Executive Summary : | Extensively drug resistant TB (XDR TB), a relatively rare type of drug resistant TB, which is resistant to most potent first line drugs, also resistant to fluoroquinolones and at least one of three injectable second-line drugs. The current first-line TB drug regimen is more than 50 years old and non-compliance can lead to drug resistant TB including MDR TB. Non-compliance to second line treatment can lead to extensively drug resistant (XDR) TB strains. TB and COVID-19 both diseases affect the lungs and have similar symptoms, and there are chances of increase in the cases in near future as in case of HIV-TB combination. Considering at global level, the common infectious diseases are showing resistance to antibiotics which is burdening for the innovation or discovery of novel chemical entities. The aim of the proposed work is divided into four parts: Part 1: Computer Aided Drug Design of novel antitubercular agent based on - a. Study the interaction between ligand and corresponding target proteins using Docking and Molecular Dynamic Simulation studies. b. Study of ADME parameters by Qikprop, docking interaction using Schrödinger Part 2: Synthesis and Characterization of the designed molecules. Part 3: Evaluation of the synthesized molecules against M. TB. Part 4: Iteration and redesigning of the active molecules New drugs and new combination regimens in clinical trials are expected to increase therapeutic efficacy and shorten treatment duration in both drug-susceptible and drug- resistant TB. A new TB drug should offer at least one of the following three improvements over the existing drugs: 1. Shorten the total duration of treatment. 2. Improve the treatment outcome of MDR-TB and or XRD-TB. 3. Provide a more effective treatment for latent TB infection. The work plan is divided into four parts- Part 1: Computer Aided Drug Design of M. tuberculosis-MbtA inhibitors - M. tuberculosis-MbtA, an enzyme involved in the biosynthesis of siderophores, having a critical role in bacterial growth and virulence. A pyrido[2,3-b]pyrazine derivatives, a fused ring of two pharmacophore moiety obtained from first line drugs - isoniazid and pyrazinamide is coupled with pharmacophore of a second line drug - Retomanid/Triclosan selected for docking studies. Part 2: Synthesis and Characterization of the designed molecules - After getting the virtual "HITS", they will be synthesized in our laboratory and characterized by various analytical technique like IR, NMR & Mass spectrometry. Part 3: Evaluation of the molecules - The synthesized molecules will be tested against M. tuberculosis H37Rv strain in order to determine the MIC values with the Resazurin Microtiter Assay (REMA) Plate method by using Isoniazid as the reference drug. Part 4: Iteration and redesigning of the active molecules - the molecules that are found to be active in biological assay will be studied for Structure Activity Relationship (SAR) and redesigned based on that SAR and isosteric replacement. |