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Design, synthesis, and cytotoxic evaluation of quinazoline derivatives bearing triazole-acetamides.

ABSTRACT: A novel series of quinazoline-based agents bearing triazole-acetamides 8a-l were designed and synthesized. All the obtained compounds were tested for in vitro cytotoxic activities against three human cancer cell lines named HCT-116, MCF-7, and HepG2, as well as a normal cell line WRL-68 after 48 and 72 h. The results implied that quinazoline-oxymethyltriazole compounds exhibited moderate to good anticancer potential. The most potent derivative against HCT-116 was 8a (X = 4-OCH₃ and R = H) with IC₅₀ values of 10.72 and 5.33 μM after 48 and 72 h compared with doxorubicin with IC₅₀ values of 1.66 and 1.21 μM, respectively. The same trend was seen in the HepG2 cancerous cell line in which 8a recorded the best results with IC₅₀ values of 17.48 and 7.94 after 48 and 72 h, respectively. The cytotoxic analysis against MCF-7 showed that 8f with IC₅₀ = 21.29 μM (48 h) exhibited the best activity, while compounds 8k (IC₅₀ = 11.32 μM) and 8a (IC₅₀ = 12.96 μM), known as the most effective cytotoxic agents after 72 h. Doxorubicin as positive control exhibited IC₅₀ values of 1.15 and 0.82 μM after 48 and 72 h, respectively. Noteworthy, all derivatives showed limited toxicity against the normal cell line. Moreover, docking studies were also presented to understand the interactions between these novel derivatives and possible targets.

SUBMITTER: Pedrood K

PROVIDER: S-EPMC9975091 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Design, synthesis, and cytotoxic evaluation of quinazoline derivatives bearing triazole-acetamides.

Pedrood Keyvan K Taayoshi Fahimeh F Moazzam Ali A Iraji Aida A Yavari Ali A Ansari Samira S Sajjadi-Jazi Sayed Mahmoud SM Mohajeri-Tehrani Mohammad Reza MR Garmsiri Nadia N Haghpanah Vahid V Soleymanibadi Meysam M Larijani Bagher B Hamedifar Haleh H Adibpour Neda N Mahdavi Mohammad M

Heliyon 20230204 2

A novel series of quinazoline-based agents bearing triazole-acetamides 8a-l were designed and synthesized. All the obtained compounds were tested for in vitro cytotoxic activities against three human cancer cell lines named HCT-116, MCF-7, and HepG2, as well as a normal cell line WRL-68 after 48 and 72 h. The results implied that quinazoline-oxymethyltriazole compounds exhibited moderate to good anticancer potential. The most potent derivative against HCT-116 was 8a (X = 4-O ...[more]

PMID: 36873155

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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.

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Design, synthesis, and cytotoxic evaluation of quinazoline derivatives bearing triazole-acetamides.

Publications

Design, synthesis, and cytotoxic evaluation of quinazoline derivatives bearing triazole-acetamides.

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