Background: Tuberculosis, is a chronic infectious disease, affects one third of the global population. Emergence of Multi-resistant (MDR) strains and high susceptibility of human immunodeficiency virus (HIV) infected persons to the disease forced to develop novel anti-tuberculosis agents and preferably have a novel mechanism of action as to avoid crossresistant with other agents. Literature survey evidences that, Pyridine, Thiadiazole , Benzimidazole; and Acetyl thiophene derivatives exhibit various pharmacological activities, including anti-mycobacterial activity. Methods: Thus, a series of Pyridine, Thiadiazole, Benzimidazole; and Acetyl thiophene based molecules were designed and docked against crucial mtb enzyme target InhA (Enoyl Acyl Carrier Protein Reductase) Enzyme. The docked molecules were screened against good docking-score and multiple interactions and opted for synthesis. Synthesized molecules were re crystallized to obtain the purity. All the purified compounds were characterized by various spectral analyses and evaluated for anti- mycobacterial activity against tuberculosis H37RV strain by Microplate Alamar Blue Assay (MABA) method. Results: The experimental results shown that schiff base of Pyridine (Compounds ‘d’ ) and Benzimidazole derivatives (Compounds ‘i’ ) possesses good anti-tubercular activity with a MIC below 1.6 μg /mL. Further compound ‘e’ of benzimdazole derivative showed good anti tubercular activity with an MIC below 6.25 μg /mL. Whereas 2 - acetyl thiopene compounds exhibited moderate anti tubercular activity at below 50μg/mL. Conclusion: The comparative in vitro and molecular docking study analysis reveals that, compared to chalcones of Acetyl thiophne derivatives, Pyridine, thiadazole and Benzimidazole based schiff bases exhibited best anti tubercular activity.