Project's information

Project's title Design and synthesis of new chimeric organic compounds with fragments of pharmacophore heterocycles of imidazole and 2-aminopyrimidine as potential multikinase inhibitors of tumor processes
Project’s code QTBY01.04/23-24
Research hosting institution Institute of Chemical Technology
Coordinating unit, co-chair The bilateral cooperation program between Vietnam Academy of Science and Technology (VAST) and Belarusian Republican Fund of Fundamental Research, Republic of Belarus
Project leader’s name Hoang Thi Kim Dung and Elena Koroleva
Project duration 01/01/2023 - 31/12/2024
Project’s budget 200 million VND
Classify Excellent
Goal and objectives of the project

Design and synthesize hybrid organic molecules by combining imidazole and 2-aminopyrimidine heterocyclic fragments, and evaluate the kinase and tumor-inhibiting activities of the generated compounds.
Enhance international collaboration, improve research capacities, and train young human resources in the field of bioactive compounds for the Institute of Chemical Technology and the Vietnam Academy of Science and Technology.

Main results

- Research:
The Mission’s research has achieved the following results:
+ 21 benzimidazole derivatives (B1a-B3g) and 07 benzimidazole-pyrimidine hybrid compounds (2a-2g) have been effectively produced by the condensation reaction of amines and aldehydes with Na2S2O5 oxidant in EtOH:H2O (9:1, v/v) solvent system. This approach has several advantages, including a straightforward synthesis and processing process, high purity products, environmentally friendly solvents and oxidants, and suitability for laboratory and climate conditions in Vietnam.
+ 17 2-amino-4,6-diarylpyrimidine hybrid compounds (1a-1q) have been synthesized successfully using a two-step microwave irradiation (MW) process. In the first stage, we performed the aldol condensation of substituted benzaldehyde and different acetophenone derivatives in ethylene glycol solvent with KOH catalyst (100 W, 80 oC) to yield intermediate chalcones. The second step of this work involved ring closure condensation of pure substituted chalcones, GHCl, and NaOH in pyridine under MW conditions (180 W, 100 °C) to produce the desired 2-amino-4,6-diarylpyrimidine. The final compounds were produced with a yield ranging from 31% to 64%, and the procedure has various advantages, such as a straightforward synthesis and processing process, faster synthesized times, and modern equipment. 
+ All synthesized compounds were structurally characterized using FIIR, HRMS, 1D-NMR, and 2D-NMR techniques.
+ Next, we evaluated the cytotoxic activity of 20 products from Belarus and 24 synthesized derivatives from Vietnam (2-amino-4,6-diarylpyrimidine, benzimidazole-pyrimidine) against leukemia cells on the K562 line to identify the active compounds and calculate their IC50 values. Some samples from Belarus (N.5, N.6, N.7, N.767, N.768, N.111, N.112, and N.644) and Vietnam d (1e and 1g) showed effective anti-tumor activity, with IC50 values of 1.60–28.84 µM and 8.77–32.43 µM, respectively. The derivatives with the best cytotoxic activity in the two groups were then evaluated for their tyrosine-protein kinase ABL1 inhibition. Compounds N.5 and 1e showed significant inhibitory activity with IC50 values of 13.40 ± 1.07 µM and 3.35 ± 0.58 µM, respectively, Imatinib (IC50 = 68.71 ± 2.41 nM).
+ Molecular docking of wild-type and mutant-type ABL1 protein kinase (PDB ID: 2HYY and 5MO4) indicated that compounds 1e and 1g interact with amino acids, forming stable hydrogen bonds and π-stacking interactions with key amino acids in the enzyme’s active site. Furthermore, molecular dynamics simulations also revealed the stability of the complexes formed by these two ligands with the wild-type enzyme, which had higher affinity than the complex with Imatinib.
+ According to the aforementioned research findings, 1e is a promising prospective agent in cancer treatment.
- Education and training: 04 Bachelors successfully defended their graduation projects in the Mission direction and obtained their degrees from Ton Duc Thang University.
- Cooperation: 
+ Take advantage of the strengths of the Belarusian research group, which has extensive experience synthesizing heterocyclic compounds, as well as the Vietnamese research group, which has experience synthesizing compounds containing imidazole fragments and can perform in vitro cytotoxicity assay.
+ Establish a link between the Institute of Chemical Technology and Belarus’s Institute of Chemistry of New Materials, laying the groundwork for future collaboration between the two Institutes' other research groups and contributing to the country's scientific research in comparison to developed countries.

Novelty and actuality and scientific meaningfulness of the results

- Some benzimidazole derivatives and benzimidazole-pyrimidine hybrid compounds were produced at room temperature, resulting in a simple synthesis and processing technique that is environmetally friendly and suitable for Vietnamese climate conditions.
- Microwave irradiation is used to generate 2-amino-4,6-diarylpyrimidines, which helps to improve synthesized times and increase yields.
- Some 2-amino-4,6-diarylpyrimidine derivatives showed anti-tumor activity against leukemia cells on the K562 line and protein kinase ABL1 inhibition.
- In silico studies using molecular docking and molecular dynamics stimulations revealed that two compounds had higher affinity for protein kinase mutant-type ABL1 than the complex with Imatinib and were considered prospective cancer treatment agents.

Products of the project

- Publications: 01 article was published with the task code in the acknowledgment section, and 02 articles are submitting their manuscripts.

- Patents: No
- Products: 21 benzimidazole derivatives, 17 2-aminopyrimidine derivatives and 07 benzimidazole-pyrimidine hybrid compounds are stored at ICT laboratory.

 

- Other products (education and training): 04 four bachelors were defended and obtained their degrees at Ton Duc Thang university.

Research area

The Mission results can be proposed for application in the following forms:
Institutes and centers for cancer research or pharmaceutical research in Vietnam can continue to investigate and broaden the use of promising substances in cancer therapy research.
Collaborate with foreign research organizations to improve prospective chemicals and create effective, internationally standardized therapy medications.

Recommendations

According to the experimental findings, further study into in vitro assays of active compounds on mutant ABL1 is necessary for verifying the simulation results, as well as the amide reaction to produce the hybrid compounds between benzimidazole  and 2-aminopyrimidine fragments, resulting in high yield and diverse biological activities (pain relief, anticancer, and antibacterial, among others) products. 

Images of project
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