Design, Synthesis, Characterization and Biological Evaluation of Some Novel Anti Tubercular Agents Targeting: Decaprenylphosphoryl-Beta-D-Ribose 2’Epimerase-1

Ramya, N (2016) Design, Synthesis, Characterization and Biological Evaluation of Some Novel Anti Tubercular Agents Targeting: Decaprenylphosphoryl-Beta-D-Ribose 2’Epimerase-1. Masters thesis, College of Pharmacy Madras Medical College, Chennai.


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INTRODUCTION: Tuberculosis is a major disease causing death every year 1.8 million worldwide and represents the leading cause of mortality resulting from a bacterial infection. Introduction in the 60’s of first-line drug regimen resulted in the control of the disease and TB was perceived as defeated. In 2011, tuberculosis (TB) remained the second cause of death from infectious disease worldwide. It mainly affects the poorest countries of Africa and Southeast Asia. In 2010, according to the world health organization (WHO), TB incidence and prevalence were estimated at 8.8 and 12 million cases respectively about 1.1 million among HIV-negative people and 0.35 million among HIV-positive people died from TB. Most importantly, one third of the world population is infected with latent infection and 10% of those infected people will develop active TB in their life. BACTERIOLOGICAL PROFILE OF MYCOBACTERIUM TUBERCULOSIS SPECIES: The mycobacterium tuberculosis complex consists of Mycobacterium bovis, Mycobacterium africanoum and Mycobacterium canettii, Mycobacterium capre, Mycobacterium microti and Mycobacterium pinnipedi. Tuberculosis (TB) is caused by the obligate human pathogen, Mycobacterium tuberculosis.Mycobacteria are a distinctive rod shaped, non spore forming aerobic bacteria that share a common property of a lipid-rich cell-wall that avidly retains carbol fushion dye in the presence of acidic alcohol (acid fast staining). Mycobacteria typically measures 0.5μm to 3μm. AIM AND OBJECTIVES: With the ongoing progress in protein crystallography and NMR, structurebased drug design is gaining increasing importance in the search for new drugs. Modeling starts from the 3D structure of a target protein in order to construct molecules which are complementary to a binding site, in their geometry as well as in the pattern of their physicochemical properties around the molecules The present study relates to the synthesis of various aryl carboxylic acid 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. SUMMARY: 1. Decaprenylphosphoryl-b-d-ribose 2’-Epimerase 1(DprE1) a enzyme of OxidoReductase family is a critical enzyme for the growth of Mycobacterium tuberculosis H37Rv. 2. From the review of literature DprE1 was chosen for our study for drug design. 3.A database of 100 molecules with high potential of inhibiting the target possessing PDB ID of 4FDO were carefully chosen by making changes to the lead molecule aryl carboxylic acid derivatives. 4. The 3D structure of the molecules were docked against the 3D structure of DprE1 using the docking platform argus lab. 5. Three compounds with good Docking score (lower Binding energy) were selected for laboratory synthesis. The reaction conditions were optimized. 6. The Compounds were labeled as R1, R2, R3 were synthesized with satisfactory yield. 7. The purity of the synthesized compounds was ensured by repeated recrystallization and column chromatography.Further the compounds were evaluated by melting point and TLC. 8. The characterizations of the synthesized compounds were done by Infrared, Nuclear magnetic resonance and Mass spectroscopic methods. 9. The final pure compounds were screened for Antimycobacterial activity by in vitro method called Microplate Alamar Blue Assay (MABA). 10. The synthesized compounds were active at 25mcg/ml to <100mcg/ml, which are compared to that of the known anti-tubercular agents at 50mcg/ml against the MIC of known TB drugs. The synthesized compounds were lesser active than that of the standard TB drugs. Pyrazinamide: 3.125mcg/ml, Ciprefloxacin: 3.125mcg/ml and Streptomycin 6.25mcg/ml. 11.The synthesized compounds were subjected to toxicity prediction assessments by OSIRS software. The results are coded as a green colour which confirms the drug likeness. CONCLUSION: Our work concludes that our synthesized molecules are effective in inhibiting Decaprenylphosphoryl-beta-D-ribose 2’-Epimerase 1(DprE1) which is important for the growth of Mycobacterium tuberculosis. Further structural refinement in the structure of the synthesized compounds will give new outlook to the development of promising molecules against the pathogen Mycobacterium tuberculosis.

Item Type: Thesis (Masters)
Additional Information: Reg. No. 261415716
Uncontrolled Keywords: Design; Synthesis ; Characterization ; Biological Evaluation ;Some Novel Anti Tubercular Agents ; Targeting ; Decaprenyl ; phosphoryl-Beta-D-Ribose 2’Epimerase-1
Subjects: PHARMACY > Pharmaceutical Chemistry
Depositing User: Ravindran C
Date Deposited: 19 Mar 2018 08:38
Last Modified: 21 Mar 2018 08:14

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