AU2020104192A4 - Process of synthesis of benzimidazole derivatives against M.tb - Google Patents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
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- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
Abstract
ABSTRAT
The present invention discloses relates to design and Synthesis novel benzimidazole derivatives against M.tb
(H37Rv strain/ ATCC No- 27294) with their delay the emergence of resistance than exiting drug therapy. The
present invention discloses Structural elucidation of synthesized compounds by using IR, 1 HNMR, 13 CNMR
and Mass spectroscopy. It is an object of the invention to boost synthesized derivatives by 2D-QSAR analysis
studies, to perform in silico molecular docking studies of synthesized derivatives, and to predict the ADME
properties of synthesized derivatives.
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Description
The present invention discloses relates to design and Synthesis novel benzimidazole derivatives against M.tb (H37Rv strain/ ATCC No- 27294) with their delay the emergence of resistance than exiting drug therapy. The present invention discloses Structural elucidation of synthesized compounds by using IR, 1 HNMR, 13 CNMR and Mass spectroscopy. It is an object of the invention to boost synthesized derivatives by 2D-QSAR analysis studies, to perform in silico molecular docking studies of synthesized derivatives, and to predict the ADME properties of synthesized derivatives.
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Process of synthesis of benzimidazole derivatives against Mtb
The present invention generally relates to a field of biotechnology and chemistry and particularly relates to a process for synthesis benzimidazole derivatives useful as anti-tubercular agents.
BACKGROUND OF THE INVENTION Tuberculosis is a deadly disease usually caused by Mycobacterium tuberculosis. It has killed an estimated one billion people over the last two spans and is still leading causes of death in the world. According to 2018 WHO report 5,58,000 peoples developed rifampicin-resistant (RR TB), multidrug-resistant tuberculosis (MDR-TB) or extensively drug-resistant (XDR TB) in the world. Existing therapy having more side effects, to treat that peoples, we required new molecule having potent effect and less toxicity. For this purpose, we design and Synthesis of novel benzimidazole derivatives useful as antitubercular agents against M.tb (H37Rv strain/ ATCC No- 27294). To avoid the resistance of synthesized derivatives and shorten the time of treatment therapy against tubercular infection. To use of CADD technique to validate antitubercular activity for synthesized derivatives.
The present invention discloses a process for synthesis benzimidazole derivatives useful as antitubercular agents.
In an embodiment, a process for synthesis benzimidazole derivatives useful as antitubercular agents is provided. The process includes of treating o-phenylene diamine with ethanol (C 2H5 OH) under catalyst of Carbon disulfide (CS 2) and potassium hydroxide (KOH) to obtain Mercaptobenzimidazole (DPK3A) and Meldrum acid; mixing the Mercaptobenzimidazole (DPK3A) with the Meldrum acid in a reflux manner for 4 hr under a catalyst of Anhydrous 1,4- dioxine to obtain Benzimidazolesulfonylcarbonyl acetic acid (DPK3B); stirring the Benzimidazolesulfonylcarbonyl acetic acid (DPK3B) with polyphosphoric acid (PPA) at 120°C for 8hrs to get Dihydrobenzimidazole hydroxythiopyranone (DPK3C); and refluxing the Dihydrobenzimidazole hydroxythiopyranone (DPK3C) with Ar-CHO and R-NH 2 for 6-8 hrs to obtain Dihydrobenzimidazole thiopyrano oxazinone derivatives.
The present invention relates to design and Synthesis of novel benzimidazole derivatives against M.tb (H37Rv strain/ ATCC No- 27294) with their delay the emergence of resistance than exiting drug therapy. During synthesis raw material and intermediate product stability was the main challenge, overcome by change the environmental condition (Specifically temperature parameter). Structural elucidation of synthesized compounds by using IR, 1HINMR, 13CNMR and Mass spectroscopy. To boost synthesized derivatives by 2D QSAR analysis studies. To perform in silico molecular docking studies of synthesized derivatives. To predict the ADME properties of synthesized derivatives.
To further clarify advantages and features of the present invention, a more particular description of the invention will be rendered by reference to specific embodiments thereof, which is illustrated in the appended drawings. It is appreciated that these drawings depict only typical embodiments of the invention and are therefore not to be considered limiting of its scope. The invention will be described and explained with additional specificity and detail with the accompanying drawings
These and other features, aspects, and advantages of the present invention will become better understood when the following detailed description is read with reference to the accompanying drawings in which like characters represent like parts throughout the drawings, wherein:
Figure 1 illustrates a schematic representation for synthesis of dihydrobenzimidazole thiopyranooxazinone derivatives; Figure 2 illustrates a schematic representation for synthesis of coupled mercaptobenzimidazole derivatives; Figure 3 illustrates a schematic representation for synthesis of (Part- A): Pyridincarbonitrile mercaptobenzimidazole derivatives. (PartB): Mercaptobenzimidazole-clubbed chalcone derivatives; Figure 4 illustrates a 96-well microtiter plate photographs for novel benzimidazole derivatives useful as antitubercular agents; Figure 5 illustrates a 96-well microtiter plate photographs for novel benzimidazole derivatives useful as antitubercular agents; Figure 6 illustrates a graphical representation novel benzimidazole derivatives useful as antitubercular agents; Figure 7 illustrates observed activity Vs Predicated activity for 2D QSAR MLR model; Figure 8 illustrates contribution plot for training set for MLR model; Figure 9 illustrates fitness plot for training set for actual value (X-axis) Vs predicted value (Y-axis) for MLR model; Figure 10 illustrates observed activity Vs predicated activity for 2D-QSAR PLS model; Figure 11 illustrates contribution plot for training set for PLS model; Figure 12 illustrates fitness plot for training set for actual value (X-axis) Vs predicted value (Y-axis) for PLS model; Figure 13 illustrates secondary structure of PDB 6CQ2; Figure 14 illustrates docking pose for dihydrobenzimidazole thiopyranooxazinone derivatives within domain of PDB 6CQ2 and hydrogen bonding shown in dashed green line; Figure 15 illustrates docking pose for coupled mercaptobenzimidazole derivatives within domain of PDB 6CQ2 and hydrogen bonding shown in dashed green line; Figure 16 illustrates docking pose for pyridincarbonitrile mercaptobenzimidazole derivatives within domain of PDB 6CQ2 and hydrogen bonding shown in dashed green line; Figure 17 illustrates docking pose for Mercaptobenzimidazole-clubbed chalcone derivatives within domain of PDB 6CQ2 and hydrogen bonding shown in dashed green line; Figure 18 illustrates a process for synthesis benzimidazole derivatives useful as antitubercular agents in accordance with an embodiment of the present invention;
Further, skilled artisans will appreciate that elements in the drawings are illustrated for simplicity and may not have been necessarily been drawn to scale. For example, the flow charts illustrate the method in terms of the most prominent steps involved to help to improve understanding of aspects of the present invention. Furthermore, in terms of the construction of the device, one or more components of the device may have been represented in the drawings by conventional symbols, and the drawings may show only those specific details that are pertinent to understanding the embodiments of the present invention so as not to obscure the drawings with details that will be readily apparent to those of ordinary skill in the art having benefit of the description herein.
For the purpose of promoting an understanding of the principles of the invention, reference will now be made to the embodiment illustrated in the drawings and specific language will be used to describe the same. The terms "comprises", "comprising", or any other variations thereof, are intended to cover a non-exclusive inclusion, such that a process or method that comprises a list of steps does not include only those steps but may include other steps not expressly listed or inherent to such process or method. Similarly, one or more devices or sub-systems or elements or structures or components proceeded by "comprises...a" does not, without more constraints, preclude the existence of other devices or other sub-systems or other elements or other structures or other components or additional devices or additional sub-systems or additional elements or additional structures or additional components.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The system, methods, and examples provided herein are illustrative only and not intended to be limiting.
Embodiments of the present invention will be described below in detail with reference to the accompanying drawings.
To use of CADD technique to validate all synthesized derivatives. [2D-QSAR analysis all synthesized derivatives. Also, in silico studies of all synthesized derivatives as Topoisomerase I (ATP-independent enzymes) inhibitors (PDB: 6CQ2) as antitubercular agent. Data about ADME properties was predicted for of all synthesized derivatives.
Figure 1 illustrates a schematic representation for synthesis of dihydrobenzimidazole thiopyranooxazinone derivatives. Figure 2 illustrates a schematic representation for synthesis of coupled mercaptobenzimidazole derivatives. Figure 3 illustrates a schematic representation for synthesis of (Part- A): Pyridincarbonitrile mercaptobenzimidazole derivatives. (Part B): Mercaptobenzimidazole-clubbed chalcone derivatives. Figure 4 illustrates a 96-well microtiter plate photographs for novel benzimidazole derivatives useful as antitubercular agents. Figure 5 illustrates a 96-well microtiter plate photographs for novel benzimidazole derivatives useful as antitubercular agents. Figure 6 illustrates a graphical representation novel benzimidazole derivatives useful as antitubercular agents. Figure 7 illustrates observed activity Vs Predicated activity for 2D QSAR MLR model. Figure 8 illustrates contribution plot for training set for MLR model. Figure 9 illustrates fitness plot for training set for actual value (X-axis) Vs predicted value (Y-axis) for MLR model. Figure 10 illustrates observed activity Vs predicated activity for 2D-QSAR PLS model. Figure 11 illustrates contribution plot for training set for PLS model. Figure 12 illustrates fitness plot for training set for actual value (X-axis) Vs predicted value (Y-axis) for PLS model. Figure 13 illustrates secondary structure of PDB 6CQ2. Ar
N S Ar HK
Dihydrobenzimidazole thiopyranooxazinone Derivatives
Figure 14 illustrates docking pose for dihydrobenzimidazole thiopyranooxazinone derivatives within domain of PDB 6CQ2 and hydrogen bonding shown in dashed green line. Molecular docking binding affinity and interactive amino acids data of coupled mercaptobenzimidazole derivatives for antitubercular activity.
N S (CH2)n
Coupled Mercaptobenzimdazole Derivatives
Note: RMSD lower bound and upper bound was zero for all compounds.
Figure 15 illustrates docking pose for coupled mercaptobenzimidazole derivatives within domain of PDB 6CQ2 and hydrogen bonding shown in dashed green line. Molecular docking binding affinity and interactive amino acids data of pyridincarbonitrile mercaptobenzimidazole derivatives for antitubercular activity
Ar
H 2N CN Pyridincarbonitrile Mercaptobenzimidazole derivatives
Note: RMSD lower bound and upper bound was zero for all compounds.
Figure 16 illustrates docking pose for pyridincarbonitrile mercaptobenzimidazole derivatives within domain of PDB 6CQ2 and hydrogen bonding shown in dashed green line.Molecular docking binding affinity and interactive amino acids data of pyridincarbonitrile mercaptobenzimidazole derivatives for antitubercular activity.
Ar
0 Mercaptobenzimidazole-clubbed chalcone derivatives
Figure 17 illustrates docking pose for Mercaptobenzimidazole-clubbed chalcone derivatives within domain of PDB 6CQ2 and hydrogen bonding shown in dashed green line.
Figure 18 illustrates a process for synthesis benzimidazole derivatives useful as antitubercular agents in accordance with an embodiment of the present invention. The process 1800 includes of step 1802 of treating o phenylene diamine with ethanol (C 2 H5 OH) under catalyst of Carbon disulfide (CS 2 ) and potassium hydroxide (KOH) to obtain Mercaptobenzimidazole (DPK3A) and Meldrum acid; step 1804 of mixing the Mercaptobenzimidazole (DPK3A) with the Meldrum acid in a reflux manner for 4 hr under a catalyst of Anhydrous 1,4- dioxine to obtain Benzimidazolesulfonylcarbonyl acetic acid (DPK3B); step 1806 of stirring the Benzimidazolesulfonylcarbonyl acetic acid (DPK3B) with polyphosphoric acid (PPA) at 120°C for 8hrs to get Dihydrobenzimidazole hydroxythiopyranone (DPK3C); and step 1810 of refluxing Dihydrobenzimidazole hydroxythiopyranone (DPK3C) with Ar-CHO and R-NH 2 for 6-8 hrs to obtain Dihydrobenzimidazole thiopyrano oxazinone derivatives.
In an embodiment, the Mercaptobenzimidazole (DPK3A) is treated with acetic anhydride ([CH 3CO]2 0) to obtain acetyle Mercaptobenzimidazole. In an embodiment, the acetyle Mercaptobenzimidazole is served with the Ar-CHO under claisen - Schmidt condensation to obtain Mercaptobenzimidazole-clubbed chalcone derivatives. In an embodiment, the Mercaptobenzimidazole (DPK3A) is treated with the Ar-CHO/ CH2(CN) 2 under a catalyst of CH3COONH4/ Ethanol (EtOH) to obtain Pyridincarbonitrile Mercaptobenzimidazole derivatives. In an embodiment, the Mercaptobenzimidazole (DPK3A) is mixed the glacial acetic acid and NH 2 R for 6hrs to obtain substituted Mercaptobenzimidazole (DPK2B1- DPK2B4).
In an embodiment, the substituted Mercaptobenzimidazole (DPK2B1- DPK2B4) is refluxed with di bromoalkane under catalyst of K 2CO3 and ethanol for 14hrs to obtain coupled Mercaptobenzimidazole derivatives (DPK2dl- DPK2d8).Table 1 shows different aromatic aldehyde and primary aromatic amine attachment with dihydrobenzimidazole thiopyranooxazinone derivatives (DPK3dl-DPK3d5). Table 2 shows primary aromatic amine attachment with Mercaptobenzoxazole to give substituted mercaptobenzimidazole (DPK2B-DPK2B4).Table 3 shows attachment of different aromatic aldehyde (Part A). Table 4 shows attachment of different aromatic aldehyde (Part B).Table 5 shows antitubercular activity, MIC values of synthesized compounds against M.tb (H37Rv strain). Table 6 shows antitubercular activity, MIC values of synthesized compounds against M.tb (H37Rv strain). Table 7 shows 2D-QSAR equation of MLR model for in vitro antitubercular activity.
Table 8 shows comparative of observed and predicted activity for 2D-QSAR MLR model of antitubercular activity. Table 9 shows 2D-QSAR equation of PLS model for in vitro antitubercular activity. Table 10 shows comparative of observed and predicted activity for 2D-QSAR PLS model of antitubercular activity. Table 11 shows centres and dimensions of the grid box for (PDB ID: 6CQ2). Table 12 shows RMSD lower bound and upper bound was zero for all compounds. Table 13 shows RMSD lower bound and upper bound was zero for all compounds. Table 14 shows Docking Affinity kcal/mol, Number of hydrogen bonds, and Amino acids involved in bonding. Table 15 shows Molecular docking binding affinity and interactive amino acids data of pyridincarbonitrile mercaptobenzimidazole derivatives for antitubercular activity.
Table 16 shows ADME prediction of synthesized some novel benzimidazole derivatives. All the molecules were synthesized by conventional method. The chemical reaction monitored and obtained compounds characterized by advanced analytical techniques (IR, 1HNMR, 13CNMR and Mass spectroscopy. This conventional synthesis and characterization technique is the base for process transferred at large scale at industrial level for new drug development.
TABLE 1
Compound Code Ar-CHO Ar-NH 2
DPK3dl 0 ___
I- ~CI H2NO
Aniline p-chlorobenzaldehyde
DPK3d2 0 -- -O CI N NH2
p-chlorobenzaldehyde p-nitroaniline
DPK3d3 0 ___
Bezleyeci NH 2 Benzaldehyde C m-chloroaniline
DPK3d4 0 -
N* NH 2
Benzaldehyde p-nitroaniline
DPK3d5 0 ____ NH 2
Benzaldehyde N
o-nitroaniline
TABLE2
Compound R-NH 2 Compound R-NH 2 Code Code DPK2B1 DPK2B3
H2N -0 CH 3
P-toluidine ci NH 2 m-chloroaniline DPK2B2 DPK2B4 -0 H2 N\/ _ +--H
Aniline i/ p-nitroaniline
TABLE3
Compound Ar-CHO Compound Ar-CHO Code Code DPK4B~d1 DPK4B~d5
() - CHO H0 DPK4B Id2 DPK4B~d6 HO0
DPK4B~d3 02N DPK4B~d7 CI
DPK4B Id4
OHO 0CI
TABLE4
Compound Ar-CHO Compound Ar-CHO Code Code DPK4B2d1 DPK4B2d4 02 N
DPK4B2d2 DPK4B2d5
OHO 0ci OHO
DPK4B2d3 CI DPK4B2d6 HO
TABLE5
Sr. No. Compound Code MIC values in pg/ml 1 DPK4B~d1 1.6 2 DPK4B~d2 0.8 3 DPK4B~d3 1.6 4 DPK4B~d4 1.6 5 DPK4B~d5 1.6 6 DPK4B~d6 1.6 7 DPK4B~d7 1.6 8 DPK4B2d1 0.8 9 DPK4B2d2 0.8 10 DPK4B2d3 1.6 11 DPK4B2d4 3.12 12 DPK4B2d5 6.25 13 DPK4B2d6 12.5 14 DPK3d1 1.6 15 DPK3d2 12.5 16 DPK3d3 6.25 17 DPK3d4 12.5 18 DPK3d5 6.25
TABLE6
Sr. No. Compound Code MIC values in pg/ml 1 DPK2dl 1.6 2 DPK2d2 1.6 3 DPK2d3 1.6 4 DPK2d4 6.25 5 DPK2d5 6.25 6 DPK2d6 6.25 7 DPK2d7 6.25 8 DPK2d8 6.25 9 Pyrazinamide 3.12 10 Ciprofloxacin 3.12 11 Streptomycin 6.25
TABLE7
Statistical Equation N r2 q2 F test r2 se q2 se Method MLR SsOHcount 11.4293 (+1.2622)+Ipc 15 0.9344 0.1813 35.58 1.2051 4.2561 Average 0.0000 (+0.0000)+ Delta AlphaA 230.9890 (+58.2261) + Delta AlphaB 107.0230 (+40.4643) -0.1101
TABLE8
Compound Observed Predicated Compound code Observed Predicated code Activity Activity Activity Activity DPK3dl 1.6 3.60 DPK4Bld1 1.6 0.96 DPK3d2 12.5 10.66 DPK4Bld2 0.8 0.11 DPK3d3 6.25 2.13 DPK4Bld3 1.6 1.82 DPK3d4 12.5 6.51 DPK4Bld4 1.6 1.28 DPK3d5 6.25 6.54 DPK4Bld5 1.6 0.21 DPK2dl 1.6 2.22 DPK4Bld6 1.6 12.28 DPK2d2 1.6 2.67 DPK4Bld7 1.6 1.28 DPK2d3 1.6 2.07 DPK4B2dl 0.8 1.06 DPK2d4 6.25 2.28 DPK4B2d2 0.8 1.96 DPK2d5 6.25 4.96 DPK4B2d3 1.6 1.96 DPK2d6 6.25 5.39 DPK4B2d4 3.12 2.03 DPK2d7 6.25 5.19 DPK4B2d5 6.25 0.10 DPK2d8 6.25 7.50 DPK4B2d6 12.5 12.38
TABLE9
Statistical Equation N r2 q2 F test r2 se q2 se Method PLS SsOHcount 11.6575 + chi6chain 15 0.8320 0.1626 29.70 1.7601 3.9293 5.3685 + Ipc 0.0000 + 0.2356
TABLE 10
Compound Observed Predicated Compound code Observed Predicated code Activity Activity Activity Activity DPK3dl 1.6 5.09 DPK4Bld1 1.6 0.98 DPK3d2 12.5 11.14 DPK4Bld2 0.8 1.53 DPK3d3 6.25 4.38 DPK4Bld3 1.6 1.43 DPK3d4 12.5 6.76 DPK4Bld4 1.6 1.42 DPK3d5 6.25 6.79 DPK4Bld5 1.6 1.53 DPK2dl 1.6 2.60 DPK4Bld6 1.6 13.08 DPK2d2 1.6 2.97 DPK4Bld7 1.6 1.4 DPK2d3 1.6 2.49 DPK4B2dl 0.8 0.68 DPK2d4 6.25 2.67 DPK4B2d2 0.8 1.13 DPK2d5 6.25 2.58 DPK4B2d3 1.6 1.13 DPK2d6 6.25 2.93 DPK4B2d4 3.12 1.13 DPK2d7 6.25 5.36 DPK4B2d5 6.25 1.22 DPK2d8 6.25 7.46 DPK4B2d6 12.5 12.78
TABLE 11
Centers of the grid box Coordinates site Dimensions of the grid box Centre X 17.2478 25 Centre Y 0.3870 25 Centre Z 31.6525 25
TABLE 12
Compound Docking Affinity Number of hydrogen Amino acids involved in bonding code (kcal/mol) bonds DPK3d1 -6.7 01 SER A: 521 DPK3d2 -7.7 DPK3d3 -7.6 - DPK3d4 -8.1 02 GLY A: 532, TYR A: 537 DPK3d5 -7.2 02 ARG A: 206, TYRA: 580 Ciprofloxacin -6.7 02 ARG A: 380, ARG A: 533 Pyrazinamide -4.8 02 ASP A: 476, GLU A: 477
Streptomycin -6.8 06 LYS A: 381, GLU A: 387, GLY A: 530, GLY A: 532, ARG A: 533, ALA A: 584
TABLE 13
Compound code Docking Affinity Number of hydrogen Amino acids involved in bonding (kcal/mol) bonds DPK2d1 -6.5 01 LYS A: 381 DPK2d2 -6.8 01 TYR A: 517 DPK2d3 -6.4 02 ARG A: 380, LYS A: 381 DPK2d4 -6.5 03 ARG A: 380, LYS A: 381, ARG A: 533 DPK2d5 -6.5 01 LYS A: 381 DPK2d6 -6.7 - DPK2d7 -7.7 02 ARG A: 318, ASP A: 476 DPK2d8 -8.3 06 GLU A: 387, ASP A: 346, GLU A: 528, ILE A: 531, GLY A: 532, TYR A: 537
TABLE 14
Compound code Docking Affinity Number of hydrogen Amino acids involved in bonding (kcal/mol) bonds DPK4Bld1 -6.6 05 ASP A: 346, ARG A: 380, LYS A: 381, GLU A: 387, ARG A: 533 DPK4Bld2 -6.6 01 GLU A: 532 DPK4Bld3 -7.3 05 GLU A: 387, GLY A: 530, ARG A: 533, GLU A: 587, ASP A: 588 DPK4Bld4 -6.6 04 GLY A: 530, ARG A: 533, GLU A: 587, ASP A: 588 DPK4Bld5 -7.0 01 GLU A: 528 DPK4Bld6 -6.9 01 GLU A: 528 DPK4Bld7 -6.9 04 GLY A: 530, ARG A: 533, GLU A: 587, ASP A: 588
TABLE 15
Compound code Docking Affinity Number of hydrogen Amino acids involved in bonding (kcal/mol) bonds DPK4B2d1 -6.4 02 ASP A: 171, THR A: 536 DPK4B2d2 -6.3 01 THR A: 536 DPK4B2d3 -6.7 DPK4B2d4 -6.3 DPK4B2d5 -6.8 01 THR A: 536 DPK4B2d6 -6.3
TABLE 16
Sr. Compound Mol. Wt. AlogP logS LogBB LogPapp nOH nOHNH nb No. Code 1 DPK3dl 572.50 8.38 -4.168 0.9738 -0.7607 06 02 03 2 DPK3d2 617.50 3.68 -3.6879 0.6238 0.3577 06 03 03 3 DPK3d3 538.05 7.73 -4.168 0.9738 -0.6629 06 02 03 4 DPK3d4 548.61 2.65 -3.3924 0.5525 -0.2738 06 03 03 5 DPK3d5 548.61 2.65 -3.3924 0.5525 -0.2738 06 03 03 6 DPK2dl 506.7 7.87 -4.938 0.9886 -0.6607 06 00 07 7 DPK2d2 520.7 8.26 -4.938 0.9886 0.6842 06 00 08 8 DPK2d3 478.6 7.25 -4.875 0.9889 -0.6382 06 00 07 9 DPK2d4 492.1 7.64 -4.875 0.9889 -0.5974 06 00 08 10 DPK2d5 547.5 8.56 -5.547 0.9870 -0.6819 06 00 07 11 DPK2d6 561.1 8.95 -5.547 0.9870 -0.6907 06 00 08 12 DPK2d7 568.6 -1.52 -3.8903 0.7948 0.4343 06 02 07 13 DPK2d8 582.7 -1.18 -3.8903 0.7948 0.4343 06 02 07 14 DPK4Bld1 333.4 3.42 -3.894 0.9725 -0.5241 07 02 02 15 DPK4Bld2 369.4 4.33 -3.877 0.9706 -0.6881 06 02 03 16 DPK4Bld3 388.4 -0.19 -3.2663 0.8725 0.9025 06 02 03 17 DPK4Bld4 377.9 4.48 -4.394 0.9712 -0.6088 06 02 02 18 DPK4Bld5 343.4 3.83 -3.841 0.9695 -0.5519 06 02 02 19 DPK4Bld6 359.4 3.54 -3.778 0.9754 -0.7156 07 03 02 20 DPK4Bld7 377.9 4.48 -4.394 0.9712 -0.6246 06 02 02 21 DPK4B2dl 270 3.27 -4.235 0.9803 -0.7912 05 01 02 22 DPK4B2d2 314 4.33 -5.529 0.9723 0.6226 04 01 02 23 DPK4B2d3 314 4.33 -5.529 0.9723 0.6320 04 01 02 24 DPK4B2d4 325 -0.82 -3.8065 0.8550 1.0428 04 01 02 25 DPK4B2d5 280 3.68 -4.851 0.9800 0.6881 04 01 02 26 DPK4B2d6 296 3.38 -4.638 0.9761 0.5726 05 02 02
The drawings and the forgoing description give examples of embodiments. Those skilled in the art will appreciate that one or more of the described elements may well be combined into a single functional element. Alternatively, certain elements may be split into multiple functional elements. Elements from one embodiment may be added to another embodiment. For example, orders of processes described herein may be changed and are not limited to the manner described herein. Moreover, the actions of any flow diagram need not be implemented in the order shown; nor do all of the acts necessarily need to be performed. Also, those acts that are not dependent on other acts may be performed in parallel with the other acts. The scope of embodiments is by no means limited by these specific examples. Numerous variations, whether explicitly given in the specification or not, such as differences in structure, dimension, and use of material, are possible. The scope of embodiments is at least as broad as given by the following claims.
Benefits, other advantages, and solutions to problems have been described above with regard to specific embodiments. However, the benefits, advantages, solutions to problems, and any component(s) that may cause any benefit, advantage, or solution to occur or become more pronounced are not to be construed as a critical, required, or essential feature or component of any or all the claims.
Claims (4)
1) A process for synthesis benzimidazole derivatives useful as antitubercular agents, said process comprising: treating o-phenylene diamine with ethanol (C 2 H 5 OH) under catalyst of Carbon disulfide (CS 2 ) and potassium hydroxide (KOH) to obtain Mercaptobenzimidazole (DPK3A) and Meldrum acid; mixing the Mercaptobenzimidazole (DPK3A) with the Meldrum acid in a reflux manner for 4 hr under a catalyst of Anhydrous 1,4- dioxine to obtain Benzimidazolesulfonylcarbonyl acetic acid (DPK3B); stirring the Benzimidazolesulfonylcarbonyl acetic acid (DPK3B) with polyphosphoric acid (PPA) at 120°C for 8hrs to get Dihydrobenzimidazole hydroxythiopyranone (DPK3C); and refluxing Dihydrobenzimidazole hydroxythiopyranone (DPK3C) with Ar-CHO and R-NH 2 in 6-8 hrs to obtain Dihydrobenzimidazole thiopyrano oxazinone derivatives.
2) The process as claimed in claim 1, wherein the Mercaptobenzimidazole (DPK3A) is treated with acetic anhydride ([CH 3CO] 2 0) toobtain acetyle Mercaptobenzimidazole.
3) The process as claimed in claim 2, wherein the acetyle Mercaptobenzimidazole is served with the Ar-CHO under claisen - Schmidt condensation to obtain Mercaptobenzimidazole clubbed chalcone derivatives.
4) The process as claimed in claim 1, wherein the Mercaptobenzimidazole (DPK3A) is treated with the Ar-CHO/ CH 2 (CN) 2 under a catalyst of CH3 COONH 4/ Ethanol (EtOH) to obtain Pyridincarbonitrile Mercaptobenzimidazole derivatives. ) The process as claimed in claim 1, wherein the Mercaptobenzimidazole (DPK3A) is mixed the glacial acetic acid and NH 2-R for 6hrs to obtain substituted Mercaptobenzimidazole (DPK2B1- DPK2B4), wherein the substituted Mercaptobenzimidazole (DPK2B1- DPK2B4) is refluxed with di-bromoalkane under catalyst of K 2 C3 and ethanol for 14hrs to obtain coupled Mercaptobenzimidazole derivatives (DPK2dl- DPK2d8).
NH2 N O CH3 C2H5OH SH + CS2 , KOH N CH3 NH2 H O
o-phenylene diamine Mercaptobenzimidazole O Meldrum acid (DPK3A)
Reflux for 4 hrs OH Anhydrous 1,4-dioxane H N A or B O O HN
N S Stirred at 120 oC for 8 hrs H A. Eaton's reagent at 70oC HO S N Dihydrobenzimidazole O hydroxythiopyranone B. Polyphosphoric acid (PPA) Benzimidazolesulfonylcarbonyl acetic acid (DPK3C) (DPK3B)
Ar-CHO Refluxed for 6-8hrs Ar R- NH2 O H N N R
N S Ar H O Dihydrobenzimidazole thiopyranooxazinone Derivatives (DPK3d1- DPK3d5)
FIG. 1
H2N N
C2H5OH SH HO CS2 , KOH O Mercaptobenzoxazole 2-amino phenol (Compound-I)
N S Glacial acetic acid 6 Hrs (CH2)n R NH2 Br-(CH2)n-Br N S N (di-Bromoalkane) N R n= 2,(di-bromoethane) n=3,(di-bromopropane SH N R K2CO3 , Ethanol N
Coupled Mercaptobenzimdazole Derivatives Reflux for 14 hrs R (DPK2d1- DPK2d8) Substituted Mercaptobenzimdazole (DPK2B1 - DPK2B4)
FIG. 2
NH2 2020104192 20 Dec 2020 N C2H5OH SH CS2 , KOH N NH2 H o-phenylene diamine Mercaptobenzimidazole
[CH3CO]2O (Acetic anhydride) N
SH N
N Ar-CHO / CH2(CN)2 SH CH3COONH4 / EtOH / Reflux N
N COCH3 Ar Acetyl Mercaptobenzimidazole
Claisen–Schmidt H2N Ar-CHO condensation CN Pyridincarbonitrile Mercaptobenzimidazole derivatives N SH (Part A)
N
Ar
O Mercaptobenzimidazole-clubbed chalcone derivatives (Part B) FIG. 3
FIG. 4A-C
FIG. 5A-B
FIG. 6
FIG. 7
FIG. 8
FIG. 10 FIG. 9
FIG. 11
FIG. 12 FIG. 13
FIG. 14
FIG. 15
FIG. 16
FIG. 17
2020104192 20 Dec 2020
1802 Treating o-phenylene diamine with ethanol (C2H5OH) under catalyst of Carbon disulfide (CS2) and potassium hydroxide (KOH) to obtain Mercaptobenzimidazole (DPK3A) and Meldrum acid
Mixing the Mercaptobenzimidazole (DPK3A) with the Meldrum acid in a reflux manner for 4 hr under a catalyst of Anhydrous 1,4- dioxine to obtain 1804 Benzimidazolesulfonylcarbonyl acetic acid (DPK3B)
1806 Stirring the Benzimidazolesulfonylcarbonyl acetic acid (DPK3B) with polyphosphoric acid (PPA) at 120oC for 8hrs to get Dihydrobenzimidazole hydroxythiopyranone (DPK3C)
1808 Refluxing Dihydrobenzimidazole hydroxythiopyranone (DPK3C) with Ar-CHO and R-NH2 for 6-8 hrs to obtain Dihydrobenzimidazole thiopyrano oxazinone derivatives
Figure 18
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