Design and synthesis of new 1,6-dihydropyrimidin-2-thio derivatives targeting VEGFR-2: Molecular docking and antiproliferative evaluation

Adel A Marzouk; Salah A Abdel-Aziz; Kamal S Abdelrahman; Amira S Wanas; Ahmed M Gouda; Bahaa G M Youssif; Mohamed Abdel-Aziz

doi:10.1016/j.bioorg.2020.104090

Design and synthesis of new 1,6-dihydropyrimidin-2-thio derivatives targeting VEGFR-2: Molecular docking and antiproliferative evaluation

Bioorg Chem. 2020 Sep:102:104090. doi: 10.1016/j.bioorg.2020.104090. Epub 2020 Jul 10.

Authors

Adel A Marzouk¹, Salah A Abdel-Aziz², Kamal S Abdelrahman¹, Amira S Wanas³, Ahmed M Gouda⁴, Bahaa G M Youssif⁵, Mohamed Abdel-Aziz⁶

Affiliations

¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut 71524, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Deraya University, Minia, Egypt.
³ National Center for Natural Products Research, University of Mississippi, MS 38677, USA; Pharmacognosy Department, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt.
⁴ Department of Medicinal Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
⁵ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt. Electronic address: bgyoussif@ju.edu.sa.
⁶ Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, 61519 Minia, Egypt. Electronic address: Abulnil@hotmail.com.

PMID: 32683176
DOI: 10.1016/j.bioorg.2020.104090

Abstract

A series of new 1,6-dihydropyrimidin-2-thiol derivatives (scaffold A) as VEGFR-2 inhibitors has been designed and synthesized. Compounds 3a, 3b, 3e and 4b have been selected for in vitro anticancer screening by the National Cancer Institute. Compound 3e showed remarkable anticancer activity against most of the cell lines tested, where a complete cell death against leukemia, non-small cell lung cancer, colon, CNS, melanoma, and breast cancer cell lines was observed. In vitro five dose tests showed that compound 3e had high activity against most of the tested cell lines with GI₅₀ ranging from 19 to 100 μM and selectivity ratios ranging between 0.75 and 1.71 at the GI₅₀ level. VEGFR-2-kinase was tested against 3a, 3b, 3e, 4b and sorafenib was used as a reference. Compounds 3a and 3e were the most potent analogues with IC₅₀ values of 386.4 nM and 198.7 nM against VEGFR-2, respectively, in comparison to sorafenib (IC₅₀ = 0.17 nM). The results of the docking study showed a good fitting of the new compounds to the active site of VEGFR-2 with binding free energies in the range of -9.80 to -11.25 kcal/mol compared to -12.12 kcal/mol for sorafenib. Compounds 4a-e with the hydroxyimino group had a higher affinity to VEGFR-2 than their parent derivatives 3a-e.

Keywords: Antiproliferative; Dihydropyrimidine; Docking; VEGFR-2.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
Molecular Docking Simulation*
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Structure-Activity Relationship
Sulfhydryl Compounds / chemical synthesis
Sulfhydryl Compounds / chemistry
Sulfhydryl Compounds / pharmacology*
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Pyrimidines
Sulfhydryl Compounds
KDR protein, human
Vascular Endothelial Growth Factor Receptor-2