:
The rationale behind drug design is strategic utilization of heterocyclic fragments with specific
physicochemical properties to form molecular targeted agents. Among the heterocyclic molecules, pyrimidine has proved
to be a privileged pharmacophore for various biological cancer targets. The anticancer potential of small molecules with
fused and substituted pyrimidine can be enhanced through bioisosteric replacements and altering their ADME parameters.
Despite of several small molecules used in cancer chemotherapy, oncology therapeutics has various limitations. Especially
in their routes of administration and their concurrent side effects. Such pernicious effects may be overcome, via selective
biological targeting. In this review we have discussed the biological targets to inhibit cancer. Structural activity
relationship of fused and substituted pyrimidine was studied. Eco friendly synthetic approaches for pyrimidine derivatives
have been discussed. This review will give an insight to scientists and researchers of medicinal chemistry discipline to
design small molecules having a pyrimidine scaffold with high anticancer potential.
Background:
The abnormal signaling from tyrosine kinase causes many types of cancers namely breast cancer,
non-small cell lung cancer, and chronic myeloid leukemia. This research reports the in-silico, synthesis, and in-vitro study
of novel pyrimidine derivatives as EGFR inhibitors.
Objective:
The objective of the research study is to discover more promising lead compounds using drug discovery
process, in which the rational drug design is achieved by the molecular docking and virtual pharmacokinetic studies.
Methods:
The molecular docking studies were carried out using discovery studio 3.5-version software. The molecules
with good docking and binding energy score were synthesized as well as their structures were confirmed by FT-IR, NMR,
Mass and elemental analysis. Subsequently molecules were evaluated for their anticancer activity using MDA-MB-231,
MCF-7 and A431 breast cancer cell lines by MTT and tyrosine kinase assay methodology.
Results:
Pyrimidine derivatives displayed anticancer activity. Particularly, compound R8 shows significant cytotoxicity
against MDA-MB-231 with an IC50 18.5 ± 0.6 µM. Molecular docking studies proved that the compound R8 has good
binding fitting by forming hydrogen bonds with amino acid residues at ATP binding sites of EGFR.
Conclusion:
Eight pyrimidine derivatives were designed, synthesized and evaluated against breast cancer cell lines.
Compound R8 significantly inhibited the growth of MDA-MB-231 and MCF-7. Molecular docking studies reveled that
compound R8 has good fitting by forming different Hydrogen bonding interactions with amino acids at ATP binding site
of epidermal growth factor receptor target. Compound R8 was a promising lead molecule that showed better results as
compared to other compounds in in-vitro studies.
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