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Some novel hybrid quinazoline-based heterocycles as potent cytotoxic agents.

ABSTRACT:

Background and purpose

In this study, some new cytotoxic hybrid structures were synthesized by combining pyrazolinone and imidazolinone rings with quinazoline pharmacophores.

Experimental approach

The benzoxazinone, pyrazolo-quinazoline fused ring, and imidazolinone anchored quinazoline derivatives were synthesized by simple ring-opening, ring expansion, and ring closure strategies from oxazolones. The molecular docking studies of the final derivatives were accomplished on the epidermal growth factor receptor enzyme. The cytotoxic effect of the final compounds on the MCF-7 cell line was evaluated by MTT assay.

Findings/results

The docking results confirmed the optimized electrostatic, H-bonding, and hydrophobic interactions of structures with the key residues of the active site (ΔG_bin< -9Kcal/mol). The derivatives have been obtained in good yield and purity, and their structures were confirmed by different methods (FT-IR, ¹H-NMR, ¹³C-NMR, and CHNS analysis). The IC₅₀s of all final derivatives against the MCF-7 cell line were lower than 10 μM, and between all, the IXa from pyrazolo-quinazolinone class (IC₅₀: 6.43 μM) with chlorine substitute was the most potent. Furthermore, all derivatives showed negligible cytotoxicity on HUVEC normal cell line which would be a great achievement for a novel cytotoxic agent.

Conclusion and implications

Based on the obtained results, pyrazolo[1,5-c] quinazolin-2-one series were more cytotoxic than imidazolinone methyl quinazoline-4(3H)-ones against MCF-7 cells. Chlorine substitute in the para position of the aromatic ring improved the cytotoxicity effect in both classes. It could be related to the polarizability of a chlorine atom and making better intermolecular interactions. Further pre-clinical evaluations are required for the promising synthesized cytotoxic compounds.

SUBMITTER: Malekzadeh M

PROVIDER: S-EPMC8621847 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Publications

Some novel hybrid quinazoline-based heterocycles as potent cytotoxic agents.

Malekzadeh Mahla M Dadkhah Shadi S Khodarahmi Ghadam Ali GA Asadi Parvin P Hassanzadeh Farshid F Rostami Mahboubeh M

Research in pharmaceutical sciences 20211111 1

<h4>Background and purpose</h4>In this study, some new cytotoxic hybrid structures were synthesized by combining pyrazolinone and imidazolinone rings with quinazoline pharmacophores.<h4>Experimental approach</h4>The benzoxazinone, pyrazolo-quinazoline fused ring, and imidazolinone anchored quinazoline derivatives were synthesized by simple ring-opening, ring expansion, and ring closure strategies from oxazolones. The molecular docking studies of the final derivatives were accomplished on the epi ...[more]

PMID: 34909041

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Project description:Based on unselectively, several side effects and drug resistance of available anticancer agents, the development and research for novel anticancer agents is necessary. In this study, a new series of quinazoline-4(3H)-one derivatives having a thiol group at position 2 of the quinazoline ring (8a-8 h) were designed and synthesized as potential anticancer agents. The Chemical structures of all compounds were characterized by 1H-NMR, 13C-NMR, and Mass spectroscopy. The antiproliferative activity of all derivatives were determined against two cancer cell lines (MCF-7 and SW480) and one normal cell lines (MRC-5) by the MTT method. Cisplatin, Erlotinib and Doxorubicin were used as positive controls. The results of in vitro screening showed that 8a with an aliphatic linker to SH group was the most potent compound with IC50 values of 15.85 ± 3.32 and 17.85 ± 0.92 µM against MCF-7 and SW480 cell lines, respectively. 8a indicated significantly better potency compared to Erlotinib in the MCF-7 cell line. The cytotoxic results obtained from testing compound 8a on the normal cell line, revealing an IC50 value of 84.20 ± 1.72 µM, provide compelling evidence of its selectivity in distinguishing between tumorigenic and non-tumorigenic cell lines. Structure-activity relationship indicated that the variation in the anticancer activities of quinazoline-4(3H)-one derivatives was affected by different substitutions on the SH position. Molecular docking and MD simulation were carried out for consideration of the binding affinity of compounds against EGFR and EGFR-mutated. The binding energy of compounds 8a and 8c were calculated at -6.7 and - 5.3 kcal.mol- 1, respectively. Compounds 8a and 8c were found to establish hydrogen bonds and some other important interactions with key residue. The DFT analysis was also performed at the B3LYP/6-31 + G(d, p) level for compounds 8a, 8c and Erlotinib. Compound 8a was thermodynamically more stable than 8c. Also, the calculated theoretical and experimental data for the IR spectrum were in agreement. The obtained results delineated that the 8a can be considered an appropriate pharmacophore to develop as an anti-proliferative agent.

Dataset Information

Some novel hybrid quinazoline-based heterocycles as potent cytotoxic agents.

Background and purpose

Experimental approach

Findings/results

Conclusion and implications

Publications

Some novel hybrid quinazoline-based heterocycles as potent cytotoxic agents.

Similar Datasets

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