INTRODUCTION:
Tuberculosis (TB), is an airborne
infectious disease caused predominantly by Mycobacterium tuberculosis
(MTB)1,2, it poses a major public health risk owing to the extended
period of treatment (around 6–9 months), associated with HIV infection, the
emergence of multidrug resistant, etc. Worldwide, TB is one of the top 10
causes of death and the leading cause from a single infectious agent (above
HIV/AIDS).
In 2017, TB caused an estimated 1.3 million
deaths among HIV-negative people and there were an additional 300000 deaths
from TB among HIV-positive people. Globally, the best estimate is that 10.0
million people developed a TB disease in 2017 ranging 5.8 million men, 3.2
million women and 1.0 million children. There were 27% cases in India were
reported for TB among the all over 22 countries. Drug-resistant TB continues to
be a public health crisis. The best estimate is that, worldwide in 2017, 558000
people have developed a TB that was resistant to rifampicin (RR-TB), the most
effective firstline drug, and of these, 82% had multidrug-resistant TB (MDR-TB)2.
In spite of enormous efforts to develop the antimycobacterial drug molecules,
tuberculosis still constitutes the leading killer disease. Therefore, the
discovery and development of new types of anti TB agents performing on novel
drug targets is urgently needed. Only a handful of compounds have entered human
trials, and it’s notable that the Nix-TB trial is the first TB clinical trial
to test a new drug combination such as pretomanid, bedaquiline and linezolid,
which has the possibility of being a shorter, all oral, and affordable treatment
for TB. The TMC207 (bedaquiline), OPC-67683 (delamanid) and PA-824 (pretomanid)
and AZD5847 are under development as potential TB drugs3. Hence,
from the above facts necessitated an urgent need to develop the novel
structural moieties having antimycobacterial properties.
Chalcones (1,3-diphenyl-2-propen-1-ones) are a major
sub class of flavonoids that possess the open chain flavonoids in which the two
aromatic rings are merged by a three-carbon α, β-unsaturated carbonyl
system4. They have been reported to own the excess of medicinal
benefits such as anti‐bacterial5,6, antiulcer7,
antifungal8, antioxidant9,10, vasodilatory11,
antimitotic12, antimalarial13,14, antileshmanial15,
and inhibition of chemical mediators release, inhibition of leukotriene B416,
inhibition of tyrosinase17, antiplasmodial18, and inhibition of aldose
reductase19, anti-inflammatory20,21, anti-gout22,
anti-histaminic23, anti-oxidant24, anti-obesity25,
anti-protozoal26, hypnotic27, anti-spasmodic28 and
etc. Apart from this, fascinatingly the many natural product inspired chalcone
analogues are exhibiting the significant antimycobacterial activity29.
The chemistry of chalcones remains fascination among
the researchers in the present scenario due to the large number of replaceable
hydrogens that allows a large number of derivatives and a variety of promising
biological activities. Recently, several research groups successfully
demonstrated their mode of action by identifying their molecular targets30.
A good safety profile, possibility of oral administration, and easy synthesis
are the major factors contributing to the growing interest in exploring the
pharmacological activities of chalcones. Despite medicinal applications of
chalcones, their wide bioactivity spectrum indicates a potentially promiscuous
target profile, which presents a challenge for clinical development31.
This is largely attributable to the electrophilic nature of the
α,β-unsaturated carbonyl system32.
In connection with this, the chalcone are considered
as an extremely good scaffold as key starting materials for the syntheses of
different classes of nitrogen containing heterocyclic compounds such as
pyrazolines, oxazoles, isoxazoles, thiophenes and pyrimidines, etc.33
Along with nitrogen containing five membered heterocycles, considerable
attention has been focused on pyrazolines conjugates owing to their fascinating
biological activities. The pharmaceutical importance of these compounds lies in
the fact that they can be effectively utilized as antibacterial, antifungal,
antiviral, antiparasitic, antitubercular, herbicidal, fungicidal, analgesic,
antioxidant, antipyretic, insecticidal, anticancer, antitumor, antidiabetic,
anticonvulsant, antidepressant and anti-inflammatory agents34,35. Pyrazolines
have been largely studied owing to their pharmacological activities36,37,
which includes anti-tumor38, anti-tubercular39,
anti-inflammatory40,41,42, anti-parasitary43,
anti-depressive, anticonvulsant44, antimicrobial45,46,47
antinociceptives48, anti fungal49, anti oxidant50
and nitric oxide synthase inhibitors, associated with diseases such as
alzheimer, and inflammatory arthritis51. Furthermore, Sameer et
al.,52 and Ali et al.,53 found that, the
pyrazole-isoniazid conjugates have an in-vitro activity against Mycobacterium
tuberculosis. Similarly, Sangeetha et al.,54 synthesized
some heterocyclic chalcone derivatives by using 2,4-dinitro phenyl hydrazine,
but they have tested for their antimicrobial activity. On the other hand, there
is a reasonable and limited work on pyrazole conjugates as an antimycobacterial
agents which is obtained by using 2,4 dinitro phenyl hydrazine.
In this context, and in view of our long
standing interest in the chemistry of the privileged chalcone scaffold
annulated pyrazoline motif, the study encouraged us to further explore the
pyrazoline motif as an active pharmacophore for further diversification to
exploit its anti TB potential. A classical synthesis of these compounds
involves the base-catalyzed aldol condensation reaction of ketones and
aldehydes to give α,β-unsaturated ketones (chalcones), which undergo
a subsequent cyclization reaction with hydrazines affording pyrazolines35.
Herein, the work describes the synthesis of some chalcone scaffold annulated
pyrazoline, and their in silico screening studies against mycobacterium
tuberculosis. To the best of our knowledge, there is limited reports on the
in silico study on antimycobacterial activities of these chalcone scaffold
annulated pyrazoline motif have been reported. However, there are numerous
examples of nitrogen containing heterocycles being used to treat TB, for
example Clofazimine, Isoniazid and Pyrazinamide. These compounds provide
structural priority that the chalcone scaffold annulated pyrazoline analogues
may lead to the generation of novel anti-TB therapeutics.
MATERIAL AND METHODS:
All the chemicals in this synthesis were of AR and LR
grade and were obtained from Merck, Hi-Media and Sigma-Aldrich, SD Fine chem.,
Mumbai. All the chemicals were
used as received without further purification.
Experimental section:
Melting points were determined in open capillaries on
a Thomas Hoover apparatus and are uncorrected. The synthesized compounds were
characterized by the following methods IR spectra of synthesized compounds were
recorded on Schimadzu (8300, Kyoto, Japan) fourier transform infrared
spectrophotometer in the range of 4000 cm-1 – 400 cm-1
using KBr pellet technique. The proton NMR Spectra were recorded using BRUKER
300MHz NMR Spectrometer using the solvent deuterated chloroform. Chemical
shifts (d) were recorded in parts per million (ppm) and trimethylsilane used as
an internal standard.
Synthesis of Chalcone Scaffolds:
The variety of chalcones has an easy
chemistry which facilitates to synthesize the compounds with assorted
substitutions. At this time, a diversity of methods and schemes are available
for the synthesis of chalcone conjugates55,56. This reaction can
take place under various reaction conditions. In our research, the chalcones
were prepared by the reaction of equimolar amount of acetophenone and various
aromatic aldehydes with activating and deactivating groups in ethanol using a
40% NaOH solution as a catalyst to yield the various chalcone scaffold. (Scheme
1).
Synthesis of Pyrazoline conjugates57:
An equimoloar mixture of assorted Chalcones (0.02
mol), 2,4-dinitro phenyl hydrazine (0.02 mol), ethanol (25 mL), followed by the
addition of 3 drops of concentrated sulphuric acid and was refluxed for 6-8
hours. The completion of the reaction was monitored by TLC (Hexane:Methanol
(9:1). After completion of the reaction, the mixture was cooled and poured into
crushed ice to get the chalcone annulated pyrazoline conjugates as a final
product. The precipitate obtained was filtered, washed and recrystallized using
absolute ethanol. (Scheme 1, Table 1).
Scheme 1: Synthetic scheme of chalcone
annulated pyrazoline conjugates
Computational studies:
In modern drug designing scenario, the
molecular docking is commonly used for the understanding of target - receptor
binding interaction and is quite often used to predict the binding orientation
of target molecule of the lead with their protein receptor in order to find out
the affinity of that target compound1. Keeping this in mind, the
work undertook to design the novel antimycobacterial candidates, which will
target promisingly with the enzymes involved in the biosynthesis of microbial
cell wall. In order to rationalize the biological results of our compounds, an
in silico molecular docking studies with the enoyl-acyl carrier protein
reductase (InhA) of MTB were carried out to determine the best conformation.
Enoyl-ACP (acyl-carrier protein) reductase (ENR), is a key enzyme of the type
II fatty acid synthesis (FAS) system.
Software used:
The designed structures of seven chalcone
annulated pyrazoline conjugates were generated by using Marvin_windows-x64_18.8
version. Marvin Sketch is an advanced chemical tool for illustrating the
chemical structures, queries, reactions, and etc.58. Then the
structures were viewed on Marvin Viewer screen to generate the SMILES notation
and to IUPAC name of the synthesized compounds. The target ligand files for the
molecular docking studies were built on Molecular Operating Environment (MOE
2009.10) by Chemical Computing Group59.
Preparation of target ligand files:
The molecular geometries were drawn and
correct 3D structures were ensured and were followed by energy optimization at
a standard MMFF94 force field level, with a 0.0001 kcal/mol energy gradient
convergence criterion60,61. The molecule builder of MOE 2009.10
program was used for this purpose and after building the molecule, it was
energy minimized and potential energy, partial energy was corrected and then it
was saved as molecular database (.mdb) file in a local directory for the
further process.
Preparation of macromolecule:
The MTB enoyl acyl carrier protein
reductase (InhA) is encoded by the inhA gene plays an important role in the MTB
fatty acid synthesis pathway as an essential NADH dependent enzyme in the
mycolic acid biosynthetic pathway. Mycolic acids are the major components of
MTB cell envelope, and they form an effective permeability barrier to protect
mycobacteria from antimicrobial agents. Therefore, inhibition of InhA could
block biosynthesis of mycolic acids, resulting in mycobacteria death.
Obviously, InhA is a well validated MTB target, so identify direct inhibitors
of InhA would have tremendous clinical value in combating TB62.
The crystal 3D structure of enzymes enoyl- acyl carrier protein reductase (PDB code 2NSD) was retrieved from RCSB Protein Data Bank. These pdb files were imported
into MOE suite in which the receptor preparation module was used to prepare the
protein. All the bound water molecules and hetero atom were removed from the
complex by using sequence (SEQ) window which is default in molecular operating
environment programme. Both polar and non-polar hydrogens were added and 3D
structure was corrected. The 3-D protonated structure was energy minimized.
Since the protein was devoid of associated ligand, so the pocket was identified
using the active site finder module of the molecular operating environment. In order to visualize the binding pocket, alpha spheres were
created followed by the generation of dummy atoms on the centers of these
spheres. The pockets
were found to be deep small canyons lined with the key residues including both
hydrophobic and hydrophilic amino acids.
Docking methodology:
With an objective to explore the potential
putative targets of the synthesized compounds among the validated Mycobacterium
receptors, we performed a docking analysis with known biological targets
reported so far for the chalcone scaffold derived anti-tubercular compounds.
The optimized target ligands were docked with the enzymes enoyl-ACP reductase
(PDB: 2NSD) protein using the MOE. 2009.10 suite. For docking simulations, the placement
was set as triangular matcher, rescoring was set as London dG, the number of
retaining was set as 10 and the refinement was set as forcefield on molecular operating environment suite to generate 10 poses of each target
ligand confirmations. As a result of docking run, the mdb. output files were
created with scoring and multiple conformations of each compound. All the
docked conformations were analyzed and the best scored pose for each compound
was selected for further interaction studies. Besides, the ligand-receptor
interaction followed by surface analysis of the selected best pose ligand
molecule was generated on molecular
operating environment suite
and viewed for interpretation.
RESULT AND DISCUSSION:
The new series of chalcone annulated pyrazoline conjugates were synthesized and
evaluated for their in silico antimycobacterial activity. The synthesized
compounds were obtained in the reasonable yield. The percentage yield and
melting point of the synthesized compounds were recorded and presented uncorrected.
The key reactions involved are the intermediate formation of hydrazones and
subsequent addition of N-H on the olefinic (CH=CH) bond that forms the
ring-closed final products of pyrazoline conjugates. In the nuclear magnetic
resonance spectra (1H-NMR) the signals of the respective protons of the final
title compounds were verified on the basis of their chemical shifts and
multiplicities. Both analytical and spectral data (IR and 1H-NMR) of all the
synthesized compounds were in full agreement with the proposed structures. IR
and 1H NMR Spectral data of the synthesized conjugates were given
below. The IR spectra of the compounds show the appearance of C=C (olefinic),
C=N, and N-CH stretching bands at 1580–1600, 1530–1600 and 3272-3300 cm-1
respectively due to the ring closure. The previous report of 1H-NMR
spectra of chalcone showed an olefinic proton as appeared as doublets at about δ
6.75 and 7.18 ppm respectively. After the ring closure, the CH proton of
pyrazoline showed at around δ 5.81-6.02 ppm.
P1:
5-(2-chlorophenyl)-1-(2,4-dinitrophenyl)-3-phenyl-4,5-dihydro-1H-pyrazole.
Orange powder. Yield: 80%; mp. 190-192ºC. IR (vmax in cm-1): 1595 (Aro
C=C str); 3020 (Ar-H str); 1514 (Ar-NO2); 1350 (N=O str); 3272 (N-CH); 1459
(-CH2-); 1583 (C=N); 1216 (C-C); 2900 (C-H); 798 (-Cl-). 1H NMR
(CDCl3, 300 MHz): 2.99-3.15 (d, 2H, -CH2), 6.02 (1H, d, -CH), 8.43
(dd, Ar-H), 8.88 (d, Ar-H), 7.12 – 7.72 (m, 10H, Ar-H).
P2:
5-(4-chlorophenyl)-1-(2,4-dinitrophenyl)-3-phenyl-4,5-dihydro-1H-pyrazole (P2):
Reddish Orange powder. Yield: 85%; mp. 194-202ºC. IR (νmax in cm-1): IR(cm-1): 1583 (Aro C=C str); 3031 (Ar-H
str); 1545 (Ar-NO2); 1268 (N=O str); 3278 (N-CH); 1483 (-CH2-); 1598 (C=N); 980
(C-C); 2860 (C-H); 800 (-Cl). 1H NMR (CDCl3, 300 MHz): 3.07-3.13 (d,
2H, -CH2), 5.94 (1H, d, -CH), 8.43 (dd, Ar-H), 8.88 (d, Ar-H), 7.12 – 7.72 (m,
10H, Ar-H).
P3:
4-[1-(2,4-dinitrophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-5-yl]-N,N-dimethylaniline:
Crystalline Black powder. Yield: 86%; mp. 212-220oC. IR (νmax in cm-1): 1598 (Aro C=C str); 3010 (Ar-H str);
1567 (Ar-NO2) 1360 (N=O str); 3282 (N-CH);1469 (-CH2-); 1567 (C=N); 1280 (C-C);
2960 (C-H); 1460 (-CH3-); 1220 (N-C). 1H NMR (CDCl3, 300 MHz): 2.73
(s, 3H, -CH3), 2.83-3.65 (d, 2H, -CH2), 5.81 (d, 1H, -CH), 8.43 (dd,
Ar-H), 8.88 (d, Ar-H), 6.71 – 7.67 (m, 11H, Ar-H).
P4: 3-chloro-4-[1-(2,4-dinitrophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-5-yl]-N,N-dimethylaniline:
Brownish black. Yield: 65%; mp. 240 oC. IR (νmax
in cm-1): 1600 (Aro C=C str); 3050 (Ar-H str); 1570 (Ar-NO2); 1370 (N=O str);
3285 (N-CH);1485 (-CH2-); 1600 (C=N); 1000 (C-C); 2940 (C-H), 1470 (-CH3-);
1220 (N-C); 800 (-Cl-). 1H NMR (CDCl3, 300 MHz): 2.78 (s, 3H, -CH3),
2.77-2.92 (dd, 2H, -CH2), 5.86 (dd, 1H, -CH), 8.43 (dd, Ar-H), 8.88 (d, Ar-H),
6.59 – 7.67 (m, 9H, Ar-H).
P5:
1-(2,4-dinitrophenyl)-5-(2-nitrophenyl)-3-phenyl-4,5-dihydro-1H-pyrazole: Brick
Brown Powder. Yield: 70%; mp. 260-263 oC, IR (νmax in cm-1): 1614 (Aro C=C str); 3050 (Ar-H str);
1515 (Ar-NO2); 1330 (N=O str.); 3302 (N-CH);1485 (-CH2-); 1589 (C=N); 1000
(C-C); 1301 (C-H), 2853 (-CH2-); 2920 (NO2). 1H NMR
(CDCl3, 300 MHz): 3.08-3.19 (d, 2H, -CH2), 6.14 (d, 1H, -CH); 7.53-8.03 (4H, m,
Ar-H); 7.42 -7.67 (5H, m, CH=C-Ar); 8.41 (1H, dd, Ar-H); 8.88 (1H, d, Ar-H).
P6:
4-[1-(2,4-dinitrophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-5-yl]-2-methoxyphenol:
Reddish brown powder. Yield: 80%; mp. 198-200 oC. IR (νmax in cm-1): 1600, ~1500, (Aro C=C str); 3050-3000
(Ar-H str); 1545 (Ar-NO2); 1348 (N=O str); 3300 (N-CH);2860, 1480 (-CH2-); 1530
- 1550 (C=N); 1100 (C-C); 2950 (C-H); 1250-1070 (-OCH3, C-O-C); 1230 (C-O),
3700 (Ar-OH); 1430 (-CH3-) 1526 (NO2); 1319 (NO2). 1H
NMR (CDCl3, 300 MHz): 2.86-3.06 (d, 2H, -CH2), 3.79 (s, 3H, -CH3), 5.88 (d, 1H,
-CH), 7.67 (d, 1H), 6.98 (d, 1H), 7.79- 8.98 (m, 9H, Ar-H), 5.39 (s, 2H, -OH).
P7:
1-(2,4-dinitrophenyl)-5-(4-methoxyphenyl)-3-phenyl-4,5-dihydro-1H-pyrazole:
Brick Red powder. Yield: 70%; mp. 222-230 oC. IR (νmax in cm-1): 1580 (Aro C=C str); 3050 (Ar-H str);
1555, 1368 (Ar-NO2, N=O str); 3298 (N-CH);1457 (-CH2-); 1560 (C=N); 986 (C-C);
2850 (C-H); 1250-1070 (-OCH3, C-O-C); 1050 (C-O). 1H NMR (CDCl3, 300
MHz): 2.84-3.04 (d, 2H, -CH2), 3.74 (s, 3H, -CH3), 5.84 (d, 1H, -CH), 7.14–7.22
(m, 4H, Ar-H), 7.34–7.37 (m, 3H, Ar-H), 7.52 (m, 1H, Ar-H), 7.63–7.67 (m, 2H,
Ar-H), 8.13 (d, 1H, CH-), 8.36 (d, 2H, Ar-H).
Result on
molecular docking studies of target molecules:
All the docked conformations for each compound were
analyzed and it was found that the most favorable docking poses with a maximum
number of interactions were those which were ranked the highest score based on
the minimal binding energy, which was computed as a negative value by the MOE
software. Then considering the root mean square deviation (RMSD) value, generally acceptable range of
the RMSD when the model is overlapped to the template is 2 Å. For protein
ligand docking 2 Angstroms is good, 1 Angstrom and less is great. But this RMSD
value may not be considered as the only criteria for evaluation of the model
constructed. Some deviations at times can be considered. Based on this
declaration, in this present report, the compounds showed the RMSD value range
of between 1.3921 to
3.2598 and this result suggests that the synthesized compounds showed a good
RMSD value.
The molecular
operating environment software
generated docking score of the all the molecules were summarized in Table 2.
The most favorable docking poses of the 10 docked conformations for each
molecule were analyzed for further investigation of the ligand interactions
within the active sites. The wonderful number of interactions with active site
residues coupled with favorable binding energy state that these target
molecules may serve as an effective replacement agent for the antimycobacterial
drugs. The four ligands viz. P1, P2, P5 and P6 (contains electron
withdrawing groups substitution) showed a proper binding pattern except the
ligands viz. P3, P4 and P7 (contains the lone pair of electrons in its
substitution such as, -N(CH3)2 and -OCH3) and anchored
tightly inside the active site canyon (Site I) of the protein. The 2D
ligand-protein interactions were visualized using the molecular operating environment ligand interaction program for all the
molecules are shown in Figure 2a, 2b, 2c and 2d.
S - The final score, rmsd_refine- The root mean
squar deviation between the pose before refinement and the pose after
refinement, E_conf- The energy of the conformer. E_place - Score
from the placement stage, E_score1- Score from the rescoring stage(s), E_refine-
Score from the refinement stage and No. of conf- number of
conformations generated by ligand.
The
best docking poses of among these 7 synthesized conjugates, the best four conjugates
viz. P1, P2, P5 and P6 ligand were formed a single cluster inside the active
site cleft of the receptor and they showed the best interaction within the
receptor and the calculated surface analysis pocket for these compounds were
shown in Figure 2a, 2b, 2c and 2d. The synthesized compounds have a highest
binding affinity with the receptors, in the narrow range of binding energy for
the protein 2NSD is -24.8788 to -29.0981 kcal/mol: London dG was -10.3945 to -12.2679
kcal/mol when compared to the standard
drug pyrazinamide was -11.6461 kcal/mol.
Fig. 2a: Ligand Receptor interaction and binding surface of
compound P1 with 2NSD
Fig. 2b: Ligand Receptor interaction and binding surface of
compound P2 with 2NSD
Fig. 2c: Ligand Receptor interaction and binding surface of
compound P5 with 2NSD
Fig. 2d: Ligand Receptor interaction and binding surface of
compound P6 with 2NSD
Further, the top docked conformation of
this compound depicted a greater alignment with the native ligand pose. Hence
it is likely to act as good binder for the enoyl acyl carrier protein reductas
receptor in mycobacterium. The key intermolecular interactions between
selected compounds and the target protein are depicted in Fig. 2a-2d. In P6
Compound, the Asp148 acts as backbone donor whereas Lys165 acts as side chain
acceptor and forms a bond with the H and O of aromatic aldehyde group of the
ligand (Fig. 2d). Apart from this bonding, the other compounds viz. P2 and P5
stabilizing intermolecular arene-arene interactions with Phe 149 were also
observed.
The number of conformations generated by
molecule was between 8 to 10 which indicate that flexibility is an important
parameter for the ligand to dock deeply within the binding pocket of enoyl acyl
reductase enzyme. The lowest docking score for molecule P6 was -29.0981,
which indicate compound is active at this energy of conformation. Further a
careful calculation of surface analysis of the binding pocket of this molecule
indicated that molecule P6 adopted a position in a hydrophobic cage surrounded
by the following amino acids residue such as, Tyr 198 &158, Ile 202, Thr
198 & 158, Met 147, 103, 18 & 199, Phe 149, Ala 191 & 198 and Gly
96 and these were approach closely to the ligand for strong interactions.
The preface SAR of the chalcone annulated
pyrazoline conjugates reveals that compounds possessing electron withdrawing
groups such as halogen atom in its structure favors better activity (P1, P2).
In addition, the activity is being influenced by functional groups present in
the chalcone moiety as well. Halogen substitution at aromatic ring, especially
chloro substitution enhances the activity (P1, P2). It is also observed that
the presence of methoxy and dimethylamino substitutions at aromatic ring (P3,
P4 & P7) doesn't seem to influence the activity63, this is may
be due to its high electro negativity and the presence of lone pair of electron
with this substitutions.
CONCLUSION:
The new series of chalcone annulated pyrazoline conjugates were synthesized and
evaluated for their in silico antimycobacterial activity. The key reactions
involved are the intermediate formation of hydrazones and subsequent addition
of N-H on the olefinic (CH=CH) bond that forms the ring closed final products
of pyrazoline conjugates. Further analysis of the synthesized compounds with
known chemoinformatics tools unequivocally established their potential as
antitubercular compounds. An in silico docking studies of the target molecules
as a ligand with enoyl-acyl carrier protein reductase results showed the best
docking score were obtained for the target molecules P1, P2, P5 and P6 among
this 7 synthesized compounds when compared to the standard drug. Therefore,
this effect is due to the presence of heterocyclic analog with electron withdrawing
like, -Cl and -NO2 moiety in its structure. Upon docking study
results it was quite understood that the compound P6, the Asp148 acts as
backbone donor whereas Lys165 acts as side chain acceptor and forms a bond with
the H and O of aromatic aldehyde group of the ligand. Apart from this bonding,
the other compounds viz. P2 and P5 stabilizing intermolecular arene-arene
interactions with Phe 149 were also observed with its target site. Thus, the
chemoinformatics analysis using MOE 2009.10. suite suggested that the chalcone
annulated pyrazoline conjugates will provide guidelines for future development
of novel agent which could act promisingly as an anti-tubercular agents.
AUTHORS CONTRIBUTION:
All Authors have an equal contribution of this work.
CONFLICTS OF INTERESTS:
The authors have no conflicts of interests.
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