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‐1H‐imidazol‐2‐yl)‐2H‐tetrazol‐2‐yl)acetamide (7 b) and N‐(4‐chloro‐3,5‐dimethoxyphenyl)‐2‐(5‐(1‐methyl‐1H‐imidazol‐2‐yl)‐2H‐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‐1H‐imidazol‐2‐yl)‐2H‐tetrazol‐2‐yl)acetyl)benzonitrile (7 j) and N‐(3,5‐dichlorophenyl)‐2‐(5‐(1‐methyl‐1H‐imidazol‐2‐yl)‐2H‐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 IC50 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.

Synthesis of Fused Isoxazoles of Iodoquinol as in vitro EGFR Aiming Anticancer Agents

“…In continuation of our work to synthesize biologically active hybrids, [24–27] here we have designed (Figure 2) the compounds that consists of two pharmacophores (quinoline and isoxazole) by taking in to consideration of the above stated biological applications of isoxazole and quinoline and advantages of the pharmacophore hybridization [28,29] …”

Novel Thiazolidine‐2,4‐Dione Derivatives as Potential VEGFR‐2 Inhibitors: Synthesis, Biological Testing, and in Silico Studies

“…[9] It has been discovered that thiazolidine-2,4-diones (TZDs), a family of heterocyclic compounds, may be used as cancer therapy scaffolds. [10,11] TZDs have been demonstrated to have anticancer effects through the modulation of the dynamics of the cell cycle, promoting apoptosis and cell differentiation, and inhibiting tumor angiogenesis in a variety of experimental cancer models. [12,13] One important marker for the development and spread of malignant tumors is tumor angiogenesis.…”