Synthesis and Biological Value of Thiouracils and Fused Thiouracils (A review)

Sayed, M. M. El; Ahmed, Nadia

doi:10.21608/aprh.2017.1970

Cited by 5 publications

(1 citation statement)

References 48 publications

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“…The heterocycles of thienopyrimidine moiety are structural analogs of the natural pyrimidines “cytosine, thymine, and uracil” [ 6 ]. They consist of a thiophene ring bonded with the pyrimidine ring.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Anticancer Assessment, and Molecular Docking of Novel Chalcone‐Thienopyrimidine Derivatives in HepG2 and MCF‐7 Cell Lines

Safwat

Hassanin

Mohammed

et al. 2021

Oxidative Medicine and Cellular Longevity

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Heterocycles containing thienopyrimidine moieties have attracted attention due to their interesting biological and pharmacological activities. In this research article, we reported the synthesis of a series of new hybrid molecules through merging the structural features of chalcones and pyridothienopyrimidinones. Our results indicated that the synthesis of chalcone-thienopyrimidine derivatives from the corresponding thienopyrimidine and chalcones proceeded in a relatively short reaction time with good yields and high purity. Most of these novel compounds exhibited moderate to robust cytotoxicity against HepG2 and MCF-7 cancer cells similar to that of 5-fluorouracil (5-FU). The results indicated that IC50 of the two compounds (3b and 3g) showed more potent anticancer activities against HepG2 and MCF-7 than 5-FU. An MTT assay and flow cytometry showed that only 3b and 3g had anticancer activity and antiproliferative activities at the G1 phase against MCF-7 cells, while six compounds (3a-e and 3g) had cytotoxicity and cell cycle arrest at different phases against HepG2 cells. Their cytotoxicity was achieved through downregulation of Bcl-2 and upregulation of Bax, caspase-3, and caspase-9. Although all tested compounds increased oxidative stress via increment of MDA levels and decrement of glutathione reductase (GR) activities compared to control, the 3a, 3b, and 3g in HepG2 and 3b and 3g in MCF-7 achieved the target results. Moreover, there was a positive correlation between cytotoxic efficacy of the compound and apoptosis in both HepG2 ( R 2 = 0.531 ; P = 0.001 ) and MCF-7 ( R 2 = 0.219 ; P = 0.349 ) cell lines. The results of molecular docking analysis of 3a-g into the binding groove of Bcl-2 revealed relatively moderate binding free energies compared to the selective Bcl-2 inhibitor, DRO. Like venetoclax, compounds 3a-g showed 2 violations from Lipinski’s rule. However, the results of the ADME study also revealed higher drug-likeness scores for compounds 3a-g than for venetoclax. In conclusion, the tested newly synthesized chalcone-pyridothienopyrimidinone derivatives showed promising antiproliferative and apoptotic effects. Mechanistically, the compounds increased ROS production with concomitant cell cycle arrest and apoptosis. Therefore, regulation of the cell cycle and apoptosis are possible targets for anticancer therapy. The tested compounds could be potent anticancer agents to be tested in future clinical trials after extensive pharmacodynamic, pharmacokinetic, and toxicity profile investigations.

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Section: Introductionmentioning

confidence: 99%

Synthesis, Anticancer Assessment, and Molecular Docking of Novel Chalcone‐Thienopyrimidine Derivatives in HepG2 and MCF‐7 Cell Lines

Safwat

Hassanin

Mohammed

et al. 2021

Oxidative Medicine and Cellular Longevity

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Conjugates of amiridine and thiouracil derivatives as effective inhibitors of butyrylcholinesterase with the potential to block β‐amyloid aggregation

Khudina,

Grishchenko,

Makhaeva

et al. 2023

Archiv der Pharmazie

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New amiridine‐thiouracil conjugates with different substituents in the pyrimidine fragment (R = CH3, CF2Н, CF3, (CF2)2H) and different spacer lengths (n = 1–3) were synthesized. The conjugates rather weakly inhibit acetylcholinesterase (AChE) and exhibit high inhibitory activity (IC50 up to 0.752 ± 0.021 µM) and selectivity to butyrylcholinesterase (BChE), which increases with spacer elongation; the lead compounds are 11c, 12c, and 13c. The conjugates are mixed‐type reversible inhibitors of both cholinesterases and practically do not inhibit the structurally related off‐target enzyme carboxylesterase. The results of molecular docking to AChE and BChE are consistent with the experiment on enzyme inhibition and explain the structure–activity relationships, including the rather low anti‐AChE activity and the high anti‐BChE activity of long‐chain conjugates. The lead compounds displace propidium from the AChE peripheral anion site (PAS) at the level of the reference compound donepezil, which agrees with the mixed‐type mechanism of AChE inhibition and the main mode of binding of conjugates in the active site of AChE due to the interaction of the pyrimidine moiety with the PAS. This indicates the ability of the studied conjugates to block AChE‐induced aggregation of β‐amyloid, thereby exerting a disease‐modifying effect. According to computer calculations, all synthesized conjugates have an ADME profile acceptable for drugs.

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Rearrangement of thiazolo[3,2-a]pyrimidines into triazolo[4,3-a]pyrimidines induced by C=N bond reduction

Lashmanova

Agarkov

Rybakov

et al. 2019

Chem Heterocycl Comp

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Synthesis and Biological Value of Thiouracils and Fused Thiouracils (A review)

Cited by 5 publications

References 48 publications

Synthesis, Anticancer Assessment, and Molecular Docking of Novel Chalcone‐Thienopyrimidine Derivatives in HepG2 and MCF‐7 Cell Lines

Synthesis, Anticancer Assessment, and Molecular Docking of Novel Chalcone‐Thienopyrimidine Derivatives in HepG2 and MCF‐7 Cell Lines

Conjugates of amiridine and thiouracil derivatives as effective inhibitors of butyrylcholinesterase with the potential to block β‐amyloid aggregation

Rearrangement of thiazolo[3,2-a]pyrimidines into triazolo[4,3-a]pyrimidines induced by C=N bond reduction

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