An Efficient Synthesis of Novel Pyrazole-Based Heterocycles as Potential Antitumor Agents

Abstract

Abstract:A new series of pyrazolylpyridines was prepared by reaction of ethyl-3-acetyl-1,5-diphenyl-1H-pyrazole-4-carboxylate with the appropriate aldehyde, malononitrile, or ethyl acetoacetate and an excess of ammonium acetate under reflux in acetic acid. Similarly, two novel bipyridine derivatives were prepared by the above reaction using terephthaldehyde in lieu of benzaldehyde derivatives. In addition, a series of 1,2,4-triazolo[4,3-a]pyrimidines was synthesized by a reaction of 6-(pyrazol-3-yl)pyrimidine-2-thione with a number of hydrazonoyl chlorides in dioxane and in the presence of triethylamine. The structure of the produced compounds was established by elemental analyses and spectral methods, and the mechanisms of their formation was discussed. Furthermore, the pyrazolyl-pyridine derivatives were tested as anticancer agents and the results obtained showed that some of them revealed high activity against human hepatocellular carcinoma (HEPG2) cell lines.

The Chemistry of Acetylpyrazoles and Its Utility in Heterocyclic Synthesis

“…A series of 2‐amino‐3‐cyano‐6‐(pyrazol‐3‐yl)‐pyridines 132a–f was prepared by one‐pot reaction of 3‐acetylpyrazole derivative 1 with the appropriate aldehyde 113 , malononitrile 131 , and ammonium acetate under reflux in acetic acid (Scheme ) .…”

“…In a similar manner, another series of pyrazolylpyridines 134a–f was synthesized using ethyl acetoacetate in lieu of malononitrile. Thus, reaction of 3‐acetylpyrazole derivative 1 with the appropriate aldehyde 113 , ethyl acetoacetate 133 , and ammonium acetate in refluxing acetic acid afforded the corresponding products 134a–f (Scheme ) .…”

Recent Progress on Nicotinonitrile Scaffold‐based Anticancer, Antitumor, and Antimicrobial Agents: A Literature Review

“…A series of pyrazolylpyridines 149a – f were prepared by condensation of ethyl‐3‐acetyl‐1,5‐diphenyl‐1 H ‐pyrazole‐4‐carboxylate 147 with the appropriate aldehyde 148 , malononitrile, and an excess of ammonium acetate under reflux in acetic acid. Also, the bipyridine derivative 149g was prepared via terephthaldehyde 140f instead of benzaldehyde derivatives (Scheme ) .…”

“…The cytotoxicity of the pyridines 149a , 149b , and 149e derivatives was evaluated against the human liver carcinoma cell line (HEPG2‐1) using doxorubicin as a reference drug; the results revealed that the descending order of the antitumor activity of the tested compound against HEPG2‐1 cell line is as follows: 149b > 149a > 149e . The pyridine derivative 149b (IC 50 = 1.9 ± 0.16 n M ) has promising antitumor activity against HEPG2‐1 compared with doxorubicin, which is used as reference drug .…”

“…To account for the formation of products 149 , it was suggested that reaction proceeds by reaction of the acetyl group of compound 147 with the aldehydes 148 to afford the corresponding arylidine, which reacts with ammonium acetate to give the imino derivative, followed by tandem Michael addition of the active methylene group of 3 to afford the non‐isolable tetrahydropyridine intermediates III . The latter undergo in situ auto‐oxidation, followed by tautomerization and formation of the final products 149 (Scheme ) .…”