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STUDY OF
PYRAZINE SUBSTITUTED THIAZOLE DERIVATIVES
Introduction
Pyrazine Derivatives
as anti tubercular
PYRAZINE
activity:
Pyrazine is a heterocyclic compound contains two nitrogen
atoms in its aromatic ring with molecular formula C4H4N2.
Pyrazine and related heterocyclic compounds play an important
role as intermediates for pharmaceuticals, agricultural chemicals.
O
N
N
NH2
pyrazinamide
Thiazole
Thiazole is a heterocyclic compound featuring both a nitrogen atom
and sulfur atom as part of the aromatic five-membered ring. Thiazole and
related compounds are called 1, 3-azoles (nitrogen and one other
heteroatom in a five-membered ring).
Thiazoles are important class of heterocyclic compounds, found in many
potent biologically active molecules such as Sulfathiazol (antimicrobial
drug), Ritonavir (antiretroviral drug), Abafungin (antifungal drug) with trade
name Abasol cream and Bleomycine and Tiazofurin (antineoplastic drug).
THIAZOLE
Molecular docking
Molecular docking is a method to predict the preferred orientation
of one molecule to a second when bound to each other to form a
stable complex. Computers and programs (software) are used to
predict or simulate the possible reaction (and interactions) between
two molecules based on their 3 dimensional structures.
AutoDock
AutoDock is a Molecular modeling simulation software. Since
2009, it has been open source and is free for non-commercial
usage. It is especially effective for Protein-ligand docking.
AutoDock is a suite of automated docking tools. It is designed to
predict how small molecules, such as substrates or drug
candidates, bind to a receptor of known 3D structure.
Used prior to the experimental screening, the molecular docking,
can be as a powerful computational tool to reduce the labor and
cost of drug development.
AutoDock consists of two main programs:
AutoDock for docking of the ligand to a set of grids describing
the target protein;
AutoGrid for pre-calculating these grids.
Ligand or guest or key The complementary partner molecule which binds to the
receptor. Ligands are most often small molecules but could also be another
biopolymer.
Docking Computational simulation of a candidate ligand binding to a receptor.
Binding mode The orientation of the ligand relative to the receptor as well as the
conformation of the ligand and receptor when bound to each other.
Pose A candidate binding mode.
Scoring The process of evaluating a particular pose by counting the number of
favorable intermolecular interactions such as hydrogen bonds and hydrophobic
contacts.
Ranking The process of classifying which ligands are most likely to interact
favorably to a particular receptor based on the predicted free-energy of binding.
EXPERIMENT - SCHEME
STEP I: Synthesis of 2-amino thiazole Derivatives
R2
R2
NH2
R1
O
NH2
R3
thiourea
R3
R1
H2N
I(a-j)
Substituted Acetophenone
2-aminothiazole derivatives
N
N
COOH
+
H2N
R2
R1
N
R3
R1
R3
NH
6-chloropyrazine-2-carboxylic acid
Cl
II(a-j)
Substituted 2-aminothiazole derivative
List of Substituents:
Compound
R1
IIa
CH3
IIb
OCH3
IIc
IId
NO2
OCH3
R2
R3
---H
---H
---H
---H
---H
---H
OCH3
IIe
---H
OCH3
---H
CF3
IIf
----OH
IIg
CH3
C
OCH3
OCH3
---H
---H
CH3
CH3
IIh
-----Br
---H
---H
IIi
-----Cl
---H
---H
IIj
----OH
---H
OCH3
b)
Open in Pymolwin
Running AutoDock4 :
Docking calculations were performed using Auto dock
software (version 4).
[Make sure the AutoDock executable is in the same
directory as the macromolecule, ligand, GPF, DPF and flex
files
Running: Run Run AutoDock... Launch.
H
N
N
Cl
6-chloro-N-(4-p-tolylthiazol-2-yl)pyrazine-2-carboxamide
H
N
N
Cl
OCH3
6-chloro-N-(4-(4-methoxyphenyl)thiazol-2-yl)pyrazine-2carboxamide
H
N
N
Cl
NO2
6-chloro-N-(4-(4-nitrophenyl)thiazol-2-yl)pyrazine-2-carboxamide
H
N
N
O
S
Cl
6-chloro-N-(4-(3,4,5-trimethoxyphenyl)thiazol-2-yl)pyrazine-2-carboxamide
H
N
N
N
Cl
S
N
CF3
6-chloro-N-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)pyrazine-2-carboxamide
S.No
H
N
N
N
Cl
OH
N
O
6-chloro-N-(4-(4-hydroxy-3,5-dimethoxyphenyl)thiazol-2-yl)pyrazine-2-carboxamide
H
N
N
S
C
Cl
N-(4-(4-tert-butylphenyl)thiazol-2-yl)-6-chloropyrazine-2-carboxamide
H
N
N
S
Br
Cl
N-(4-(4-bromophenyl)thiazol-2-yl)-6-chloropyrazine-2-carboxamide
H
N
N
S
Cl
Cl
6-chloro-N-(4-(4-chlorophenyl)thiazol-2-yl)pyrazine-2-carboxamide
10
H
N
N
N
Cl
S
OH
N
6-chloro-N-(4-(4-hydroxy-3-methoxyphenyl)thiazol-2-yl)pyrazine-2-carboxamide
Figure : 1 Docking results of compound IIa with the active site of the (DAHP). (PDB ID: 2B7O)
Docking studies are carried out against (DAHP). (PDB ID: 2B7O) :
binding energy =
-10.919 kcal/mole
Figure : 2 Docking results of compound IIb with the active site of the (DAHP). (PDB ID: 2B7O)
Docking studies are carried out against (DAHP). (PDB ID: 2B7O) :
binding energy = -11.790 kcal/mole
and hydrogen bond interactions were observed at Tyr533- 2.6 0,
Tyr936-3.4 0
Figure : 3 Docking results of compound IIc with the active site of the (DAHP). (PDB ID: 2B7O)
Docking studies are carried out against (DAHP). (PDB ID: 2B7O) :
binding energy = -11.919 kcal/mole
and hydrogen bond interactions were observed at Tyr533- 2.4 0,
Figure : 4 Docking results of compound IId with the active site of the (DAHP). (PDB ID: 2B7O)
Docking studies are carried out against (DAHP). (PDB ID: 2B7O) :
binding energy = -11.869 kcal/mole
and hydrogen bond interactions were observed at Tyr533- 2.4 0,
Leu812- 2.8 0
Figure : 5 Docking results of compound IIe with the active site of the (DAHP). (PDB ID: 2B7O)
Docking studies are carried out against (DAHP). (PDB ID: 2B7O) :
binding energy = -9.472 kcal/mole
and hydrogen bond interactions were observed at Tyr936- 3.0 0,
Leu812- 3.4 0
Tyr936-3.4 0
Figure : 6 Docking results of compound IIf with the active site of the (DAHP). (PDB ID: 2B7O)
Docking studies are carried out against (DAHP). (PDB ID: 2B7O) :
binding energy = -8.827 kcal/mole
and hydrogen bond interactions were observed at Tyr517- 3.0 0,
Leu812- 2.6 0
Figure : 7 Docking results of compound IIg with the active site of the (DAHP). (PDB ID: 2B7O).
Docking studies are carried out against (DAHP). (PDB ID: 2B7O) :
binding energy = -11.378 kcal/mole
and hydrogen bond interactions were observed at Tyr517- 3.0 0,
Leu812- 2.6 0
Figure : 8 Docking results of compound IIh with the active site of the (DAHP). (PDB ID: 2B7O)
Docking studies are carried out against (DAHP). (PDB ID: 2B7O) :
binding energy = -12.378 kcal/mole
and hydrogen bond interactions were observed at Tyr936- 1.9 0,
Figure : 9 Docking results of compound IIi with the active site of the (DAHP). (PDB ID: 2B7O)
Docking studies are carried out against (DAHP). (PDB ID: 2B7O) :
binding energy = -12.198 kcal/mole
and hydrogen bond interactions were observed at Tyr533- 2.0 & 2.4 0,
Figure : 10 Docking results of compound IIj with the active site of the (DAHP). (PDB ID: 2B7O)
Docking studies are carried out against (DAHP). (PDB ID: 2B7O) :
binding energy = -10.744 kcal/mole
and hydrogen bond interactions were observed at Tyr517- 3.0 & 2.2 0,
4).
Docking studies for the synthesized compounds were carried out against
3-Deoxy-D-arabino-heptulosonate-7-phosphate
(DAHP). (PDB ID: 2B7O)
Compounds
carboxamide
N-(4-(4-bromophenyl)thiazol-2-yl)-6-chloropyrazine-2(IIh),
6-chloro-N-(4-(4-chlorophenyl)thiazol-2-
activity
by
inhibiting
heptulosonate-7-phosphate
3-Deoxy-D-arabino(DAHP).
(PDB
ID:
(Kcal/mole)
Rank
(Based on binding
energy)
IIa
-10.919
IIb
-11.790
IIc
-11.919
Tyr533- 2.4
IId
-11.869
IIe
-9.4722
IIf
-8.8279
Tyr517-3.0, leu812-2.6
10
IIg
-11.378
Tyr517-3.0, leu812-2.6
IIh
--12.378
IIi
-12.198
IIj
-10.744
Tyr517-3.0, 2.2
References
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2.
Kadam SS, Mahadik KR, Bothara KG. Principles of medicinal chemistry, 6th ed.
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3.
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http://en.wikipedia.org/wiki/Tuberculosis
5.
http://en.wikipedia.org/wiki/Tuberculosis treatment.
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