Synthesis, in-silico, and in-vitro study of novel chloro methylquinazolinones as PI3K-δ inhibitors, cytotoxic agents
Through a two-step procedure, 3-amino-7-chloro-2-methylquinazolin-4(3H)-one was synthesized from 2-amino-4-chlorobenzoic acid as a starting material. The latter reacted with chloro acetylchloride, then nucleophilically substituted with various secondary amines to produce acetamide derivatives (5a-e)...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-02-01
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| Series: | Arabian Journal of Chemistry |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1878535221006298 |
| _version_ | 1819261469104013312 |
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| author | Sherin M. Elfeky Samar J. Almehmadi Samar S. Tawfik |
| author_facet | Sherin M. Elfeky Samar J. Almehmadi Samar S. Tawfik |
| author_sort | Sherin M. Elfeky |
| collection | DOAJ |
| description | Through a two-step procedure, 3-amino-7-chloro-2-methylquinazolin-4(3H)-one was synthesized from 2-amino-4-chlorobenzoic acid as a starting material. The latter reacted with chloro acetylchloride, then nucleophilically substituted with various secondary amines to produce acetamide derivatives (5a-e), or underwent condensation reaction with various aldehydes to produce arylidine derivatives (6a-e). In-silico study of drug-likeness and ADME descriptors was conducted for all compounds. Compounds showed good oral bioavailability, as well as good gastrointestinal absorption potential and no symptoms of liver or CNS adverse effects. In-vitro cytotoxic activity of the compounds was moderate to good when compared to staurosporine in three cell lines: HCT, MCF-7, and HepG-2. Compound 5c showed the highest cytotoxic activity against the HCT cell line (IC50 = 8.00 ± 0.33 μM), Compound 5d showed the highest cytotoxic activity against the HepG-2 cell line (IC50 = 17.78 ± 0.58 μM). Acetamide derivatives revealed higher cytotoxic activity compared to arylidine derivatives. Compound 5d had the highest enzyme inhibition activity in the in-vitro PI3k-δ enzyme inhibition assay (IC50 = 1.24 ± 0.03 μM) followed by 5c (IC50 = 8.27 ± 0.19 μM). Both 5c and 5d were able to bind at the ATP binding site of the PI3k-δ enzyme in a mode similar to the native ligand where they formed H-bond interactions with the hinge region amino acid Val828 and hydrophobic interactions with other amino acids indicating an agreement between molecular docking simulation study and the biological screening. |
| first_indexed | 2024-12-23T19:42:17Z |
| format | Article |
| id | doaj.art-8d756dfdfc524ef5bef91a45de69f054 |
| institution | Directory Open Access Journal |
| issn | 1878-5352 |
| language | English |
| last_indexed | 2024-12-23T19:42:17Z |
| publishDate | 2022-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Arabian Journal of Chemistry |
| spelling | doaj.art-8d756dfdfc524ef5bef91a45de69f0542022-12-21T17:33:39ZengElsevierArabian Journal of Chemistry1878-53522022-02-01152103614Synthesis, in-silico, and in-vitro study of novel chloro methylquinazolinones as PI3K-δ inhibitors, cytotoxic agentsSherin M. Elfeky0Samar J. Almehmadi1Samar S. Tawfik2Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 355516, Egypt; Corresponding author.Department of Chemistry, Faculty of Applied Science, Umm Al-Qura University, Mecca 24451, Saudi ArabiaDepartment of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 355516, EgyptThrough a two-step procedure, 3-amino-7-chloro-2-methylquinazolin-4(3H)-one was synthesized from 2-amino-4-chlorobenzoic acid as a starting material. The latter reacted with chloro acetylchloride, then nucleophilically substituted with various secondary amines to produce acetamide derivatives (5a-e), or underwent condensation reaction with various aldehydes to produce arylidine derivatives (6a-e). In-silico study of drug-likeness and ADME descriptors was conducted for all compounds. Compounds showed good oral bioavailability, as well as good gastrointestinal absorption potential and no symptoms of liver or CNS adverse effects. In-vitro cytotoxic activity of the compounds was moderate to good when compared to staurosporine in three cell lines: HCT, MCF-7, and HepG-2. Compound 5c showed the highest cytotoxic activity against the HCT cell line (IC50 = 8.00 ± 0.33 μM), Compound 5d showed the highest cytotoxic activity against the HepG-2 cell line (IC50 = 17.78 ± 0.58 μM). Acetamide derivatives revealed higher cytotoxic activity compared to arylidine derivatives. Compound 5d had the highest enzyme inhibition activity in the in-vitro PI3k-δ enzyme inhibition assay (IC50 = 1.24 ± 0.03 μM) followed by 5c (IC50 = 8.27 ± 0.19 μM). Both 5c and 5d were able to bind at the ATP binding site of the PI3k-δ enzyme in a mode similar to the native ligand where they formed H-bond interactions with the hinge region amino acid Val828 and hydrophobic interactions with other amino acids indicating an agreement between molecular docking simulation study and the biological screening.http://www.sciencedirect.com/science/article/pii/S18785352210062987-chloro-2-methylquinazolin-4(3H)-onesPI3k-δ enzymeCytotoxic ActivityMolecular dockingEnzyme inhibitionADME studies |
| spellingShingle | Sherin M. Elfeky Samar J. Almehmadi Samar S. Tawfik Synthesis, in-silico, and in-vitro study of novel chloro methylquinazolinones as PI3K-δ inhibitors, cytotoxic agents Arabian Journal of Chemistry 7-chloro-2-methylquinazolin-4(3H)-ones PI3k-δ enzyme Cytotoxic Activity Molecular docking Enzyme inhibition ADME studies |
| title | Synthesis, in-silico, and in-vitro study of novel chloro methylquinazolinones as PI3K-δ inhibitors, cytotoxic agents |
| title_full | Synthesis, in-silico, and in-vitro study of novel chloro methylquinazolinones as PI3K-δ inhibitors, cytotoxic agents |
| title_fullStr | Synthesis, in-silico, and in-vitro study of novel chloro methylquinazolinones as PI3K-δ inhibitors, cytotoxic agents |
| title_full_unstemmed | Synthesis, in-silico, and in-vitro study of novel chloro methylquinazolinones as PI3K-δ inhibitors, cytotoxic agents |
| title_short | Synthesis, in-silico, and in-vitro study of novel chloro methylquinazolinones as PI3K-δ inhibitors, cytotoxic agents |
| title_sort | synthesis in silico and in vitro study of novel chloro methylquinazolinones as pi3k δ inhibitors cytotoxic agents |
| topic | 7-chloro-2-methylquinazolin-4(3H)-ones PI3k-δ enzyme Cytotoxic Activity Molecular docking Enzyme inhibition ADME studies |
| url | http://www.sciencedirect.com/science/article/pii/S1878535221006298 |
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