Design, Synthesis and Pharmacological Evaluation of Some Newer Imidazolyl Heterocycles as Potent Btk Inhibitors for the Treatment Of Rheumatoid Arthritis

Menaka, A (2017) Design, Synthesis and Pharmacological Evaluation of Some Newer Imidazolyl Heterocycles as Potent Btk Inhibitors for the Treatment Of Rheumatoid Arthritis. Masters thesis, College of Pharmacy Madras Medical College, Chennai.


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INTRODUCTION:RHEUMATOID ARTHRITIS:A healthy immune system protects the body by attacking foreign bacteria and viruses, but an autoimmune disease causes the body to attack healthy tissue. Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease causing pain, swelling, stiffness and loss of function in the joints. In people with Rheumatoid Arthritis, white blood cells cause inflammation in the synovium. This causes the tissue that lines the walls of the joints to thicken and become swollen and painful when moved. The uncontrollable inflammation leads to joint erosion, a loss of motion and damage to many associated parts of the body such as lungs, heart.CAUSES:Environmental factors, including smoking and pathogens have long been implicated as risk factors of rheumatoid arthritis.AIM:The Main aim of this study is to identify, design, synthesize certain newer substituted imidazolyl derivatives as potent anti-rheumatoid arthritic agents with good predicted capability to inhibit the BTK involving Computational drug designing methods OBJECTIVE OF WORK:The plan of work includes the following steps, 1. Selection of target responsible for producing rheumatoid arthritis from the literature review which is carried out as part of the current research. 2. Identification of common Pharmacophoric features responsible for inhibiting Bruton’s Tyrosine Kinase. 3. Designing a series of leads that selectively modulate the activities of Bruton’s Tyrosine Kinase for exhibiting anti-rheumatoid arthritic activity. 4. The binding mechanism of BTK receptor and newly designed leads have to be studied using molecular docking with GLIDE 10.2 (PDB ID: 5fbn). 5. Optimisation of designed leads based on the Lipinski rule of five, ADMET properties using Molinspiration and Osiris software 6. Synthesis of certain optimized leads based on the synthetic feasibility. 7. Characterization of chemical nature of the synthesized compounds by IR, 1H NMR, 13C NMR and GC-MS analysis. 8. Docking studies of all the synthesized compounds using GLIDE 10.2 and Argus Lab 4.0 8. Evaluation of all the synthesized compounds by performing In-vitro anti-arthritic activity -Protein inhibition assay method. 9. In-vivo Pharmacological screening studies of the synthesized compounds i) Evaluation of acute oral toxicity studies. ii) Evaluation of Anti- Rheumatoid Arthritic activity. SUMMARY:Over the last few years, BTK has been considered as therapeutic target for selective B-Cell inhibition in the treatment of Rheumatoid Arthritis. Though many BTK inhibitors are reported and few are in clinical trials, none are FDA approval. Based on the literature review, all the existing BTK inhibitors found to possess mainly five Pharmacophoric features like 1HBAL Hydrogen Bond Acceptor Lipid, 1HBD Hydrogen Bond Donor, 3 HYP Hydrophobic. Hence, a scaffold library has been generated with 33 newly designed ligands which were screened with high docking score against BTK using GLIDE 10.2 and further optimized by Drug likeness properties such as Lipinski rule of five and ADMET properties. Based on the synthetic feasibility, scaffold containing 4,5 di-phenyl 2-substituted imidazole nucleus like Ligand 6, Ligand 9, Ligand 14, Ligand 13 and Ligand 12 were selected for synthesis. All the selected ligands were chemically synthesized involving Radiswieski reaction and condensation with different aromatic carboxylic acids. Five different synthesized compound such as IPABA, ISA, IAA, IHA, IPAA were prepared and its purity were established by singe spot on TLC plate. The chemical nature of the synthesized compounds were characterized by Melting point determination and different spectral studies such as IR, 1H NMR, 13C NMR and GC-MS analysis. Then the synthesized compounds were subjected to molecular docking studies using both GLIDE 10.2 and ARGUSLAB 4.1. All the synthesized compounds were subjected to In-vitro Anti-Arthritic activity by Protein inhibition assay method at different concentration 50 μg, 100 μg, 200 μg, 400 μg, 600 μg, 800 μg, 1000 μg and also compared with standard Diclofenac sodium. The synthesized derivatives IPABA, ISA, IAA, IHA, IPAA were found to significantly inhibit the protein denaturation. Compounds IPABA was found to effectively inhibit the denaturation of protein at a minimum concentration of 50 μg/ml and maximum concentration of 1000 μg/ml as equipotent as that of Diclofenac sodium.CONCLUSION:Drug design approach as well as clinical studies have revealed that the tyrosine kinase (Bruton’s tyrosine kinase) have a crucial role in the inhibition of B-cells for treatment of Rheumatoid Arthritis. The present study also provides important structural insights of 4,5 di-phenyl 2 substituted imidazole moieties in designing better BTK inhibitor as potent anti- rheumatoid arthritic agents and thus the synthesized compound IPABA (4-amino-N-[(4,5-diphenyl-1H-imidazol-2-yl)methyl]benzamide) was found to be an effective BTK inhibitor for treatment of rheumatoid arthritis.

Item Type: Thesis (Masters)
Additional Information: Reg.No.261515707
Uncontrolled Keywords: Design ; Synthesis ; Pharmacological Evaluation ; Imidazolyl Heterocycles ; Potent Btk Inhibitors ; Treatment ;f Rheumatoid Arthritis
Subjects: PHARMACY > Pharmaceutical Chemistry
Depositing User: Ravindran C
Date Deposited: 19 Mar 2018 09:55
Last Modified: 19 Mar 2018 09:55

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