Thiouracil Derivatives Research Articles

New Quinazolinone‐Thiouracil Derivatives: Design, Synthesis, Anticancer Evaluation, and In Silico Analysis

AbstractQuinazolinone and thiouracil derivatives are key scaffolds in anticancer development. This study used a molecular hybridization approach to synthesize new quinazolinone‐thiouracil derivatives and evaluated their anticancer activity against three human cancer cell lines, namely breast, lung, and glioblastoma, using SRB assay. Structural elucidation was performed using IR spectroscopy, 1H‐NMR, 13C‐NMR, mass spectrometry, and elemental analysis. Most compounds show moderate to significant cytotoxic effects, with compound 5d displaying the highest potency (IC50 values of 5.28, 4.02, and 2.88 µM, respectively). Compound 5d also demonstrated comparable potency to positive controls cisplatin and temozolomide in lung and glioblastoma cancer cell lines and was nearly as effective as mitochondrial division inhibitor‐1 (mdivi‐1). Furthermore, molecular docking analyses revealed strong binding interactions of the synthesized compounds with dynamin‐related protein‐1 (drp1). Protein–ligand stability studies and all‐atom simulation confirmed the stable binding of compound 5d with drp1. In conclusion, this study identified compound 5d as a potent drp1 inhibitor and promising anticancer drug candidate, deserving further investigation.

Synthetic design of novel uracil and thiouracil derivatives

Synthetic design of novel uracil and thiouracil derivatives

Induction of breast cancer cell apoptosis by novel thiouracil-fused heterocyclic compounds through boosting of Bax/Bcl-2 ratio and DFT study

Breast cancer is a common public health disease causing mortality worldwide. Thus, providing novel chemotherapies that tackle breast cancer is of great interest. In this investigation, novel pyrido[2,3-d]pyrimidine derivatives 3,4,(6a-c),(8a,b),9–20 were synthesized and characterized using a variety of spectrum analyses. The geometric and thermal parameters of the novel thiouracil derivatives 3,4,6a,(8a,b),11,12,17,18, 19 were measured using density functional theory (DFT) via DFT/B3LYP/6–31 + G(d,p) basis set. All synthesized compounds were evaluated by MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) method using MCF-7 and MDA-MB-231 breast cancerous cells, compound 17 had the maximum anticancer activity against both breast cancerous cells, recording the lowest half-maximal inhibitory concentration (IC50) values (56.712 μg/mL for MCF-7 cells and 48.743 μg/mL for MDA-MB-231 cells). The results were confirmed in terms of the intrinsic mechanism of apoptosis, where compound 17 had the highest percentage in the case of both cancer cells and recorded Bax (Bcl-2 associated X)/Bcl-2 (B-cell lymphoma 2) ratio 17.5 and 96.667 for MCF-7 and MDA-MB-231 cells, while compound 19 came after 17 in the ability for induction of apoptosis, where the Bax/Bcl-2 ratio was 15.789 and 44.273 for both cancerous cells, respectively. Also, compound 11 recorded a high Bax/Bcl-2 ratio for both cells. The safety of the synthesized compounds was applied on normal WI-38 cells, showing minimum cytotoxic effect with undetectable IC50. Compounds 17, 11, and 19 recorded a significant increase of p53 upregulated modulator of apoptosis (PUMA) expression levels in the cancerous cells. The DFT method was also used to establish a connection between the experimentally determined values of the present investigated compounds and their predicted quantum chemical parameters. It was concluded that Compounds 17, 11, and 19 had anti-breast cancer potential through the induction of apoptotic Bax/Bcl-2 and PUMA expression levels.

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

New amiridine-thiouracil conjugates with different substituents in the pyrimidine fragment (R = CH3 , CF2 Н, CF3 , (CF2 )2 H) 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.

Synthesis, antibacterial activity evaluation and molecular docking studies of coumarin modified thiouracil derivatives as SecA inhibitor

A series of thiouracil derivatives containing coumarin were designed and synthesized with SecA inhibitor 1 as the lead. The in vitro antibacterial activities of the newly synthesized compounds were evaluated, and the results revealed that some of the new compounds (such as 14k and 14q) had strong inhibitory effect against the tested bacteria. The inhibitory activities of 14k, 14 l, 14r, 14p and 14q against SecA were tested, and the IC50 of 14K was 17.6 μg/mL which was significantly lower than that of lead compound 1. The molecular docking of the compounds 14k, 14 l, 14r, 14p and 14q with SecA were investigated and these compounds can successfully bind to SecA in the two selected pocket. Compound 14k had strong SecA inhibitory activity and antibacterial activity, which was worthy of further study.

Discovery of New Uracil and Thiouracil Derivatives as Potential HDAC Inhibitors.

Background: Histone deacetylase inhibitors (HDACIs) are a relatively new class of potential drugs for treating cancer. Aim: Discovery of new anticancer agents targeting HDAC. Methods: New uracil and thiouracil derivatives panels were designed and synthesized as HDAC inhibitors. The synthesized compounds were tested against MCF-7, HepG2, and HCT-116. HDAC1 and HDAC4 inhibitory activities of these compounds were tested. The most active member was tested for its potential against cell cycle, apoptosis, caspase-3, and caspase-8. Docking studies were carried out against HDAC1. Results: Compounds 5a, 5b, 5f, 5i, 5k, and 5m exhibited promising cytotoxic activities. HDAC1 and HDAC4 inhibitory activities of these compounds were tested. Regarding the HDAC1 inhibitory activity, compound 5m was the most potent member (IC50 = 0.05 µg/mL) compared to trichostatin A (IC50 = 0.0349 µg/mL). For HDAC4, compound 5m showed superior activity (IC50 = 2.83 µg/mL) than trichostatin A (IC50 = 3.349 µg/mL). Compound 5m showed a high potential to arrest the HCT116 cell cycle at the G0-G1 phase. In addition, it showed an almost 17 times apoptotic effect (37.59%) compared to the control cells (2.17%). Furthermore, Compound 5m showed significant increases in the levels of caspase-3 and caspase-8. Finally, the uracil and thiouracil derivatives showed accepted binding mods against HDAC. Conclusions: Compound 5m has potential anticancer activity targeting HDAC with a significant apoptotic effect.

Design, Synthesis, in Vitro and Molecular Dynamic Study of Antifungal Activity of the Alcoholic Extract of Sygysium aromaticum in Comparison to Some New Sulphonamide Derivatives

Five synthetic 2-Thiouracil-5-sulphonamides were evaluated as antifungal agents against the same fungal isolates. Their synergistic effect with clove extract was assessed in an attempt to formulate a potential combination therapy for the future. The goal was to evaluate whether thiouracil derivatives and clove extract can enhance antifungal activity against drug-resistant strains of locally isolated fungi. Both natural and synthetic samples were tested against fungal isolates including Geotrichum candidum, Alternaria alternata, Fusarium oxysporum, and Mucorhiemalis, which are responsible for infections in potato and tomato plants. Clove extract demonstrated varying potent wide-spectrum activity against all fungal isolates, while the effectiveness of thiouracil derivatives depended on their chemical structures. Compounds 3b and 3e exhibited the most potent antifungal activity and showed a broad spectrum of effectiveness. Compound 3d displayed moderate antifungal activity compared to clove extract, while compound 3a exhibited weaker activity and was inactive against F. oxysporum and G. candidum. Compound 3c displayed the weakest antifungal activity and was inactive against A. alternata, F. oxysporum, and G. candidum. Both clove extract and 3e demonstrated synergistic antifungal activity. Moreover, the combination of clove extract and 2-thiouracil-5-sulphonamides displayed variable antifungal activity, suggesting the potential for synergistic effects in their activity.

New thiouracil derivatives as histone deacetylase inhibitors and apoptosis inducers: design, synthesis and anticancer evaluation.

Background: Histone deacetylase (HDAC) inhibitors have good contributions in cancer management. Aim: To introduce new active HDAC inhibitors. Methods: Design and synthesis of 16 thiouracil derivatives with deep biological and computational investigation. Results: Compounds 7a, 7c, 7d, 7e, 8a and 8f showed the highest antiproliferative effects against MCF7, HepG2 and HCT116 cell lines. Compound 7e exhibited the highest activities against HDAC1 and HDAC4. Compound 7e arrested the cell cycle of HCT116 cells at G0-G1 with significant apoptotic effect. In addition, treatment with compound 7e was associated with a significant increase in the levels of caspase-3 and caspase-8. The docking studies gave good insight about the binding patterns of the synthesized compounds against HDAC1. Conclusion: Compound 7e has a promising anticancer activity targeting HDAC.

Study by Quantum Chemical of Relationship between Electronic Structure and SecA Inhibitory Activity of a Series 5-cyano Thiouracil Derivatives

Study by Quantum Chemical of Relationship between Electronic Structure and SecA Inhibitory Activity of a Series 5-cyano Thiouracil Derivatives

Kinetics and adsorption isotherm model of 2-thiouracil adsorbed onto the surface of reduced graphene oxide-copper oxide nanocomposite material

Graphene-construct nanocomposite materials have gathered considerable scientific importance for their unique ability to detect and remove various bioactive molecules/pollutants. Herein, we report on rGO-CuO nanocomposite as an adsorbent material for removing thiouracil biomolecules, viz-6A2TU and 6A5N2TU, respectively. The synthesized rGO-CuO nanocomposite is characterized using UV-vis, FTIR, XRD, SEM-EDX, Raman, and TEM analysis. The surface morphology of rGO-CuO shows well exfoliation with rGO wrapped on the surface of Cu and CuO nanoparticles. While the FTIR, X-ray diffraction, and UV-vis spectroscopic analysis show successful adsorption of 6A2TU and 6A5N2TU on the outer surface of rGO-CuO. rGO-CuO selectively adsorb the uracil derivatives with good efficiency compared to individual components. The binding kinetics of 6A2TU & 6A5N2TU on rGO-CuO are studied using UV-vis spectroscopy. The order of the reaction; pseudo 2nd order kinetics suites well with correlation coefficient (R2– 0.9999), representing proper surface-oriented chemisorption via coordination mechanism. The rGO-CuO shows excellent adsorption behavior with a maximum removal efficiency of 78.36% and 84.56% for 6A2TU and 6A5N2TU, respectively, and following the Temkin adsorption isotherm model. These characteristic features of the material provide the huge removal capacity of the thiouracil derivatives and reusability up to 92%. This nanocomposite material can remove antibiotics/bioactive molecules (organic pollutants) in the aquatic environment.

Synthesis of S-glycosides analogues containing Thiouracil unite and Evaluated as antibacterial and Antifungal active

Preparation of new S-glycosides including thiouracil derivatives as heterobase. The main step of this work is the formation of thiouracil derivatives [1-3] by the condensation reaction of ethyl cyanoacetate, aromatic aldehydes and thiourea to form target compounds [1-3], after protection of the hydroxyl groups in sugar (D-fructose, L- sorbose, and D-galactose), react with hydrobromic acid 45% in glacial acetic acid give different Bromo sugars [a-c], which coupled with prepares thiouracil derivatives [1-3] and propylthiouracil [4] in the presence of K2CO3 to afford the corresponding product S-glycoside analogs [1-4a, 1-4b, 1-4c]. deprotection of the S-glycoside analogs in acid and base medium, led to the free S-glycoside derivatives [1-4d,1-4e,1-4f]. The obtained compounds were tested for their antibacterial and antifungal actives.

Synthesis of C- glycoside analogs containing thiouracil derivatives and evaluated as antibacterial, antifungal and antioxidant activities

This work focused on the synthesis of C-glycoside that contained thiouracil unite, which were synthesized from glucon-2-carbothioate thiouracil derivatives [C1-C4] via reaction of gluconic acid, thionyl chloride, and thiouracil derivatives in a one-pot reaction in the presence of triethylamine as a catalyst. Furthermore, we performed synthesis of 2-(glucofuranose) thiouracil derivatives [C5, C6] via condensation reaction of D- glucurone, ethyl cyanoacetate, and thiourea or phenyl thiourea in presence of potassium carbonate, and studying the possibility for their application as antifungal, antibacterial, and antioxidant.

Synthesis, antibacterial activities and molecular docking study of thiouracil derivatives containing oxadiazole moiety

A series of novel thiouracil derivatives 9 containing an oxadiazole moiety have been synthesized by structural modification of a lead SecA inhibitor, 2. These compounds have been evaluated for their antibacterial activities against Bacillus amyloliquefaciens, Staphylococcus aureus and Bacillus subtilis. Among them, compounds 9g and 9n exhibited promising antibacterial activities against the tested strains. Compound 9g was also tested for its inhibitory activities against SecA ATPase, and the IC50 value of compound 9g was 19.9 μg/mL, lower than that of compound 2 (20.8 µg/mL). Molecular docking work indicates that compound 9g likely occupies the pocket formed by SecA IRA2 and NBD domain.

Novel cyanothiouracil and cyanothiocytosine derivatives as concentration-dependent selective inhibitors of U87MG glioblastomas: Adenosine receptor binding and potent PDE4 inhibition.

Thiouracil and thiocytosine are important heterocyclic pharmacophores having pharmacological diversity. Antitumor and antiviral activity is commonly associated with thiouracil and thiocytosine derivatives, which are well known fragments for adenosine receptor affinity with many associated pharmacological properties. In this respect, 33 novel compounds have been synthesized in two groups: 24 thiouracil derivatives (4a-x) and 9 thiocytosine derivatives (5a-i). Antitumor activity of all the compounds was determined in the U87 MG glioblastoma cell line. Compound 5e showed an anti-proliferative IC50 of 1.56μM, which is slightly higher activity than cisplatin (1.67μM). The 11 most active compounds showed no signficant binding to adenosine A1, A2A or A2B receptors at 1μM. Brain tumors express high amounts of phosphodiesterases. Compounds were tested for PDE4 inhibition, and 5e and 5f showed the best potency (5e: 3.42μM; 5f: 0.97μM). Remakably, those compounds were also the most active against U87MG. However, the compounds lacked a cytotoxic effect on the HEK293 healthy cell line, which encourages further investigation.

Design, synthesis, biological assessment and molecular docking studies of some new 2-Thioxo-2,3-dihydropyrimidin-4(1H)-ones as potential anticancer and antibacterial agents

In this study, a series of thiouracil derivatives were designed and synthesized based on conventional approach and pharmacophoric features essential for TS inhibitors. The chemical structures of all synthesized compounds were elucidated by various techniques ranging from micro-elemental analyses to spectral analyses. The new thiouracil derivatives were evaluated for their anticancer and antibacterial activities. All the new synthesized compounds were evaluated in vitro against MCF-7 cell line. The anticancer results displayed that compounds 8, 11, 13a, and 12, exhibit the highly significant effect against breast cancer cell line with IC50 values of 3.80, 4.00, 4.50, and 4.70 µg/ml, respectively compared with doxorubicin. Furthermore, molecular docking studies were performed to suggest possible mechanism of action of the designed compounds and explain the anti-breast cancer results with prospective target, thymidylate synthase (PDB:1JU6). On the other hand, the antibacterial activity of the new compounds was screened against three significant representative strains including Escherichia coli, and Pseudomonas aeruginosa as gram negative bacterium and Staphylococcus aureus as gram positive bacterium using agar well diffusion method. The antibacterial activity results revealed that most of the tested compounds exhibited significant antibacterial activity. In particularly, compounds 13a, and 13b were found to be the most potent antibacterial agent with inhibition zone values of 38 and 35 mm at the concentration of 50 µg/ml against Escherichia coli, and inhibition zone values of 25 and 23 mm at the concentration of 50 µg/ml against Staphylococcus aureus. However, all tested strains showed resistance to synthesized compounds except, compound 7 which exhibited significant activity only against Pseudomonas aeruginosa with inhibition zone values of 22 mm at the concentration of 50 µg/ml. Further, molecular docking investigation was carried out to gain insight into the binding mode of the most promising compounds using crystal structure of S. aureus DNA gyrase complex with ciprofloxacin (PDB ID: 2XCT).

Synthesis and biological evaluation of novel 4-oxo-5-cyano thiouracil derivatives as SecA inhibitors

Abstract The continuous emergence of drug-resistant strains of bacteria poses an urgent risk to human health and dictates the need for new antimicrobials. Along this line, we have been working on developing inhibitors of SecA, a key component of the bacterial Sec-dependent secretion machinery. Herein, we describe the synthesis and antimicrobial evaluation of 6-oxo-1,6-dihydropyrimidine-5-carbonitrile derivatives as potential SecA inhibitors.

Heterocyclization of a Thiouracil Derivative as a Synthetic Entry to Novel Condensed Pyrimidines of Biological Interest

Chlorination of an S-methyl-5-cyano-6-arylthiouracil derivative afforded a chloropyrimidine which underwent aminolysis followed by cyclization to give pyrimidothiazolpyrimidine and imidazopyrimidines. The same thiouracil derivative was also used to prepare oxadiazolopyrimidines, triazolopyrimidines, and pyrimidotriazepines via a diaminopyrimidine and its cyclization with a variety of reagents. Some of the newly synthesized compounds showed a high antibacterial activity against Gram (+ve) and Gram (–ve) bacteria.

A Unified Experimental/Theoretical Description of the Ultrafast Photophysics of Single and Double Thionated Uracils.

Photoinduced processes in thiouracil derivatives have lately attracted considerable attention due to their suitability for innovative biological and pharmacological applications. Here, sub-20 fs broadband transient absorption spectroscopy in the near-UV are combined with CASPT2/MM decay path calculations to unravel the excited-state decay channels of water solvated 2-thio and 2,4-dithiouracil. These molecules feature linear absorption spectra with overlapping ππ* bands, leading to parallel decay routes which we systematically track for the first time. The results reveal that different processes lead to the triplet states population, both directly from the ππ* absorbing state and via the intermediate nπ* dark state. Moreover, the 2,4-dithiouracil decay pathways is shown to be strongly correlated either to those of 2- or 4-thiouracil, depending on the sulfur atom on which the electronic transition localizes.

Design, Synthesis, Molecular Modeling, and Biological Evaluation of Novel Thiouracil Derivatives as Potential Antithyroid Agents.

Hyperthyroidism is the result of uncontrolled overproduction of the thyroid hormones. One of the mostly used antithyroid agents is 6-n-propyl-2-thiouracil (PTU). The previously solved X-ray crystal structure of the PTU bound to mammalian lactoperoxidase (LPO) reveals that the LPO-PTU binding site is basically a hydrophobic channel. There are two hydrophobic side chains directed towards the oxygen atom in the C-4 position of the thiouracil ring. In the current study, the structural activity relationship (SAR) was performed on the thiouracil nucleus of PTU to target these hydrophobic side chains and gain more favorable interactions and, in return, more antithyroid activity. Most of the designed compounds show superiority over PTU in reducing the mean serum T4 levels of hyperthyroid rats by 3% to 60%. In addition, the effect of these compounds on the levels of serum T3 was found to be comparable to the effect of PTU treatment. The designed compounds in this study showed a promising activity profile in reducing levels of thyroid hormones and follow up experiments will be needed to confirm the use of the designed compounds as new potential antithyroid agents.

Removal of Pb+2, Cu+2 and Ag+ cations from wastewater by modified ZnO nanoparticles with S, N-substituted thiouracil derivative

Removal of Pb+2, Cu+2 and Ag+ cations from wastewater by modified ZnO nanoparticles with S, N-substituted thiouracil derivative