Design, Synthesis, Characterization and Biological Evaluation of Some Novel 3, 4-Dihydropyrimidin-2(1h)-One as Anti Tubercular Agents.

The present study the ongoing progress in protein crystallography and NMR, structure-based 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 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. DOCKING: Several chemical libraries containing various scaffolds will be sketched and docked against the 3D structure of DprE1. The compounds for the synthesis will be chosen based on the high GScore and their feasibility in synthetic chemistry. SYNTHESIS: Based upon the Docking parameters, the following compounds will be synthesized Synthesis of 4-(4-hydroxyphenyl)-6-(pyridin-4-yl)-3,4-dihydropyrimidin-2(1H)-one(MBS2) Synthesis of 4-(4-chlorophenyl)-6-(pyridin-4-yl)-3,4-dihydropyrimidin-2(1H)-one (MBS3) Synthesis of 4-[4-(dimethylamino)phenyl]-6-(pyridin-4-yl)-3,4-dihydropyrimidin-2(1H)-one (MBS 6): CHARACTERIZATION: The above compounds will be characterized by using Infrared Spectroscopy, Nuclear Magnetic Spectroscopy and Mass spectroscopy. BIOLOGICAL EVALUATION: The synthesized compounds will be screened for their anti-tubercular activity by various in-vitro methods. CONCLUSION: Decaprenylphosphoryl-b-d-ribose 2’-Epimerase 1(DprE1) a enzyme of Oxido Reductase family is a critical enzyme for the growth of Mycobacterium tuberculosis H37Rv. From the review of literature DprE1 was chosen for our study for drug design. A database of 100 molecules with high potential of inhibiting the target possessing PDB ID of 4FDO were carefully chosen by making changes into the lead molecule 3,4- Dihydro pyrimidinones. The 3D structure of hopeful molecules were docked against the 3D structure of 4FDO using the docking platform Glide® (Grid Based Ligand Docking with Energetics). Three compounds with good Glide score( lower Binding energy) were selected for laboratory synthesis. Reaction conditions were optimized. The Compounds were labeled as MBS 2, MBS3, MBS6 were synthesized with satisfactory yield by Biginelli reaction. The purity of the synthesized compounds were evaluated by melting point and TLC. Recrystallization was done. The characterization of the synthesized compounds were done by Infrared, Nuclear magnetic resonance and Mass spectroscopic methods. The synthesized compounds were subjected to computer aided drug design (CADD) tool,for toxicity risk assessment by OSIRIS property calculator. The results are color coded as green color which confirms the drug likeness. The final pure compounds were screened for Antimycobacterial activity by in vitro method called Microplate Alamar Blue Assay(MABA). The Minimum Inhibitory Concentration (MIC) of the synthesized compounds were at 50mcg/ml against the MIC of known TB drugs Pyrazinamide: 3.125mcg/ml, Ciprofloxacin: 3.125mcg/ml and Streptomycin 6.25mcg/ml. Our work concludes that our synthesized molecules are effective in inhibiting Decaprenylphosphoryl-b-d-ribose 2’-Epimerase 1(DprE1) which is important for the growth of Mycobacterium tuberculosis. Further structural improvement in the structure of the synthesized compounds will give new outlook to the development of promising molecules against the pathogen Mycobacterium tuberculosis