Efficient one-pot tandem synthesis and cytotoxicity evaluation of 2,3-disubstituted quinazolin-4(3H)-one derivatives

Bui, Hue Thi Buu; Minh, Kiep; Nguyen, Huy T.; Van, Hieu; Danh, Thanh La Duc; Tran, De Quang; Morita, Hiroyuki

doi:10.1016/j.tet.2021.132426

Cited by 7 publications

(5 citation statements)

References 39 publications

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“…The synthesis of the target quinazolinone bearing the hydroxamic acid at the C-2 position through a thioether linkage ( 1–10 ) and at the N-3 position through the 3-piperazinylethyl linkage ( 11–12 ) is presented in Scheme 1 . Starting from isatoic anhydride ( 16 ), ring opening occurred by appropriate substituted benzylamines or 2-(piperazin-1-yl)ethan-1-amine in water at room temperature to provide the corresponding N -substituted 2-aminobenzamides 18 , which were then condensed with either carbon disulfide or aromatic aldehyde 19 to afford 2-mercaptoquinazolinones 20 or 3-piperazinylethyl quinazolinone 21 , respectively ( Scheme 1 ) [ 29 , 32 , 33 , 34 ]. The thiol moiety of 20 was then coupled with ethyl 2-chloroacetate 22 or ethyl 5-bromopentanoate 23 via nucleophilic substitution mechanism under basic conditions (K 2 CO 3 ) to incorporate the ester function which then underwent aminolysis with hydroxylamine to afford the desired hybrid thioether linked hydroxamate quinazolinones 1–10 in moderate to good yields over three steps (13–69%, Table 1 ) [ 35 ].…”

Section: Resultsmentioning

confidence: 99%

“…To the best of our knowledge, there have been no reports in the literature using the 2-mercaptoquinazoline as a cap for HDAC6 selective inhibitors. In continuation with our anticancer drug development studies [ 29 , 30 , 31 ], herein, we extended our approach with quinazolinone-conjugated hydroxamic acid, which leads to potent and selective HDAC6 inhibitors. Our design used a quinazolinone core as a cap with the hydroxamic acid side chains at C-2 or N-3 position.…”

Section: Introductionmentioning

confidence: 99%

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Target Design of Novel Histone Deacetylase 6 Selective Inhibitors with 2-Mercaptoquinazolinone as the Cap Moiety

et al. 2022

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Epigenetic alterations found in all human cancers are promising targets for anticancer therapy. In this sense, histone deacetylase inhibitors (HDACIs) are interesting anticancer agents that play an important role in the epigenetic regulation of cancer cells. Here, we report 15 novel hydroxamic acid-based histone deacetylase inhibitors with quinazolinone core structures. Five compounds exhibited antiproliferative activity with IC50 values of 3.4–37.8 µM. Compound 8 with a 2-mercaptoquinazolinone cap moiety displayed the highest antiproliferative efficacy against MCF-7 cells. For the HDAC6 target selectivity study, compound 8 displayed an IC50 value of 2.3 µM, which is 29.3 times higher than those of HDAC3, HDAC4, HDAC8, and HDAC11. Western blot assay proved that compound 8 strongly inhibited tubulin acetylation, a substrate of HDAC6. Compound 8 also displayed stronger inhibition activity against HDAC11 than the control drug Belinostat. The inhibitory mechanism of action of compound 8 on HDAC enzymes was then explored using molecular docking study. The data revealed a high binding affinity (−7.92 kcal/mol) of compound 8 toward HDAC6. In addition, dock pose analysis also proved that compound 8 might serve as a potent inhibitor of HDAC11.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Target Design of Novel Histone Deacetylase 6 Selective Inhibitors with 2-Mercaptoquinazolinone as the Cap Moiety

et al. 2022

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“…Based on these findings and also in the continuation of our studies on the synthesis and bioactivity evaluation of hybrid heterocycles, especially benzimidazole derivatives (Bui et al, 2022(Bui et al, , 2021(Bui et al, , 2019Hue et al, 2020), in the current study, the structure-based virtual screening of a small library of fifty-two 1,3,4-oxadiazole based benzimidazole hybrid derivatives against the methionyl-tRNA synthetase (MetRS) was performed. These preliminary results could serve as references for in vitro screening investigation of new and potent MetRS inhibitors and also aaRS inhibitors in general.…”

Section: Figure 1 General Structures Of the Designed Compounds For Vi...mentioning

confidence: 86%

Docking-Based Virtual Screening for the Discovery of 1,3,4-Oxadiazoles as Aminoacyl-tRNA Synthetase Inhibitors

Bui¹,

Nguyen²,

Tran³

2022

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Aminoacyl-tRNA synthetases (aaRSs) are one of the leading targets for the development of antibiotic agents. In this paper, we reported the discovery of aaRS inhibitors using a structure-based virtual screening method. The interactions of 52 designed structures with the methionyl-tRNA synthetase (MetRS) target were performed by docking the ligands into the active zone of the MetRS using Autodock Vina. The data revealed 14 compounds displaying interactions with key amino acids (Asp287, Tyr250, Val473, Trp474, Phe522, Ile519, Ala477, Leu478, and His523) at the binding pocket of the enzyme, indicating their potential as MetRS inhibitors. These results could be served as the references for further synthetic work and bioassays experiments for discovering MetRS inhibitors and other pharmaceutical agents that may assist in the generation of new antibiotics.

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“…Quinazolin-4(3 H )-ones ( 308 ) can also be directly obtained in a sequence protocol in which ceric ammonium nitrate [ 162 ] or I 2 are used as oxidants ( Scheme 93 ) [ 163 , 164 ].…”

Section: Reactions With Isatoic Anhydridementioning

confidence: 99%

The Castagnoli–Cushman Reaction

et al. 2023

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Since the first reports of the reaction of imines and cyclic anhydrides by Castagnoli and Cushman, this procedure has been applied to the synthesis of a variety of lactams, some of them with important synthetic or biological interest. The scope of the reaction has been extended to the use of various Schiff bases and anhydrides as well as to different types of precursors for these reagents. In recent years, important advances have been made in understanding the mechanism of the reaction, which has historically been quite controversial. This has helped to develop reaction conditions that lead to pure diastereomers and even homochiral products. In addition, these mechanistic studies have also led to the development of new multicomponent versions of the Castagnoli–Cushman reaction that allow products with more diverse and complex molecular structures to be easily obtained.

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Efficient one-pot tandem synthesis and cytotoxicity evaluation of 2,3-disubstituted quinazolin-4(3H)-one derivatives

Cited by 7 publications

References 39 publications

Target Design of Novel Histone Deacetylase 6 Selective Inhibitors with 2-Mercaptoquinazolinone as the Cap Moiety

Target Design of Novel Histone Deacetylase 6 Selective Inhibitors with 2-Mercaptoquinazolinone as the Cap Moiety

Docking-Based Virtual Screening for the Discovery of 1,3,4-Oxadiazoles as Aminoacyl-tRNA Synthetase Inhibitors

The Castagnoli–Cushman Reaction

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