro-
matography (TLC) to check the purity of the compounds.
Syntheses
Pyrroles 13. The title compounds were prepared accord-
ing to the general procedure previously described.5
Mannich bases 1–10. To a stirred solution of the appro-
priate pyrrole 13 (5.6 mmol) in 20 mL of acetonitrile, a
mixture of N-methylpiperazine or thiomorpholine (5.6
Figure 1. Compound 2 mapped to the pharmacophore model.

M.Biava et al./ Bioorg.Med.Chem.11 (2003) 515–520
519
mmol), formaldehyde (5.6 mmol) (40% in water) and 5
mL of acetic acid was added dropwise. After the addi-
tion was complete the mixture was stirred at room tem-
perature for 3 h. The mixture was then treated with a
solution of sodium hydroxide (20%, w/v) and extracted
with ethyl acetate. The organic extracts were combined,
washed with water and dried. After removal of solvent,
the residue was purified by column chromatography.
The eluates were combined after TLC control and the
solvent was removed to give the pure product.
MIC was defined as the lowest concentration of drug
that yielded an absence of visual torbidity. Stock solu-
tions of substances were prepared by dissolving a
known weight of agent in DMSO. The stock solutions
were sterilized by passage throught a 0.2 mm Nylon
membrane filter. Serial 2-fold dilutions of the com-
pounds with water were prepared. The tubes were incu-
bated at 37 ꢀC for 3–21 days. A control tube without
any drug was included in each experiment. Isoniazid
(INH), Streptomycin and pyrrolnitrin were used as
controls.
Physicochemical data are reported in Table 5.
Inhibitory activity of BM 212 and 2 on multidrug-resis-
tant and intramacrophagic mycobacteria. The myco-
bacteria used were M.tuberculosis 15, M.tuberculosis
150, M.tuberculosis 585, M.tuberculosis 535 and M.
tuberculosis 541. The MIC of the compound BM 212
was tested on multiresistant M.tuberculosis strain in
Middlebrook 7119 broth enriched with 10% ADC
(Difco) using the macrodilution broth method. The
bactericidal activity of BM 212 on intracellular
mycobacteria was studied on U937 cells (INC-
FLOW), a human histiocytic cell line. The cells were
differentiated into macrophages with 20 ng/mL of
phorbol myristate acetate (PMA, Sigma) and grown
in RPMI 1640 medium with 10% fetal calf serum.
1
1: H NMR (CDCl3) d: 1.98 (s, 3H, N–CH3), 2.29 (s,
3H, pyrrole 2-CH3), 2.45 (m, 8H, N-methylpiperazine 2
and 3-CH2), 3.42 (s, 2H, CH2–N), 6.30 (s, 1H, pyrrole
4H), 7.1–7.34 (m, 10H, aromatic protons).
1
2: H NMR (CDCl3) d: 1.97 (s, 3H, pyrrole 2-CH3),
2.56–2.69 (m, thiomorpholine 8H), 3.39 (s, 2H, 3-CH2-
thiomorph), 6.24 (s, 1H, pyrrole 4H), 6.83–7.29 (m, 9H,
aromatic protons).
Microbiology
Compounds. All compounds 1–10 and drug references
were dissolved in DMSO at a concentration of 10 mg/
mL and stored cold until used.
Antimycotic activity. Antiyeast activity was tested with a
broth microdilution method12 and the minimal inhibi-
tory concentration (MIC), the range of MICs and the
mean susceptibility (nX) have been calculated as descri-
bed elsewhere.13 Ketoconazole and miconazole were
used for comparative studies.
Antimycobacterial activity. All compounds were pre-
liminarily assayed against two freshly isolated clinical
strains, M.fortuitum CA10 and M.tuberculosis B814,
according to the dilution method in agar.11 Growth
media were Mueller–Hinton (Difco) containing 10% of
OADC (oleic acid, albumine and dextrose complex) for
M.fortuitum and Middlebrook 7H11 agar (Difco) with
10% of OADC (albumine dextrose complex) for M.
tuberculosis. Substances were tested at the single dose of
100 mg/mL. The active compounds were then assayed for
inhibitory activity against a variety of mycobacterium
strains in Middlebrook 7H9 broth using the NCCLS
procedure. They are reported in Tables 1 and 2. The
mycobacterium species used were M.tuberculosis
103471 and among the atypical mycobacteria M.smeg-
matis 103599, M.gordonae 6427, M.marinum 6423 and
M.avium 103317 (from the Institute Pasteur collection).
Antiviral activity. Antiviral activity was assayed on
VERO cell monolayers infected with Herpes simplex
virus type 2 (HSV2) and Poliovirus type 1 (1S) (all from
NIH, USA). VERO cells in 24-cell culture plates were
infected with the viruses at a ratio of about 1000 cells/
viral infectious unit. After 48 h of incubation, the viral
cytopathic effect was detected under a light microscope
and the antiviral effect of drugs was reported as the dose
which inhibited by 50% the cytopathic effect of viruses
(ID50). Foscarnet was used as control.
Computational methods
In all cases, minimum inhibitory concentrations (MICs
in mg/mL) for each compound were determined. The
All calculations and graphic manipulations were per-
formed on a Silicon Graphics O2 workstation by means
of the Catalyst 4.6 software package.
Table 5. Chemical–physical data of compounds 1–10
All the compounds used in this study were built using
the 2D–3D sketcher of the program. A representative
family of conformations was generated for each mole-
cule using the poling algorithm and the ‘best quality
conformational analysis’ method.10 The parameter set
employed to perform all the conformational calcula-
tions derives from the CHARMm force field,14 oppor-
tunely modified and corrected.15
Compound
Mp (ꢀC)
Yield (%)
Formula (MW)
1
2
3
4
5
6
7
8
9
10
137–140
95–97
102–105
107–110
115–118
90–93
109–111
110–111
59–60
60
54
58
50
35
85
68
88
80
50
C23H26N3F (363.47)
C22H23N2SF (366.43)
C23H26N3F (363.47)
C22H23N2SF (366.43)
C23H25N3FCl (397.91)
C22H22N2SFCl (400.92)
C23H25N3F2 (381.46)
C22H22N2SF2 (384.47)
C23H25N3FCl (397.91)
C22H22N2SFCl (400.92)
The best quality conformational analysis approach has
been selected because it provides the best possible
conformational coverage within the catalyst.16
149–150

520
M.Biava et al./ Bioorg.Med.Chem.11 (2003) 515–520
Conformational diversity was emphasized by selection
of the conformers that fell within the 20 kcal/mol range
above the lowest energy conformation found.
References and Notes
1. Bass, J. B., Jr.; Farer, L. S.; Hopewell, P. C.; O’Brien, R.;
Jacobs, R. F.; Ruben, F.; Snider, D. E., Jr.; Thornton, G. Am.
J.Respir.Crit.Care Med. 1994, 149, 1359.
2. Davidson, P. T.; Le, H. Q. Drugs 1992, 43, 651.
3. Grosset, J. H. Bull.Int.Union Tuberc.Lung Dis. 1990, 65,
86.
4. Deidda, D.; Lampis, G.; Fioravanti, R.; Biava, M.; Por-
retta, G. C.; Zanetti, S.; Pompei, R. Antimicrob.Agents
Chemother. 1998, 3035.
The compare/fit command within the catalyst has been
used to predict activity values of the studied com-
pounds. Particularly, the best fit option has been selec-
ted which manipulates the conformers of each
compound to find, when possible, different mapping
modes of the ligand within the model.
5. Biava, M.; Fioravanti, R.; Porretta, G. C.; Sleiter, G.;
Ettorre, A.; Deidda, D.; Lampis, G.; Pompei, R. Med.Chem.
Res. 1999, 19.
Acknowledgements
6. Biava, M.; Fioravanti, R.; Porretta, G. C.; Deidda, D.;
1999, 9,
Supported by a contribution of the Istituto Pasteur
Fondazione Cenci-Bolognetti Universita di Roma ‘La
Sapienza’.
Maullu, C.; Pompei, R. Bioorg.Med.Chem.Lett.
2983.
7. Barbachyn, M. R.; Hutchinson, D. K.; Brickner, S. J.;
Cynamon, H.; Kilburn, J. O.; Klemens, S. P.; Glickman, S. E.;
Grega, K. C.; Hendges, S. K.; Toops, D. S.; Ford, C. W.;
Zurenko, G. E. J.Med.Chem. 1996, 39, 680.
Appendix. Microanalysis data for compounds 1–10
8. Manetti, F.; Corelli, F.; Biava, M.; Fioravanti, R.; Por-
retta, G. C.; Botta, M. Il Farmaco 2000, 55, 484.
9. Biava, M.; Fioravanti, R.; Porretta, G.C.; Deidda, D.;
Maullu, C.; Pompei, R. Med.Chem.Res. 2002, 11 (1), 50–66.
10. Catalyst Software; Accelrys, Inc.
11. Hawkins, J. E.; Wallac, R. J. Jr.; Brown, A. Antibacterial
Susceptibility Test: Mycobacteria. In Balows, A., Hausler, W.
J. Jr., Hermann, K. L., Isenberg, H. D., Shadomy, H. J., Eds.
Manual of Clinical Microbiology, 5th ed.; American Society
for Microbiology: Washington, DC, 1996.
12. McGinnis, M. R.; Rinaldi, M. G. Antibiotics in
Laboratory Medicine; Williams & Wilkins: Baltimore, 1986;
p 223.
Compd %C %H %N %S
%F %Cl
5.23
5.19
1
2
3
4
5
6
7
8
9
10
76.03 7.16 11.57
76.05 7.12 11.59
72.13 6.28 2.19 8.74 5.19
72.00 6.30 2.19 8.70 5.20
76.03 7.16 11.57
76.08 7.18 11.55
72.13 6.28 2.19 8.74 5.19
72.22 6.32 2.15 8.72 5.22
69.43 6.29 10.57
69.41 6.20 11.00
65.92 5.49 10.49 7.99 4.74 8.86 Calcd
65.96 5.52 10.44 8.00 4.71 8.89 Found
72.44 6.56 11.02
72.49 6.50 10.98
68.75 5.73 7.29 8.33 9.89
68.93 5.69 7.30 8.34 9.93
Calcd
Found
Calcd
Found
Calc
Found
Calcd
Found
5.23
5.27
4.78 8.93 Calcd
4.80 8.89 Found
13. Fioravanti, R.; Biava, M.; Porretta, G. C.; Lampis, G.;
Deidda, D.; Pompei, R. Med.Chem.Res. 1999, 162.
14. (a) Smellie, A.; Teig, S. L.; Towbin, P. J.Comp.Chem.
1995, 16, 171. (b) Smellie, A.; Kahn, S. D.; Teig, S. L. J.
9.97
10.02
Calcd
Found
Calcd
Found
Chem.Inf.Comp.Sci.
S. D.; Teig, S. L. J.Chem.Inf.Comp.Sci.
1995, 35, 285. (c) Smellie, A.; Kahn,
1995, 35, 295.
15. Brooks, B. R.; Bruccoleri, R. E.; Olafson, B. D.; States,
D. J.; Swaminathan, S.; Karplus, M. J.Comp.Chem. 1983, 4,
187.
16. Catalyst force field and potential energy functions are
described in the file REFenergy.doc.html provided by Accelrys
along with the program Catalyst 4.6.
69.52 6.30 10.58
69.55 6.27 10.60
65.92 5.49 10.49 7.99 4.74 8.86 Calcd
65.89 5.52 10.44 8.00 4.69 8.91 Found
4.79 8.93 Calcd
4.83 8.89 Found