Design, Synthesis, Characterization and Biological Evaluation of Some Novel Antitubercular Agents.

AIM: The present study to develop novel and potent methoxy mycolic acid (mmaa2) 1TPY inhibitors with anti- tubercular –activity. OBJECTIVE: Identification of the common Pharmacophore responsible for the inhibition of mmaa2 using hip-hop molecule of catalyst software 4.11 from accelrys. Using scaffold hopping technique, generation of 10,000 scaffolds from the drug. Prediction of anti-tubercular activity for the designed using the hyporefine model and to identify novel and potent mmaa2 inhibitor using Lipinski rule of five. The potent mmaa2 inhibitors attained as results can be used as lead for drug development. Docking of the lead with various derivatives using glide software to the target 1TPY. The derivatives of the compounds from the lead molecule which has higher glide score value were synthesized. Justification of the purity of synthesized compounds using the method of melting point, thin layer chromatography. Characterization of the synthesized compounds by using IR spectroscopy, MASS spectroscopy and NMR spectroscopy. In vitro screening anti-tubercular activity of synthesized compounds. CONCLUSION: 1TPY a critical enzyme for the growth of Mycobacterium tuberculosis was chosen for our study after review of literature. A database of 50 molecules with high prospect of inhibiting the target 1TPY were carefully chosen by making changes into the known hit molecule, here the acridine nucleus. Candidate molecules were designed and docked against 1TPY protein using Glide® (grid based ligand docking with energetics) program. Two molecules with good G-Score (high stablility/lower binding energy ) were shortlisted for the synthesis . They were labelled as MI3, and MI4 Two compounds were synthesized with good yield by conventional Schiff base reaction involving condensation between the 9-Amino Acridine and different types of aromatic aldehydes. The purity of the synthesized compounds were evaluated by melting point, TLC, recrystallization. The synthesized compounds were characterized by IR spectroscopy, NMR spectroscopy and Mass spectroscopy. The pure compounds were screened for In-vitro Anti-tubercular activity by Microplate Alamar Blue Assay (MABA) method. Two compounds showed significant invitro antitubercular activity. The compounds MI3, MI4, showed minimum inhibitory concentration at 6.25mg/ml against the MIC of standard drugs Pyrazinamide: 3.125mcg/ml, Ciprofloxacin: 3.125 mcg/ml, Streptomycin: 6.25 mcg/ml. The G-Score of the synthesized compounds ranged between -8.86 to -8.66. The docking scores of Standard drugs against 1TPY were Pyrazinamide: -5.8 kcal/mol, Ciprofloxacin: -7.5 kcal/mol, Streptomycin: -4.9 kcal/mol. So there is correlation between the docking study and In-vitro Antimycobacterial activity. The results of our study conclude that 1TPY is a critical enzyme for Antimycobacterial activity. These compounds can be attractive starting point to find newer molecules by fine tuning the structures to yield compounds with better activity against Mycobacterium tuberculosis