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Published on: February 15, 2016
Design, synthesis, in-silico studies and apoptotic activity of novel amide enriched 2-(1H)- quinazolinone derivatives
Naganjaneyulu Gariganti1,2, Anjaneyulu Bandi3, K R S Naresh Gatta3
1Department of Chemistry, School of Applied Science and Humanities, Vignan's Foundation for Science Technology and Research, Vadlamudi, Guntur, Andhra Pradesh, 522213, India.
Abstract:
Cancer is a broad classification of diseases that can affect any organ or body tissue due to aberrant cellular proliferation for unknown reasons. Many present chemotherapeutic drugs are highly toxic and have little selectivity. Additionally, they lead to the development of medication resistance. Therefore, developing tailored chemotherapeutic drugs with minimal side effects and good selectivity is crucial for cancer treatment. 2-(1H)-Quinazolinone is one of the vital scaffold and anticancer activity is one of the prominent biological activities of this class. Here we report the novel set of amide-enriched 2-(1H)-quinazolinone derivatives (7a-j) and their apoptotic activity with the help of MTT assay method against four human cancer cell lines: PC3 (prostate cancer), DU-145 (prostate cancer), A549 (lung cancer), and MCF7 (breast cancer). When compared to etoposide, every synthetic test compound (7a-j) exhibited moderate to excellent activity. The IC50 values of the new amide derivatives (7a-j) varied from 0.07 ± 0.0061 μM to 10.8 ± 0.69 μM. While the positive control, etoposide, exhibited 1.97 ± 0.45 μM to 3.08 ± 0.135 μM range. Among the novel amide derivatives (7a-j), in particular, 7i and 7j showed strong apoptotic activity against MCF7; 7h showed against PC3, and 7g showed against DU-145. Molecular docking studies of test compounds (7a-j) with the EGFR tyrosine kinase domain (PDB ID: 1M17) protein provided the significant docking scores for each test compound (7a-j) (-9.00 to -9.67 kcal/mol). Additionally, DFT investigations and MD simulations validated the predictions of molecular docking. According to the findings of the ADME analysis, oral absorption by humans is anticipated to be higher than 85 % for all test compounds.
Insights
Novel amide-enriched 2-(1H)-quinazolinone derivatives show potent anticancer activity against various cancer cell lines. These compounds exhibit promising apoptotic effects and favorable pharmacokinetic properties, suggesting their potential as targeted cancer therapeutics.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Molecular Biology
Background:
- Conventional chemotherapy often suffers from toxicity and drug resistance.
- Developing selective and effective anticancer agents with minimal side effects is a critical need.
- 2-(1H)-Quinazolinone scaffolds are recognized for their significant anticancer properties.
Purpose of the Study:
- To synthesize and evaluate novel amide-enriched 2-(1H)-quinazolinone derivatives for their apoptotic activity.
- To assess the efficacy of these compounds against human cancer cell lines.
- To investigate the molecular interactions and pharmacokinetic profiles of the synthesized derivatives.
Main Methods:
- Synthesis of amide-enriched 2-(1H)-quinazolinone derivatives (7a-j).
- MTT assay to determine cytotoxic and apoptotic activity against PC3, DU-145, A549, and MCF7 cancer cell lines.
- Molecular docking studies with EGFR tyrosine kinase domain (PDB ID: 1M17), DFT investigations, and MD simulations.
- ADME analysis to predict oral absorption.
Main Results:
- All synthesized compounds (7a-j) demonstrated moderate to excellent anticancer activity compared to etoposide.
- IC50 values ranged from 0.07 ± 0.0061 μM to 10.8 ± 0.69 μM.
- Compounds 7i and 7j showed potent activity against MCF7, 7h against PC3, and 7g against DU-145.
- Molecular docking revealed significant binding scores (-9.00 to -9.67 kcal/mol) with EGFR.
- ADME analysis predicted >85% oral absorption for all compounds.
Conclusions:
- The novel amide-enriched 2-(1H)-quinazolinone derivatives possess significant apoptotic and anticancer potential.
- Specific derivatives (7g, 7h, 7i, 7j) show promising targeted activity against distinct cancer cell lines.
- Computational studies support the molecular mechanisms and favorable pharmacokinetic profiles of these compounds.
- These derivatives represent promising candidates for further development as targeted cancer chemotherapeutics.
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