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Open AccessArticle

Phenylpyrazalopyrimidines as Tyrosine Kinase Inhibitors: Synthesis, Antiproliferative Activity, and Molecular Simulations

1
Department of Chemistry, Aditi Mahavidyalaya, University of Delhi, Bawana, Delhi 110039, India
2
Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Rhode Island, Kingston, RI 02881, USA
3
Dr. Panjwani Center for Molecular Medicine and Drug Research, ICCBS, University of Karachi, Karachi 75210, Pakistan
4
Center For Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus, California, Irvine, CA 92618, USA
*
Authors to whom correspondence should be addressed.
Academic Editor: Qiao-Hong Chen
Molecules 2020, 25(9), 2135; https://doi.org/10.3390/molecules25092135
Received: 15 April 2020 / Revised: 27 April 2020 / Accepted: 29 April 2020 / Published: 2 May 2020
(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation)
N1-(α,β-Alkene)-substituted phenylpyrazolopyrimidine derivatives with acetyl and functionalized phenyl groups at α- and β-positions, respectively, were synthesized by the reaction of 3-phenylpyrazolopyrimidine (PhPP) with bromoacetone, followed by a chalcone reaction with differently substituted aromatic aldehydes. The Src kinase enzyme assay revealed modest inhibitory activity (half maximal inhibitory concentration, IC50 = 21.7–192.1 µM) by a number of PhPP derivatives. Antiproliferative activity of the compounds was evaluated on human leukemia (CCRF-CEM), human ovarian adenocarcinoma (SK-OV-3), breast carcinoma (MDA-MB-231), and colon adenocarcinoma (HT-29) cells in vitro. 4-Chlorophenyl carbo-enyl substituted 3-phenylpyrazolopyrimidine (10) inhibited the cell proliferation of HT-29 and SK-OV-3 by 90% and 79%, respectively, at a concentration of 50 µM after 96 h incubation. The compound showed modest inhibitory activity against c-Src (IC50 = 60.4 µM), Btk (IC50 = 90.5 µM), and Lck (IC50 = 110 µM), while it showed no activity against Abl1, Akt1, Alk, Braf, Cdk2, and PKCa. In combination with target selection and kinase profiling assay, extensive theoretical studies were carried out to explore the selectivity behavior of compound 10. Specific interactions were also explored by examining the changing trends of interactions of tyrosine kinases with the phenylpyrazolopyrimidine derivative. The results showed good agreement with the experimental selectivity pattern among c-Src, Btk, and Lck. View Full-Text
Keywords: protein kinase; phenylpyrazolopyrimidine; antiproliferative activity; enzyme inhibition; molecular simulation protein kinase; phenylpyrazolopyrimidine; antiproliferative activity; enzyme inhibition; molecular simulation
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MDPI and ACS Style

Chhikara, B.S.; Ashraf, S.; Mozaffari, S.; St. Jeans, N.; Mandal, D.; Tiwari, R.K.; Ul-Haq, Z.; Parang, K. Phenylpyrazalopyrimidines as Tyrosine Kinase Inhibitors: Synthesis, Antiproliferative Activity, and Molecular Simulations. Molecules 2020, 25, 2135.

AMA Style

Chhikara BS, Ashraf S, Mozaffari S, St. Jeans N, Mandal D, Tiwari RK, Ul-Haq Z, Parang K. Phenylpyrazalopyrimidines as Tyrosine Kinase Inhibitors: Synthesis, Antiproliferative Activity, and Molecular Simulations. Molecules. 2020; 25(9):2135.

Chicago/Turabian Style

Chhikara, Bhupender S.; Ashraf, Sajda; Mozaffari, Saghar; St. Jeans, Nicole; Mandal, Dindyal; Tiwari, Rakesh K.; Ul-Haq, Zaheer; Parang, Keykavous. 2020. "Phenylpyrazalopyrimidines as Tyrosine Kinase Inhibitors: Synthesis, Antiproliferative Activity, and Molecular Simulations" Molecules 25, no. 9: 2135.

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