Design, Synthesis, Characterization and Biological Evaluation of Few Novel Diaminopimelate Decarboxylase Inhibitors of Tuberculosis

Ravikumar, R (2016) Design, Synthesis, Characterization and Biological Evaluation of Few Novel Diaminopimelate Decarboxylase Inhibitors of Tuberculosis. Masters thesis, College of Pharmacy Madras Medical College, Chennai.


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INTRODUCTION: TUBERCULOSIS- AN INSIGHT: Tuberculosis, MTB, or TB (short for tubercle bacillus) is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis typically attacks the lungs, but can also affect other parts of the body. It is spread through the air when people, who have an active TB infection, cough, sneeze, or otherwise transmit their saliva through the air. Most infections are asymptomatic and latent, but about one in ten latent infections eventually progresses to active disease which, if left untreated, kills more than 50% of those so infected. Consumption, phthisis, scrofula, Pott's disease, and the White Plague are all terms used to refer to tuberculosis throughout history. It is generally accepted that the microorganism originated from other, more primitive organisms of the same genus Mycobacterium. Human bones from the Neolithic show presence of the bacteria, although the exact magnitude (incidence and prevalence) is not known before the 19th century. AIM:The aim is to design and synthesis never antitubercular agents which will be more potent and possess less side effects and effective against resistant form of Tb. OBJECTIVE: The present study relates to the synthesis of various pyridine-4-carbohydrazide and pyridine-3-carbohydrazide derivatives and subsequent screening for their anti-tubercular activity. Due to several toxic effects of isoniazid, attempts were made to eliminate the toxicophore and substituting with a group contributing to the anti-tubercular action. This work also aims the same motive and the compounds were synthesized according to the developed and valid synthetic route. The plan of work includes: Design of DiAminoPimelate DeCarboxylase (DAPDC) inhibitors by docking studies using Argus lab 4.0 software. SUMMARY: Diaminopimelate decarboxylase (LysA), a critical enzyme for the lysine biosynthesis of Mycobacterium tuberculosis was chosen for study after review of literature. Candidate molecules were designed and docked against 3C5Q protein using Argus lab 4.0software. Molecules with good Docking score (lower binding energy) and interactions were shortlisted for synthesis. The reaction conditions were optimized. The selected molecules were subjected to Toxicity prediction assessments by OSIRIS software. Only those molecules which did not indicate any form of toxicity were selected for synthesis. Compounds were synthesized by conventional method and labeled as RK 1, RK 2, RK 2a, RK 3, RK 4, RK 5, RK 6, RK 7, RK 8 and RK 9. Purity of the synthesized compounds was ensured by repeated recrystallization and purified by column and gas chromatography. Further the compounds were evaluated by TLC and Melting point determination. The structures of the compounds were assigned on the basis of IR, NMR and MASS spectral data. The pure compounds were screened for IN-VITRO Anti- tubercular activity by Micro plate Alamar Blue Assay (MABA). All compounds showed significant anti-mycobacterium activity.The synthesized compounds were active at 3.125 – 50 μ g/ml, which is comparable to the known anti-TB drugs: MIC of Pyrazinamide - 3.125μg/ml, MIC of Ciprofloxacin - 3.125μg/ml and MIC of Streptomycin - 6.25μg/ml. Though the synthesised molecules were designed for the target Diaminopimelate Decarboxylase (LysA), the molecules were docked against other critical anti-tubercular targets like Alpha 1,4-N- Acetyl glycosaminyl transferase(1,4NAGT), D-3 Phosphoglycerate dehydrogenase(D3PD), Pyridoxamine 5-phosphate oxidase(P5PO) and D-Alanyl D-Alanine carboxypeptidase(DADAC). CONCLUSION:It is found that compounds RK1, RK2, RK2a, RK3, RK4, RK5, RK6, RK7, RK8 and RK9 show better G-Score for the targets Alpha 1,4-N-Acetyl glycosaminyl transferase,D-3 Phosphoglycerate dehydrogenase, Pyridoxamine 5-phosphate oxidase and D-Alanyl D-Alanine carboxypeptidase.

Item Type: Thesis (Masters)
Additional Information: Reg. No. 261415717
Uncontrolled Keywords: Design ; Synthesis ; Characterization ; Biological Evaluation ; Few Novel Diaminopimelate Decarboxylase ; Inhibitors ; Tuberculosis.
Subjects: PHARMACY > Pharmaceutical Chemistry
Depositing User: Ravindran C
Date Deposited: 19 Mar 2018 08:43
Last Modified: 21 Mar 2018 08:09

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