Design, Synthesis, Characterization and Biological Evaluation of Some Novel Anti Tubercular Agents Targeting Glutamine Synthetase 1

INTRODUCTION:The latest world health organization (WHO) reports show that there were 9.0 million new tuberculosis (TB) cases and 1.5 million tuberculosis (TB) deaths, leading cause of death from an infectious disease worldwide, after the human immunodeficiency virus (HIV). Co-infection with the HIV fuels the global TB crisis, and successful TB treatment is further complicated and hampered by the existence of multidrug- resistant (MDR) TB and extensively drug resistant (XDR) TB [1] Tuberculosis, MTB, or TB (short for tubercle bacillus), in the past also called phthisis, phthisis pulmonalis, or consumption, is a widespread, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis generally affects the lungs, but can also affect other parts of the body.TYPES OF TUBERCULOSIS:Tuberculosis is a contagious disease; it affects almost all the important organs of the body. Clinically, tuberculosis is broadly categorized into three major categories 1. Primary tuberculosis. 2. Secondary tuberculosis. 3. Disseminated tuberculosis.AIM:The aim of this project is to design molecules into potential anti-tubercular activity that is capable of inhibiting cell wall synthesis by inhibiting glutamine synthetase. The designed compounds will be synthesized, characterized and evaluated for activity and toxicity.OBJECTIVE:The compounds are designed and docked against a specific crucial target, Glutamine Synthetase I, which is involved in the cell wall biosynthesis and nitrogen metabolism. The synthesized compounds are expected to act on the same.SUMMARY:Glutamine synthetase 1 is a vital enzyme present in the cell wall of Mycobacterium tuberculosis H37Rv. It belongs to the Ligase family. This enzyme was chosen as the target for the drug design study after thorough literature review. A database of 200 molecules with potential to inhibit the target (PDB id: 4 ACF) was chosen by altering the lead molecules, amino thiophene. The designed molecules were docked against the target chosen using ARGUS LAB. From among the docked molecules, 8 molecules with good Score were chosen for laboratory synthesis. The drug likeness and toxicity prediction was carried out for the filtered 8 compounds in silico. Then further the compounds were synthesized. The reaction conditions were optimized. The compounds were labeled as MM, CM, MMF, CMG, MMG, MC, CC,TM. These compounds were synthesized and recrystallized. PURITY: The purity of the compounds was evaluated by sharp melting point and TLC and was characterized by Infrared Spectroscopy, Nuclear Magnetic Resonance Spectroscopy and MASS Spectroscopy. A single peak obtained from GC-MS analysis predicted that the synthesized compounds are formed at correct manner. The molecular weight of the compounds are also determined. Further, compounds are characterized by IR, NMR (H1NMR) functional groups , number of protons are determined respectively. All the synthesized compounds exhibited molecular ion peak (M+ ) of varying intensities ascertaining the molecular weights of the compounds. ANTI-MICROBIAL ACTIVITY The purified compounds were screened for anti-tubercular activity by invitro Micro Plate Alamar Blue Assay. It showed that the synthesized compounds are sensitive at 3.12- 1.6 mcg/ml level. So the following results concluded that the synthesized compounds have better anti-tubercular activity.CONCLUSION:It is concluded that the synthesized compounds might effectively inhibit the chosen target Glutamine Synthetase I which is essential for the Mycobacterial Tuberculosis. Further structural modifications of the synthesized compounds will aid in the development of potential molecule against the pathogen.