Synthesis of Amide Derivatives as Tubulin Polymerization Inhibiting Antiproliferative Agents

Abstract Herein, we synthesized some new imidazole‐tetrazole‐amide hybrids ( 7 a – o ) and investigated their antiproliferative activity on three human cancer cell lines like HEPG2, A549 and MCF‐7. Generally, most of them displayed more activity on A549 than other two cell lines. Specifically, compounds N‐(3,5‐dimethoxyphenyl)‐2‐(5‐(1‐methyl‐1 H ‐imidazol‐2‐yl)‐2 H ‐tetrazol‐2‐yl)acetamide ( 7 b) and N‐(4‐chloro‐3,5‐dimethoxyphenyl)‐2‐(5‐(1‐methyl‐1 H ‐imidazol‐2‐yl)‐2 H ‐tetrazol‐2‐yl)acetamide ( 7 m ) had almost similar potency on A549, while, they had significant activity on MCF‐7 in comparison to the standard drug Combretastatin A‐4 (CA‐4). Besides, compounds 4‐(2‐(5‐(1‐methyl‐1 H ‐imidazol‐2‐yl)‐2 H ‐tetrazol‐2‐yl)acetyl)benzonitrile ( 7 j ) and N‐(3,5‐dichlorophenyl)‐2‐(5‐(1‐methyl‐1H‐imidazol‐2‐yl)‐2 H ‐tetrazol‐2‐yl)acetamide ( 7 k ) showed most promising activity against A549 as compared to the CA‐4. The uppermost activity against A549 found for the compounds 7 j and 7 m have IC 50 values 1.09 and 1.26 μM respectively. The ability of potent compounds 7 b , 7 j , 7 k and 7 m to inhibit the tubulin polymerization was then studied and found that compounds 7 b and 7 m exhibited promising potency in comparison to the CA‐4. Further, molecular docking studies of compounds 7 b , 7 j , 7 k and 7 m into the tubulin's colchicine‐binding site revealed the possible interactions with tubulin. Finally, in silico ADMET studies revealed that compounds 7 b , 7 j , 7 k and 7 m showed high GI absorption and followed rules of Lipinski, Ghose, Veber, Egan and Muegge without any deviation. Further anticancer mechanism studies are under progress.