Natural alkaloid, tryptanthrin (indolo[2,1-b]quinazoline-6,12-dione) and its analogues are found to exhibit potent anti-tubercular activity against MDR-TB. A novel class of indolo[2,1-b]quinazolinones have been synthesized to evaluate their anti-mycobacterial activity. Enoyl-acyl carrier protein reductase (InhA) of Mycobacterium tuberculosis is one of the key enzymes and has been validated as an effective anti-microbial target. In silico molecular docking study demonstrates that the synthesized compounds exhibit high affinity for the M. tuberculosis drug target InhA. Phaitanthrin is a natural product, which belongs to a family of tryptanthrin and exhibits structural similarity except at position 6. Phaitanthrin derivatives are prepared by modifying the keto functionality of tryptanthrin. These phaitanthrin congeners are found to display promising anti-tubercular activity.