Design, Synthesis, Characterisation and Biological Evaluation of Some Novel 1, 3, 4-Thiadiazole Derivatives as Anti-Tubercular Agents Targeting Decaprenyl Phosphoryl Beta-D-Ribose 2’ Epimerase-1

Dhineshkumar, S (2017) Design, Synthesis, Characterisation and Biological Evaluation of Some Novel 1, 3, 4-Thiadiazole Derivatives as Anti-Tubercular Agents Targeting Decaprenyl Phosphoryl Beta-D-Ribose 2’ Epimerase-1. Masters thesis, College of Pharmacy Madras Medical College, Chennai.


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INTRODUCTION:Tuberculosis [TB] is caused by mycobacterium tuberculosis that most often affect the lungs. Tuberculosis is curable and preventable. In 1882, the German physician Robert Koch isolated the bacterium. Tuberculosis is contagious and airborne disease. In 1944, streptomycin was to treat tuberculosis [TB]. This amino glycoside interferes with protein biosynthesis through an interaction with the small 30s subunit of the ribosome. The discovery of Para amino salicylic acid in 1946 was quickly followed by the important discovery of Isoniazid [INH], as one of the most active anti-TB drugs used today. Inhibition of mycolic acids biosynthesis, one of the essential components of the mycobacterium cell wall was determined as the mechanism of action. Pyrazinamide [PZA] appeared as a potential Anti-TB drug in 1952. The TB treatment in the 1980s was a great success as it allowed to shorten the duration of the therapy from 9 to 6 months. Ethambutol [EMB] and Rifampin [RIF], the two last derivatives used in the TB first-line treatment, were discovered during the 60s. Ethambutol is an ethylenediamine discovered in 1961, which affects the cell wall by specifically targeting the polymerization of arabinogalactan and lipoarabinomannan. Finally, Rifampin appeared as a drug of choice for TB treatment around 1970, by acting on replicating and non-replicating mycobacteria. This derivative belongs to the rifampicin family and inhibits bacterial RNA synthesis by binding to the b-subunit of the DNA-dependent polymerase. AIM: The aim of this project is to design molecules with potential anti-tubercular activity that is capable of inhibiting cell wall synthesis by inhibiting Decaprenylphosphoryl-beta-D-ribose2-epimerase-1. The designed compounds will be synthesized, characterized and evaluated for biological activity and toxicity. OBJECTIVE:The compounds are designed and docked against a specific crucial target, Decaprenylphosphoryl-beta-D-ribose2epimerase-1.This is involved in the cell wall biosynthesis and Lipid metabolism. The synthesized compounds are expected to act on the same.SUMMARY:Decaprenylphosphoryl-beta-D-ribose 2-epimerase a critical enzyme for the growth of Mycobacterium tuberculosis was chosen for our study after review of literature. It belongs to the Oxidoreductase family. A database of 200 molecules with high prospects of inhibiting the target Dpre1 were carefully chosen by making changes to the known hit molecules, here the thiadiazole nucleus was chosen. Selected molecules were designed and docked against Dpre1 using Argus lab® software. Six molecules with good docking score [lower binding energy] and interactions were shortlisted for synthesis. Reaction conditions were optimized. The selected molecules were subjected to toxicity prediction assessment by OSIRIS® property explorer developed by Acetilon Pharmaceuticals limited which is available online. The results are color coded as green color which predicts the drug likeness and possibly better activity. The molecules were labelled as SDK1, SDK2, SDK3, SDK5, PAA, HA, and were synthesized with satisfactory yield. The purity of the synthesized compounds was ensured by repeated recrystallization. Further the compounds were evaluated by TLC and Melting point determination. The characterization of the synthesized compounds was done using Infra-red, Nuclear Magnetic Resonance [H1 NMR] and Mass spectrometric methods [LC-MS, GC-MS]. All the Synthesized compounds exhibited molecular ion peak (M+) of varying intensities. The final pure compounds were screened for Anti-mycobacterial activity by in vitro method called Micro plate Alamar Blue Assay [MABA]. The synthesized compounds showed sensitivity [Minimum inhibitory concentration] at 3.12mcg/ml. The standard drugs Pyrazinamide, Streptomycin, Ciprofloxacin exhibited anti mycobacterial activity at 3.125mcg/ml, 6.25mcg/ml, and 3.125mcg/ml concentrations respectively. This indicates that the synthesized compounds are as Potent as the standard drugs.CONCLUSION:All the compounds gave Docking score between -8.73 to 11.37 kcal/mol Pyrazinamide gave docking score 11.55kcal/mol for 4P8Y, Streptomycin gave docking score of 10.87kcal/mol for 4P8Y and Ciprofloxacin gave docking score of 11.25kcal/mol for 4P8Y. There is a correlation between the score and activities of all the compounds which were tested and compared with the standard drugs. This goes to prove that Decaprenyl phosphoryl beta-D-ribose 2’ epimerase-1’ (PDBID: 4P8Y) is a critical enzyme for anti-mycobacterial activity. So the fine tuning the structures of these compounds will yield molecules with better anti mycobacterial activity. Further structural modifications of the synthesized compounds will aid in the development of potential molecules against the tuberculosis pathogen.

Item Type: Thesis (Masters)
Additional Information: Reg.No.261515702
Uncontrolled Keywords: Design ; Synthesis ; Characterisation ; Biological Evaluation ; Novel 1, 3, 4-Thiadiazole Derivatives ; 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 09:20
Last Modified: 19 Mar 2018 09:20

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