Antimycobacterial compounds. New pyrrole derivatives of BM212

Article abstract of DOI:10.1016/j.bmc.2003.12.037

We have identified BM212 as a lead compound among a series of pyrrole derivatives with good in vitro activity against mycobacteria and candidae. First studies led us to synthesize some pyrrole compounds in which the thiomorpholine fragment was present. Some compounds revealed very active and these findings prompted us to prepare new pyrrole derivatives 2-15 in the hope of increasing the activity. The microbiological data showed interesting in vitro activity against Mycobacterium tuberculosis and atypical mycobacteria.

Full text of DOI:10.1016/j.bmc.2003.12.037

Bioorganic & Medicinal Chemistry 12 (2004) 1453–1458
Antimycobacterial compounds. New pyrrole derivatives of BM212
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
Cattedra di Microbiologia Applicata, Facolta di Scienze Matematiche Fisiche Naturali, Universita degli Studi di Cagliari, Via Porcell 4,
09124 Cagliari, Italy
b
`
`
c
`
Dipartimento Farmaco Chimico Tecnologico, Universita degli Studi di Siena, Via Aldo Moro snc, 53100 Siena, Italy
Received 29 July 2003; accepted 22 December 2003
Abstract—We have identified BM212 as a lead compound among a series of pyrrole derivatives with good in vitro activity against
mycobacteria and candidae. First studies led us to synthesize some pyrrole compounds in which the thiomorpholine fragment was
present. Some compounds revealed very active and these findings prompted us to prepare new pyrrole derivatives 2–15 in the hope
of increasing the activity. The microbiological data showed interesting in vitro activity against Mycobacterium tuberculosis and
atypical mycobacteria.
# 2004 Elsevier Ltd. All rights reserved.
1. Introduction
A program followed by us to systematically modify BM
212 led us to individuate the importance of the sub-
stituents in C5, N15 and C3.6 The microbiological
results showed the importance of the presence of the
thiomorpholine at C3 of the pyrrole and the p-chloro-
phenyl substituents in N1 and C5. The choice to employ
the thiomorpholine has been done on the basis of what
previously observed by Barbachyn,7 while the introduc-
tion of the p-Cl-phenyl rings on the basis of what was
previously observed by us.
The increase of tuberculosis (TB) cases due in particular
to the increased incidence of M.avium complex infection
in HIV-infected individuals, has prompted a vigorous
search for new drugs for the treatment of the disease.
The drug-resistant TB has become a serious concern as
increasing numbers of TB cases are reported to be
caused by strains of Mycobacterium tuberculosis resis-
tant to one or more antituberculosis drugs.1À3 An
urgent need exists for the development of new anti-
mycobacterial agents with a unique mechanism of
action, that, endowed with different mode of action,
look like a possible solution of this problem.
New synthesized compounds exhibited a good in vitro
activity against both M.tuberculosis and non tubercu-
losis species of mycobacteria and a similar behaviour
for both thiomorpholine and N-methylpiperazine deriv-
atives; moreover the presence of the chlorine atom in
the phenyl moiety at C5 seemed to be an important
parameter for the activity against atypical myco-
bacteria.
In our previous work we have reported on the synthesis
and both antimycobacterial and antifungal activities of
some pyrrole derivatives,4À6 and most of the synthesized
compounds showed interesting antimycobacterial activ-
ities. Among them, BM 212 revealed the most active,
and it appeared to be endowed with particularly potent
and selective both antimycobacterial and antifungal
properties.4
Moreover, we previously built and optimized a four-
feature pharmacophore model for antimycobacterial
compounds with different structure, and consisting in a
hydrophobic, a hydrogen bond acceptor group and two
aromatic ring pharmacophore features.8
Keywords: Pyrrole derivatives; Thiomorpholine substituent; Anti-
mycobacterial activity; Pharmacophore model.
* Corresponding author. Tel.: +39-6-49913812; fax: +39-6-49913133;
e-mail: mariangela.biava@uniroma1.it
More recently we synthesized new pyrrole derivatives9 and
among them, compound 1 was found more potent, less
toxic and more selective than the lead compound BM 212.
0968-0896/$ - see front matter # 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2003.12.037

1454
M.Biava et al./ Bioorg.Med.Chem.12 (2004) 1453–1458
Scheme 1.
The above findings suggest further studies directed
towards improving the inhibiting activities and reducing
the cytotoxicity.
From these results and as consequence of the computa-
tional studies, in this paper we report the synthesis of
new compounds 2–15, alternatively introducing thio-
morpholinomethyl, as in 1, or N-methylpiperazinemethyl,
as in BM 212 at C3 of the pyrrole ring, and substituting
the phenyl ring in N1 and/or C5 with more lipophylic
aromatic groups, as the a-naphtyl or with ortho-Cl or
ortho-F-phenyl groups. In fact, since these derivatives
possess the chemical features required by the pharma-
cophore model, we decided to apply it to compounds 2–
15, assuming that a-naphtyl or ortho-Cl or ortho-F-
phenyl groups, could furnish an increase in the super-
imposition with the aromatic areas of the model and, as
consequence, a better bind to the hypothetical receptor.
2. Chemistry
Compounds 2–15 were prepared as illustrated in
Scheme 1, from the appropriate arylaldehyde and
methyl vinyl ketone and 4-methylthiazolium bromide
modifying what reported in literature,10 about the reac-
tion conditions, as reported in the Experimental Part.
The pyrroles and the Mannich bases were obtained by a
procedure previously described by us.5
As reported in the experimental part we carried out the
same biological screening previously performed to bet-
ter compare the activity of new compounds with those
previously tested. BM 212 and 1 were obviously
employed as reference compounds.
All new compounds were identified by elemental ana-
lyses and NMR data, that were reported in the experi-

M.Biava et al./ Bioorg.Med.Chem.12 (2004) 1453–1458
1455
mental part only for compounds 2 and 3 as representa-
tive for thiomorpholine or N-methylpiperazine deriva-
tives respectively.
103317 are listed in Tables 1 and 2. Cytotoxicity and
Protection Index (PI) were also evaluated for all syn-
thesized compounds and data are reported in Table 1.
Physicochemical data for compounds 2–15 are shown in
Table 5.
4. Discussion
4.1. Antimycobacterial activity
3. Results
Interesting results were obtained from data regarding
antimycobacterial activity. In fact in general, by a com-
parison between N-methylpiperazine and thiomorpho-
line derivatives, we can confirm the importance of the
thiomorpholine introduction in the pyrrole structure
regarding the in vitro antimycobacterial activity.9 In
any case some considerations have to be done regarding
the substituent in N1 and C5. It is important to point
out that, contrary to our expectations, compounds 2, 4,
6 and 8 were less active and more toxic than the corres-
ponding p-F or p-Cl derivatives.9 These results under-
line that the fluorine atom in para position at both the
phenyl rings in N1 and/or C5 of the pyrrole ring is fun-
damental for the activity. In fact, compounds 2 and 4
are 20- and 8-fold less active than the corresponding
para fluoro derivative 1, respectively, suggesting that the
ortho substitution does not increase the superimposition
with the aromatic areas. The results are even worse for
compound 10 and 12, that are completely inactive. On
the contrary, for compound 14, in which both the
phenyl rings in N1 and C5 are unsubstituted, a very
interesting profile was found. It besides to be less toxic
than 1 and BM 212 shows also a very good Protection
Index (PI) (Table 1). In particular, even if 14 is not the
most active compound, its activity is comparable to that
of reference compounds and PI is the best among all the
compounds synthesized till now. This findings is in
contrast with what previously reported about the intro-
duction of the fluorine atom in a structure, about a
better activity and a lower toxicity.
The in vitro activities of compounds 2–15 against
Mycobacterium tuberculosis 103471, M.gordonae 6427,
M.smegmatis 103599, M.marinum 6423 and M.avium
Table 1. Cytotoxicity, in vitro activity against M.tuberculosis and
Protection Index (PI) of compounds BM 212, 1, 2–15, Isoniazid,
Streptomycin and Rifampin
Compd
MIC (mg/mL)
MTD50
VERO cells
M.tuberculosis
103471
Protection
Index (PI)
BM 212
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
4
8
8
2
4
2
2
4
2
4
4
2
4
0.70
0.4
8
5.6
20
1
—
1
>16
4
16
16
>16
16
>16
>16
>16
>16
>16
1
—
—
—
—
—
—
—
—
—
32
—
128
128
213
4
32
4
32
>64
64
16
Isoniazid
Streptomycin
Rifampin
0.25
0.50
0.3
Table 2. In vitro activity against M.smegmatis, M.marinum, M.
gordonae and M.avium of compounds BM 212, 1, 2–15, Isoniazid,
Streptomycin and Rifampin
As 14 is analogue of 1 and 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 14, and it exerts
bactericidal activity also on intracellular mycobacteria.
The MIC is the same of BM 212 and lower than
Rifampin and 1. This result is very important because
mycobacteria can reside for years inside lymphoid cells
and macrophage, and traditional drugs are not able to
get throw it. One other important aspect is the high
selectivity of derivative 14 against mycobacteria. In fact,
this compound is very active only against M.tubercu-
Compd
MIC (mg/mL)
M.smegmatis M.marinum M.gordonae M.avium
6427
103599
6423
103317
BM 212
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
25
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
64
100
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
8
>100
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
16
0.4
2
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
>16
16
Table 3. Inhibition of intramacrophagic Mycobacterium tuberculosis
of compound 1, 14, BM 212 and Rifampin
Compd
MIC (mg/mL)
Inhibition of intramacrophagic mycobacteria
>16
32
14
1
1
3
1
3
Isoniazid
Streptomycin
Rifampin
16
32
0.6
32
16
0.6
8
32
8
0.3
BM 212
Rifampin

1456
M.Biava et al./ Bioorg.Med.Chem.12 (2004) 1453–1458
Table 4. Sensitivity of different strains of Mycobacterium tuberculosis resistant to different inhibitors
Strains resistant N.
Strept.
Isoniazid
Rifamp.
Ethamb.
BM 212
1
14
M.tuberculosis 15
M.tuberculosis 150
M.tuberculosis 585
M.tuberculosis 535
M.tuberculosis 541
sa
s
s
s
rb
s
s
r
s
r
r
r
r
s
s
s
s
s
r
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
a Sensitive.
b Resistant.
losis, while it is completely inactive against atypical
mycobacteria, with the exception of M.avium (see Table 2).
the pharmacophoric model led to the finding that the
ortho-halogen is located in a region of space where any
pharmacophoric feature lies. It also suggested that a
decreased activity associated with an increased halogen
size could derive from an unfavorable steric interaction
between the same halogen atom and the corresponding
receptor counterpart.
In conclusion compound 14 is the most interesting pyr-
role derivative studied so far, as active and selective as 1
but less toxic than both 1 and BM 212.
Regarding compounds 10 and 12 bearing a 1-naphthyl
moiety at the nitrogen atom or at the position 5 of the
pyrrole nucleus, we found that such a large ring was
unable to satisfy at the same time the hydrophobic por-
tion HY and the aromatic region RA1 of the pharma-
cophore, with a consequent decrease in activity in
respect to the corresponding p-fluorophenyl derivatives.
5. Computational investigations
The new pyrrole derivatives have been computationally
analysed by means of the Catalyst software11 for their
fit properties to a pharmacophoric model previously
built from us for antitubercular compounds. As a result,
it has been highlighted that a fluorine atom at the para
position of one of the two aromatic rings directly linked
to the pyrrole nucleus, plays a crucial role for anti-
tubercular activity, according to our previously reported
data. In fact, compounds 2 (MIC=8 mg/mL) and 4
(MIC=4 mg/mL) were found 20- and 8-fold less active
than p-fluoro derivative (Figs 1 and 2) 1. This trend in
activity could be justified considering that the fluorine
atom at the para position is accommodated into the
hydrophobic region HY of the pharmacophoric model.
As a consequence, lacking such a substituent corre-
sponds to the impossibility of interacting with the
hydrophobic zone, with a consequent decrease in activ-
ity. Moreover, introduction of a halogen atom at the
ortho position instead of the para position was detri-
mental to activity. In fact, comparison of biological
data associated with 2, 4 and 8 suggested that increasing
the substituent size led to a decreased activity of the
corresponding compound. In addition, analysis of the
superposition model of the above three compounds into
Figure 1. 1 mapped to the pharmacophore model.
Table 5. Chemical-physical data of compounds 2–15
Compd
mp (ꢀC)
Yield (%)
Formula (MW)
2
3
4
5
6
7
8
9
10
11
12
13
14
15
95–96
Oil
90–91
73–74
70–71
oil
98–99
73–74
130–131
Oil
120–121
112–113
Oil
45
35
75
40
45
60
50
30
30
30
98
70
96
55
C22H23N2 SF (366.50)
C23H26N3 F (363.48)
C22H23N2 SF (366.50)
C23H26N3 F (363.48)
C22H23N2 SCl (382.96)
C23H26N3 Cl (379.94)
C22H23N2 SCl (382.96)
C23H26N3 Cl (379.94)
C26H26N2 S (398.57)
C27H29N3 (395.55)
Figure 2. Compound 2 (MIC=8 mg/mL) and the corresponding p-
fluoro derivative 1 (MIC=0.4 mg/mL) mapped to the pharmacophore
model. It is important to note that the orientation of both compounds
into the pharmacophore is very similar. The most important difference
in orientation is represented by the fact that 2 is unable to occupy the
HY hydrophobic region, with a consequent decrease of 20-fold in
antitubercular activity.
C26H26N2 S (398.57)
C27H29N3 (395.55)
C22H24N2S (348.51)
C23H27N3 (345.49)
104–107

M.Biava et al./ Bioorg.Med.Chem.12 (2004) 1453–1458
1457
All these considerations led to the suggestions that 1) an
aromatic system with a reduced overall size (with
respect to the naphthyl group) but more extended in
length (i.e., a biphenyl moiety), or (2) a phenyl ring
bearing a lipophilic group (such as a methyl, ethyl, or
isopropyl subtituent) at the para position could have
profitable interactions with the pharmacophoric model
(with a consequent enhancement in activity), especially
with its HY lipophilic portion.
6.1.2. Mannich bases 2–1. To a stirred solution of the
appropriate pyrrole 19 (5.6 mmol) in 20 mL of acetoni-
trile, a mixture of N-methylpiperazine or thiomorpho-
line (5.6 mmol), formaldehyde (5.6 mmol) (40% in
water) and 5 mL of acetic acid was added dropwise.
After the addition was complete the mixture was stirred
at room temperature for 3 h. The mixture was then
treated with a solution of sodium hydroxide (20%, w/v)
(100 mL) and extracted with ethyl acetate (200 mL).
The organic extracts were combined, washed with water
(200 mL) and dried. After removal of solvent, the resi-
due was purified by column chromatography. The elu-
ates were combined after TLC control and the solvent
was removed to give the pure product.
The thiomorpholino sulphur atom of each pyrrole deri-
vative corresponded to the hydrogen bond acceptor
feature of the pharmacophoric model.
Finally, the methyl group at the position 2 of the pyr-
role nucleus seemed to be not important for interacting
directly with the pharmacophoric elements. On the con-
trary, it played a crucial role in determining the
conformational properties of each compound, in parti-
cular the orientation of the aromatic ring directly linked
to the pyrrole nitrogen with respect to the side chain
bearing the thiomorpholine system. On the basis of all
the above results, compounds with unsubstituted phenyl
rings, such as 14, were found unexpectedly to have an
interesting profile that the pharmacophoric model is at
the moment unable to justify.
Physicochemical data are reported in Table 5.
1
2: Yield: 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).
1
3: Yield: H NMR (CDCl3) d: 1.98(s, 3H, N-CH3), 2.29
(s, 3H, pyrrole 2-CH3), 2.45 (m, 8H, N-methylpiper-
azine 2 and 3-CH2), 3.42 (s, 2H, CH2-N), 6.30 (s, 1H,
pyrrole 4H), 7.1–7.34 (m, 10H, aromatic protons).
6.2. Microbiology
6. Experimental
6.2.1. Compounds. All compounds 2–15 and drug refer-
ences were dissolved in DMSO at a concentration of 10
mg/mL and stored cold until used.
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 2–15 were
performed by the Servizio di Microanalisi dell’ Area di
Ricerca di Roma del CNR (Dr.F.Tarli, Dr. Petrilli and
Mr. Dianetti). Carlo Erba aluminum oxide (activity II-
III, according to Brockmann) was used for chromato-
graphic purifications. Fluka Stratocrom aluminum
oxide plates with fluorescent indicator were used for
thin-layer chromatography (TLC) to check the purity of
the compounds.
6.2.2. Antimycobacterial activity. All compounds were
preliminarily assayed against two freshly isolated clinical
strains, M.fortuitum CA10 and M.tuberculosis B814
according to the dilution method in agar.12 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 g/mL. The active compounds were then assayed for
inhibitory activity against a variety of mycobacterium
strains in Middlebrok 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).
6.1. Syntheses
6.1.1. Diketones 18. To a solution of the suitable ary-
laldehyde (0.09 mol), triethylamine (0.14 mol), methyl
vinyl ketone (0.07 mol) and 3-ethyl-5-(2-hydroxyethyl)-
4-methylthiazolium bromide (0.014 mol) were added.
The mixture was heated at 70 ꢀC for 24 h under nitrogen
atmosfere. At the end the mixture was treated with 2 N
HCl (10 mL) and after extraction with methylene chlo-
ride (200 mL), the organic layer was washed with aqu-
eous sodium bicarbonate (100 mL) and water (200 mL).
The organic fractions were dried over Na2SO4, filtered
and concentrate to give a crude product that was chro-
matographed (Al2O3; hexane/ethylacetate, 1/1).
In all cases, minimum inhibitory concentrations (MICs
in mg/mL) for each compound were determined. The
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.
6.1.2. Pyrroles 19. The title compounds were prepared
according to the general procedure previously described.5

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M.Biava et al./ Bioorg.Med.Chem.12 (2004) 1453–1458
6.2.3. Inhibitory activity of BM 212, 1 and 14 on multi-
drug-resistant and intramacrophagic Mycobacteria. The
mycobacteria used were M.tuberculosis 15, M.tubercu-
losis 150, M.tuberculosis 585, M.tuberculosis 535 and
M.tuberculosis 541. The MIC of the compound BM
212, 1 and 14 as 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, 1 and 14 on intra-
cellular mycobacteria was studied on U937 cells (INC-
FLOW), a human hystiocytic 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.
Compd
%C
%H
%N
7.03
7.02
10.62
10.62
7.03
%S
F
Cl
10
78.35
78.31
81.99
81.97
78.35
78.55
81.99
81.98
75.82
75.79
79.96
79.94
6.58
6.59
7.39
7.38
6.58
6.60
7.39
7.38
6.94
6.98
7.88
7.90
8.04
8.07
Calc
found
Calc
found
Calc
found
Calc
found
Calc
11
12
13
14
15
8.04
8.05
7.03
10.62
10.65
8.04
8.03
12.16
12.16
9.20
9.23
found
Calc
found
Acknowledgements
7. Computational methods
Supported by a grant of MIUR of Italy (40%). Uni-
versita di Roma ‘La Sapienza’.
All calculations and graphic manipulations were per-
formed on a Silicon Graphics O2 workstation by means
of the Catalyst 4.6 software package.
References and notes
All the compounds used in this study were built using
the 2D-3-D sketcher of the program. A representative
family of conformations were generated for each mole-
cule using the poling algorithm and the ‘best quality
conformational analysis’ method11 The parameter set
employed to perform all the conformational calcula-
tions derives from the CHARMm force field,13 oppor-
tunely modified and corrected.14
1. Hamilton, C. D. Curr.Infect.Dis.Rep. 1999, 1, 80.
2. Migliori, G. B.; Ambrosetti, M.; Fattorini, L.; Penati, V.;
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W. D., Jr. Clin.Infect.Dis. 2000, 31, 1495.
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retta, G. C.; Zanetti, S.; Pompei, R. Antimicrob.Agents
Chemother. 1998, 3035.
The best quality conformational analysis approach has
been selected because it provides the best possible con-
formational coverage within Catalyst.15
5. Biava, M.; Fioravanti, R.; Porretta, G. C.; Sleiter, G.;
Ettorre, A.; Deidda, D.; Lampis, G.; Pompei, R. Med.
Chem.Res. 1999, 19.
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Maullu, C.; Pompei, R. Bioorg.Med.Chem.Lett. 1999, 9,
2983.
Conformational diversity was emphasized by selection
of the conformers that fell within 20 kcal/mol range
above the lowest energy conformation found.
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,
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1997, 40, 1619.
The Compare/Fit command within Catalyst has been
used to predict activity values of the studied compounds.
Particularly, the Best Fit option has been selected which
manipulates the conformers of each compound to find,
when possible, different mapping modes of the ligand
within the model.
8. Table of microanalyses
11. Catalyst software, Accelrys, Inc.
Compd
%C
%H
%N
7.64
7.65
11.56
11.59
7.64
%S
F
Cl
12. Hawkins, J. E.; Wallace, R. J., Jr.; Brown, A. Anti-
bacterial susceptibility test: Mycobacteria. In Manual of
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W. J., Jr., Hermann, K. L., Isenberg, H. D., Shadomy,
H. J., Eds.; American Society for Microbiology:
Washington, D, 1991.
13. (a) Smellie, A.; Teig, S. L.; Towbin, P. J.Comp.Chem.
1995, 16, 171. (b) Smellie, A.; Kahn, S. D.; Teig, S. L. J.
Chem.Inf.Comp.Sci. 1995, 35, 285. (c) Smellie, A.; Kahn,
2
72.10
72.14
76.00
75.98
72.10
72.10
76.00
76.02
69.00
69.04
72.71
72.69
69.00
69.03
72.71
72.70
6.33
6.30
7.21
7.24
6.33
6.31
7.21
7.24
6.05
6.05
6.90
6.87
6.05
6.06
6.90
6.93
8.75
8.72
5.18
5.21
5.23
5.19
5.18
5.22
5.23
5.26
Calc
found
Calc
found
Calc
found
Calc
found
Calc
found
Calc
found
Calc
found
Calc
found
3
4
5
6
7
8
9
8.75
8.74
7.65
11.56
11.53
7.31
8.37
8.39
9.26
9.23
9.33
9.31
9.26
9.28
9.33
9.30
S. D.; Teig, S. L. J.Chem.Inf.Comp.Sci.
1995, 35, 295.
7.31
14. Brooks, B. R.; Bruccoleri, R. E.; Olafson, B. D.; States,
D. J.; Swaminathan, S.; Karplus, M. J.Comp.Chem.
1983, 4, 187.
15. 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.
11.06
11.09
7.31
7.30
11.06
11.10
8.37
8.34