Design, Synthesis, In Silico and In Vitro Evaluation of Novel Pyrimidine Derivatives as EGFR Inhibitors.

BACKGROUND: The abnormal signaling from tyrosine kinase causes many types of cancers, including 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 the drug discovery process, in which a rational drug design is achieved by 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, and their structures were confirmed by FT-IR, NMR, Mass and elemental analysis. Subsequently, molecules were evaluated for their anti-cancer activity using MDA-MB-231, MCF-7, and A431 breast cancer cell lines by MTT and tyrosine kinase assay methodology. RESULTS: Pyrimidine derivatives displayed anti-cancer activity. Particularly, compound R8 showed significant cytotoxicity against MDA-MB-231 with an IC50 value of 18.5±0.6µM. 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 revealed that compound R8 has good fitting by forming different Hydrogen bonding interactions with amino acids at the 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.

Fused and Substituted Pyrimidine Derivatives as Profound Anti-Cancer Agents.

The rationale behind drug design is the 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 anti-cancer potential of small molecules with fused and substituted pyrimidines can be enhanced through bioisosteric replacements and altering their ADME parameters. Although several small molecules are 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, the biological targets, to inhibit cancer, have been discussed. The structural activity relationship of fused and substituted pyrimidines was studied. Eco-friendly synthetic approaches for pyrimidine derivatives have also 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 anti-cancer potential.

Neurodegeneration by oxidative stress: a review on prospective use of small molecules for neuroprotection.

The intricate physiology of many Central Nervous System (CNS) disorders points towards oxidative damages of neurons. Various studies have established that oxidative stress is a big threat to integrity of neurons. All the sections of central nervous system are exposed to free radicals and charged species formed during oxidative degradation of catecholamines and polyunsaturated fatty acids which are present abundantly in CNS. By products of other biochemical reactions also contribute to oxidative stress in central nervous system. If these charged species are not counter neutralized by antioxidants, it leads to neurodegenerative disorders like Alzheimer's disease, Parkinson's disease, Amyotropic lateral sclerosis, Multiple sclerosis, Spinal cord injury, Schizophrenia etc. The level of charged species and free radicals is found to be higher in neurodegenerative diseases than normal physiological condition and it is related to oxidative damages to neuronal cells. In many of such cases, use of antioxidants decreases oxidative stress and contribute to neuroprotection. This review intends to compile approach of managing oxidative stress in various neurodegenerative disorders. The perspective of this review is to study antioxidants and their role in neuroprotection.