Design, synthesis, and molecular docking study of novel cinnoline derivatives as potential inhibitors of tubulin polymerization

Abstract

The preparation of a novel 4-methylbenzo[h] cinnolines entity via a three-step synthetic protocol is described. Cyclization of the naphthylamidrazones, in the presence of polyphosphoric acid (PPA), furnishes the respective target benzo[h]cinnolines directly. This one-pot synthesis involves intramolecular Friedel–Crafts acylation followed by instant elimination under heating conditions. It is noteworthy that the yield of the product from this step decreases dramatically if the heating is extended beyond 3 h. The target novel cinnolone derivatives were identified by mass spectrometry and their structures elucidated by spectroscopic techniques. Subsequently, molecular docking was performed to shed light on the putative binding mode of the newly synthesized cinnolines. The docking results indicate that these derivatives are potential inhibitors of tubulin polymerization and the best interaction was achieved with a computational ki = 0.5 nM and posed correctly over the lexibulin.

Thiazolobenzamide‐Naphthalene Hybrids as Potent Anticancer agents compared to Doxorubicin: Design, Synthesis, SAR, In‐silico and Toxicity Analysis

“…Between 2010 and 2015, over two thirds of the FDA‐approved new molecular anticancer drugs had one or more integrated heterocyclic rings in their structures [6] . Heterocycles such as pyrazole, [7] imidazole, [8] triazine, [9] quinoxaline, [10] and cinnoline [11] are a few instances of those used in cancer treatment. The structure of thiazole consists of a five‐membered ring with atoms of nitrogen and sulfur.…”