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.

[1]  Yaming Zhou,et al.  Discovery of Cinnoline Derivatives as Potent PI3K Inhibitors with Antiproliferative Activity. , 2021, Bioorganic & medicinal chemistry letters.

[2]  R. Stoll,et al.  Synthesis and Cytotoxic Activity Study of Novel 2-(Aryldiazenyl)-3-methyl-1H-benzo[g]indole Derivatives , 2021, Molecules.

[3]  M. Amini,et al.  Triarylpyrazole Derivatives as Potent Cytotoxic Agents; Synthesis and Bioactivity Evaluation “Pyrazole Derivatives as Anticancer Agent” , 2021, Drug Research.

[4]  Sathish Kumar Boda,et al.  Synthesis and antibacterial activity of novel cinnoline-isoxazole derivatives , 2020 .

[5]  M. Amini,et al.  Design, Synthesis and Biological Evaluation of Novel Diaryl Pyrazole Derivatives as Anticancer Agents , 2020 .

[6]  Sathish Kumar Boda,et al.  Novel 4-(1H-1,2,3-triazol-4-yl)methoxy)cinnolines as potent antibacterial agents: Synthesis and molecular docking study , 2020 .

[7]  S. Ostad,et al.  Synthesis, Anti-proliferative Evaluation, and Molecular Docking Studies of 3-(alkylthio)-5,6-diaryl-1,2,4-triazines as Tubulin Polymerization Inhibitors , 2019, Letters in Drug Design & Discovery.

[8]  M. Amini,et al.  Synthesis and anti-breast cancer activity of novel indibulin related diarylpyrrole derivatives , 2019, DARU Journal of Pharmaceutical Sciences.

[9]  S. Bawa,et al.  Therapeutic potential of cinnoline core: A comprehensive review. , 2019, Mini reviews in medicinal chemistry.

[10]  M. Faramarzi,et al.  2,4-Disubstituted Quinazoline Derivatives Act as Inducers of Tubulin Polymerization: Synthesis and Cytotoxicity. , 2019, Anti-cancer agents in medicinal chemistry.

[11]  M. El-abadelah,et al.  Synthesis, Characterization, and Bioactivity of Novel Bicinnolines Having 1‐Piperazinyl Moieties , 2018, Journal of Heterocyclic Chemistry.

[12]  S. Ostad,et al.  Design, synthesis and cytotoxicity evaluation of indibulin analogs , 2018, Heterocyclic Communications.

[13]  M. Taha,et al.  Synthesis and Structure-Activity Relationship; Exploration of some Potent Anti-Cancer Phenyl Amidrazone Derivatives. , 2017, Medicinal chemistry (Shariqah (United Arab Emirates)).

[14]  B. Gatto,et al.  Indenocinnoline derivatives as G-quadruplex binders, topoisomerase IIα inhibitors and antiproliferative agents. , 2017, Bioorganic & medicinal chemistry.

[15]  F. Mendicuti,et al.  Imidazopyridinium cations: A new family of azonia aromatic heterocycles with applications as DNA intercalators , 2017 .

[16]  A. Amr,et al.  Pharmacological activities of some new polycyclic triazolopyrazolopyridazine derivatives. , 2012, International journal of biological macromolecules.

[17]  W. Voelter,et al.  Synthesis, antitumor activity, and electrochemical behavior of some piperazinyl amidrazones , 2010 .

[18]  Raimond B G Ravelli,et al.  Variations in the colchicine-binding domain provide insight into the structural switch of tubulin , 2009, Proceedings of the National Academy of Sciences.