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Transcript
COMPUTER AIDED PREDICTION OF BIOLOGYCAL ACTIVITY
OF NOVEL HETEROCYCLIC COMPOUNDS
V. Kurtskhalia*, T. Matitaishvili, I. Lagvilava, E. Elizbarashvili
Technical University of Georgia, Faculty of Chemical technology and metallurgy
INTRODUCTION
Today only the special chemical compounds undergo
testing on biological activity, because the screening is
very long-time and expensive process. To these
special compounds commonly belong drugs;
emulsifiers; test-modifiers; colorants and pigments
used in food technology, body-care, etc. But the
number of chemicals, to which humans have direct
contact in everyday life, is rather larger and each of
them, especially organic ones, has some biological
activity1.
ABSTRACT
Moreover, the number of existing potentially biological
active compounds is expected to increase from about
500 to about 5000–10,000 in each years. Thus,
experimental evaluation of potential biological activity
is becoming more complicated2.
Today only the special chemical
compounds undergo testing on
biological activity, because the
screening is very long-time and
expensive process. To these special
compounds commonly belong
drugs; emulsifiers; test-modifiers;
colorants and pigments used in food
technology, body-care, etc. But the
number of chemicals, to which
humans have direct contact in
everyday life, is rather larger and
each of them, especially organic
ones, has some biological activity.
Computer-aided structure–activity relationship analysis
and molecular modeling are widely used now by
pharmaceutical and non- pharmaceutical chemists to
discover new lead compounds and optimize their
structure and properties. However, the majority of
available approaches are focused on a single
macromolecular target, or on the only known
pharmacological/biochemical action, and/or
compounds from the same chemical series. Most
(Q)SAR methods are focused on a single biological
activity, whereas in reality each compound has both
main and side pharmacological effects. Therefore, in
the current report PASS C&T has been used for
calculation of biological activity of novel heterocyclic
systems.
The one way to avoid of this
problem is prediction of biological
activity by special software.
In the current report PASS C&T has
been used for calculation of
biological activity of novel
heterocyclic systems.
EXPERIMENTAL
SYNTHESIS
All of the chemicals used were of commercial grade
and were further purified by recrystallisation and
redistilled before use. The solvents used were
spectroscopic grade. 1H NMR spectra were obtained
by use of BRUKER WM-300 (300MHz). The IR spectra
were obtained on a Thermo Nikolet spectrometer
scanning between 4,000-400 cm-1 using KBr pellets.
UV-Vis absorption spectra were measured in CF-26
spectrometer. Elemental analyses were performed
using Heraeus CHNO-Rapid analyzer. Melting points
were determined by Electrothermal 9100.
General procedure of preparation of aldehydes.
To a stirred solution of bisphenol in ethanol (150 mL)
was added the solution of sodium hydroxide (3.2 g, 80
mmol) in water (20 mL). The reaction mixture was
heated up to 80 °C. Then, chloroform (9 mL, 0.11 mol)
was added dropwise and the reaction mixture was
boiled for a period of 1 hour. The excess of ethanol and
chloroform was distilled. Hydrochloric acid was added
subsequently until pH 5-6. The residue was dissolved
in the minimal amount of diethyl ether and equal
amount of saturated solution of Na2S2O5 was added.
The mixture was kept for 24 hours and the precipitated
solids were filtered off. The solid was dissolved in
water and treated with sulfuric acid (10%). The yellow
crystals were obtained by filtration and dried on air.
For molecular modeling studies, structures were
generated with the aid of Chem3D Ultra-9.00 and
HyperChem-v.6.02, Wolfram Reserach Mathematics
6.0 software. Lone pairs of electrons and hydrogen
atoms were added where appropriated. The
equilibrium geometries of compounds were located
using MM+ (for HyperChem) and MM2 (for Chem3D)
functional set. In the next step, RHF calculation
(semiempirical AM1 method, self-consistent field of
Hartree - Fock) were performed and bond length,
angles, torsion angles and partial charges have been
calculated. Calculations were performed on a Intel (R)
Core2 (TM) CPU [email protected] 2.4 GHz Pentium IV
computer with 2 MB RAM.
TABLE 1. Spectrum of Pharmacological Activity Predicted for
Compound 1
ACTIVITY TYPE
AIM
The purpose of this work was to study the possibility of
synthesizing the novel heterocyclic systems 1-4 and
to investigate the spectral and pharmacological
properties of the synthesized compounds.
OH
R
CONTACT
Prof. Elizbar Elizbarashvili, D.Sc
Technical University of Georgia
77 Kostava Street, Tbilisi, 0175
Georgia
OH
R
N N
N N
R
OH
R
OH
1
R1 O
NH
NH
O
2
R1 O
HN
HN
R1 3O
R1 O
HN
NH
NH
HN
O
NH
NH
R1
Figure 1. Geometrically optimized model of 1
4
where: R=H, Br COH; R1= H, Alk (C1-C11)
Email: [email protected]
Phone: (995 91) 191 -723
Website:
http://www.gtu.ge/katedrebi/dep33/el
iz/index.htm
Scheme 1. Synthesis of macrocyclic polyazomethines 1.
Figure 2. Charge distribution in 1
Poster Design & Printing by Genigraphics® 800.790.4001
General procedure of preparation of macrocyclic
polyazomethines 1.
Into the four-necked flask fitted with two dropping
funnels, mechanical stirrer and reflux condenser
2-propanol (100 mL) was placed and heated until
boiling. The solution of aldehydes (1.0 mmol) in 2propanol (10 mL) and freshly obtained hydrazine
hydrate (2.2 mmol, 50%) were added from different
dropping funnels simultaneously for a period of 30
min. The reaction mixture had been heated for 1 hour
and precipitated pale yellow crystals were isolated.
Probability, %
active
inactive
Antimicrobial
Reversible MAO inhibitor
Antihelminthic
Antifungal
Antihypoxic
Dopaminergic receptor stimulator
78
71
63
60
52
1
3
4
3
14
41
9
Antitrichomonacidal
Mutagenic
Antituberculous
Myorelaxant
MAO inhibitor
Antiallergic
Antiviral
Antiprotozoal
Reversible acetylcholinesterase inhib.
Antispirochetal
Antiparkinsonic
Immunomodulator
Antiandronogenic
35
40
36
36
30
30
34
24
27
23
32
31
24
5
12
13
15
17
17
23
13
17
14
27
26
23
ESTIMATION
A potential pharmacological activity of compounds 1-4,
was estimated using a computer program PASS C&T
(Prediction of Activity Spectrum for a Substance), which
is capable of predicting some types of activity of a given
compound upon analysis of its structural formula. The
prognosis is based on the structure-activity relationships
established by analysis of the data for more than 10,000
compounds forming the learning sample set. The PASS
system either predicts the possible type of
pharmacological activity or indicates a possible
mechanism of the biological
action. The activity prognosis has the form of a
probability of the corresponding manifestations or their
absence, since the learning sample set contains data on
both definitely active and definitely inactive compounds.
An analysis of the prognosis suggests the possible
biological activity of compounds 1-4 studied. The
experimental investigation showed that compounds 1-4
exhibited weak antibacterial activity with respect to both
the Gram-positive and Gram-negative species (table 1).
CONCLUSIONS
The polyazomethines 1 were obtained in two steps
from corresponding bis-phenols with consecutive
conversions of carbonylation under Reimer- Tiemann
conditions and condensation with hydrazine hydrate.
The satisfactory purity of aldehydes have been
achieved by purification via corresponding bisulphite
derivatives (see scheme 1)3-5.
Pyridone and dipyridone containing heterocyclic
compounds 2-4 have been synthesized from
corresponding amino anthraquinones with acylation,
cyclization and aminolysis reactions.
The spectral investigation of obtained compounds are
in good agreemnet with calculated one.
The posibility of formation of 1-4 is also confirmed with
quantum-chemical calculation.
REFERENCES
1. Poroikov V., Filimonov D. (2001) Rational Approaches to Drug
Design, Eds. H.-D. Holtje, W.Sippl, Prous Science, Barcelona,
403-407
2. Geronikaki A., Lagunin A., Poroikov V., Filimonov D.,
Hadjipavlou-Litina D., Vicini P. (2002). 13 (3/4), 457-471.
3. Elizbarashvili E., Matitaishvili T., Topuria Kh. Journal of Brazilian
Chemical Society. 2007, 18, 6, 1254-1258.
4. Lagvilava I., Matitaishvili T., Iardalashvili I., Elizbarashvili E.
Collection of Czechoslovak Chemical Communications, 2008,
74, 3, 409-418.
5. E. N. Elizbarashvili, I. V. Lagvilava, Sh. A. Samsoniya.
Chemistry of Heterocyclic Compounds. 2005, 12, 1868-1869