Rational design and synthesis of novel dibenzo[b,d]furan-1,2,3-triazole conjugates as potent inhibitors of Mycobacterium tuberculosis

• A series of novel dibenzofuran-1,2,3-triazole conjugates were synthesized via click chemistry.
• All the new analogues were evaluated for their in vitro antimycobacterial activity.
• Three derivatives 5a, 5d and 5f were resulted as best active antitubercular agents with selectivity index >25.
• Dibenzofuran–triazole conjugates were emerged as lead antitubercular agents for optimization.

A series of novel dibenzo[b,d]furan-1,2,3-triazole conjugates, rationally designed by reorientation of dibenzo[b,d]furan pharmacophore and alkyl/aryl groups appended on 1,2,3-triazole core, were synthesized using click chemistry. The required key intermediate, 2-ethynyl dibenzo[b,d]furan 3 was prepared from dibenzofuran-2-carboxaldehyde using Corey–Fuchs reaction. Further reaction of 3 with various alkyl/aryl azides in the presence of copper catalyst produced 1,2,3-triazole conjugates in excellent yields. Evaluation of all the new compounds for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (ATCC27294), resulted 5a (MIC: 1.56 μg/mL), 5d (MIC: 0.78 μg/mL) and 5f (MIC: 0.78 μg/mL) as promising lead analogues. Among these three compounds, 1-(4-bromobenzyl)-4-(dibenzo[b,d]furan-2-yl)-1H-1,2,3-triazole (5f) emerged as the most promising antitubercular agent with lowest cytotoxicity (selectivity index: ≫25) against the HEK-293T cell line.

Figure optionsDownload as PowerPoint slide