Thione Derivatives Research Articles

Synthesis, cytotoxicity and molecular docking of novel quinazoline-4(3H)-thione derivatives as EGFR-TKIs

Quinazoline nucleus is a distinct scaffold with fascinating pharmacological characteristics. New quinazoline-4(3H)-thiones were synthesized and evaluated for their cytotoxic properties against two human cancer cell lines. Molecular investigations on their mechanism of action were conducted. The most potent derivatives were examined by molecular docking as EGFR-TKIs, and their ADME properties were predicted using the SwissADME tool. Derivatives 4, 10, and 12 exhibited the most notable cytotoxicity, as evidenced by their ability to upregulate p53 and caspase-3 expression while downregulating CDK1, inhibiting EGFR activity and downregulating EGFR and ERK1/2 signaling. These derivatives docked well with EGFR and had promising drug-like properties. Our derivatives deserve further optimization not only as novel anticancer agents but also as potent EGFR-TKIs.

In vitro cytotoxicity screening of some 3-substituted-4-oxo-imidazolidin-2-(1H)-thione derivatives as anticancer drug.

Aim: This study aimed to investigate the in vitro antitumor activity of new series of 2-thiohydanotin derivatives (7 and 9) against two cancer cell lines.Materials & methods: A new series of 2-thioxoimidazolidine derivatives (3-9) were synthesized and investigated for its structure through spectral analysis and also tested against (HepG-2) and (HCT-116) cell line.Results: Among the synthesized compounds, compound 7 halted liver cancer cells at the G0/G1 phase and triggered apoptosis of liver cancer. Contrarily, compound 9 caused colon cancer cells to be arrested at the S phase and trigger apoptosis. Also, they had a good inhibitory effect on (Nrf2).Conclusion: Both compounds had attractive lead molecules for the creation of colon and liver cancer medications.

Iron-Catalyzed Oxidative C(sp3)–C(sp3) Radical Coupling Reaction between Thiohydantoins and O-Acetyloximes for the Synthesis of 1,3-Dibenzyl-3,4-dihydropyrrolo[2,3-d]imidazole-2(1H)-thione Derivatives

AbstractA unified heteroannelation method to achieve the synthesis of 1,3-dibenzyl-3,4-dihydropyrrolo[2,3-d]imidazole-2(1H)-thione derivatives with an iron catalyst is proposed. The annelation reaction follows a C(sp3)–C(sp3) radical coupling between a thiohydantoin and an O-acetyloxime. The synthetic approach enables access to several alkynylated thiohydantoins and O-acetyloximes with controlled selectivity toward C(sp3)–C(sp3) coupling rather than C(sp3)–C(sp3)–O coupling in moderate to high yields. An optimization study has been carried out by changing the catalyst loading, oxidants, solvents, and temperature. Synthesized compounds were characterized through 1H and 13C NMR and mass spectral studies.

An efficient three-component one-pot synthesis of 3, 4-dihydropyrimidin-2-(1H)-thione derivatives with a mesoporous iron ion exchanged Indian clay catalyst

An efficient three-component one-pot synthesis of 3, 4-dihydropyrimidin-2-(1H)-thione derivatives with a mesoporous iron ion exchanged Indian clay catalyst

Exploring the effect of substituents on the supramolecular assemblies built by non-covalent interactions in three closely related 1,3,4-oxadiazole-2(3H)-thione derivatives: An evaluation of antimicrobial and anti-proliferative activities

Three closely related 1,3,4-oxadiazole-2(3H)-thione N-Mannich bases were synthesized and characterized by spectroscopic and single crystal X-ray diffraction methods. X-ray analysis reveals that the title molecules adopt l-shaped conformation, and a slight structural deviation around substituent groups is noted. The Hirshfeld surface and 2D fingerprint plots demonstrate the effect of substituents (piperidine, morpholine, and thiomorpholine) on the intermolecular interactions. The CLP-PIXEL energy analysis identified the most significant interactions in the molecular dimers (that characterize the crystal packing) with respect to the total intermolecular interaction energies. These dimers are held together by various non-covalent interactions including C–H⋅⋅⋅S/N/O/Cl/π interactions in addition to unconventional lone pair⋅⋅⋅π interactions. A molecule with thiomorpholine substituent is favoured by two σ-hole interactions (Cl⋅⋅⋅Cl halogen bond and S⋅⋅⋅N chalcogen bond) in the solid state. Furthermore, the molecular electrostatic potential (MEP) surfaces and deformation electron density help to describe the existence of σ-hole on the Cl and thione S atoms. Noncovalent interaction index (NCI) and quantum theory of atoms in molecules (QTAIM) methods are used to delineate the nature of observed noncovalent interactions in the molecular dimers. In vitro data of antibacterial and anti-proliferative activities indicate that compound with morpholine substituent showed a moderate antibacterial activity against all tested Gram-positive bacterial strains. However, molecules with piperidine and thiomorpholine showed notable effectiveness against the HepG-2 cell line. Molecular docking analysis was performed with two liver cancer targets, VEGFR2 and RET, in order to understand the interactions between the ligand and the active site residues of these targets.

Synthesis, spectral study and evaluation of antibacterial activity of some novel 4-(6-methoxynaphthalen-2-yl)-6-(substituted aryl)pyrimidine-2(1H)-thiones

Abstract The objective of this study was to synthesize some novel substituted 4-(2-methoxynaphthalen-6-yl) pyrimidine- 2(1H)-thione compounds using sodium hydroxide catalyzed three component condensation and cyclization reaction of substituted 6-methoxy-2-acetonapthone, various substituted benzaldehydes and thiourea. These thione derivatives were characterized by their analytical, physical, and spectroscopic data. In addition, the in vitro antibacterial activities of these pyrimidine derivatives were evaluated using Bauer-Kirby disc diffusion method.

Exploring substituted 3,4-dihydropyrimidinone and thione derivatives as anti-prostate cancer agents: Computational screening, synthesis, characterization, and in vitro efficacy assessment

Despite decades of research, anticancer medication therapy is still largely constrained to prevent growth and limit the spread of tumour cells. To speed up the process of finding anticancer drugs, exploring novel therapeutic macromolecules and identifying the right small molecules using an integration of computational and experimental approaches is a recent tactic adopted by investigators. In the present study, we designed and created a library of 200 ligands with 3,4-dihydropyrimidinones or their thiones linked with imidazolidinones through amide linkage and explored the extent of their in vitro anticancer activity towards human topoisomerase IIalpha (TOP2α or TOP2A) using DU-145 and PC-3 prostate cancer cell lines using the SRB assay method. This was accomplished by the molecular docking and synthesis of the titled compounds using a series of organic nucleophilic addition reactions, including the Biginelli one-pot condensation reaction. The preliminary physical character evaluation was employed for the synthesized compounds, and the structural parameters were analyzed using FTIR, proton NMR, 13C NMR, and LC-MS/MS. The anti-prostate cancer activity of the prepared Biginelli analogues was evaluated against cancer cell lines and mild-to-moderate reduction in the viability of cell lines was observed with compounds 5, 6, 9, 14, 15, 16, 17, and 19. Among them, compounds 5, 14, 15, and 16 exhibited significant potent activity against TOP2α or TOP2A. This result indicated that the derivatives of Biginelli (3,4-dihydropyrimidinones/thiones) could be promising anti-prostate cancer drug candidates.

MW Assisted Synthesis of New 4,6-diaryl-3,4-Didhydropyrimidines-2(1H)-thione Derivatives: Tyrosinase Inhibition, Antioxidant, and Molecular Docking Studies

A number of new methoxy-substituted 4,6-diaryl-3,4-dihydropyrimidine-2(1H)-thiones (DH-Pyr-S, 17-28) were designed and synthesized by the reaction of methoxy-substituted chalcones (1–14) with thiourea using solid-phase microwave method (MW) in view of the structural requirements as suggested in the pharmacophore model for tyrosinase inhibition (TI). Synthesized compounds were assessed for their in vitro TI potential and compounds 16, 17, and 21 exhibited notable tyrosinase inhibitory properties at the concentrations of 31.86 ± 2.45 µM, 44.58 ± 0.46 µM, and 48.47 ± 0.66 µM, respectively. Compounds (16, 17, and 21) were exhibited experimentally more potent TI than the standard used in terms of the IC50 value (Kojic acid, 55.38 ± 2.30 µM; p<0.0001). Additionally, DPPH activity of 15-28 were evaluated and compound 17 showed the moderate DPPH activity (45.64 ± 0.34%). Binding affinities of synthesized molecules to the tyrosinase catalytic core were further investigated through in silico molecular docking studies using AutoDock Vina (version 1.2.5), discovery studio accelyrs (BIOVIA, Dassault Systèmes) and predicting small-molecule pharmacokinetic properties using graph-based signatures (pkCSM) programs were used for ADMET calculations. Among synthesized compounds 15, 21, and 24 revealed high binding affinity to tyrosinase active site with lowest binding free energy (ΔG) values of -7.9 kcal/mol, thereby outperformed kojic acid affinity. In conclusion most modeling results were in agreement with their experimental data, suggesting the TI potential of lead compounds.

Molecular Mechanism of Labelling Functional Cysteines by Heterocyclic Thiones.

Heterocyclic thiones have recently been identified as reversible covalent warheads, consistent with their mild electrophilic nature. Little is known so far about their mechanism of action in labelling nucleophilic sidechains, especially cysteines. The vast number of tractable cysteines promotes a wide range of target proteins to examine; however, our focus was put on functional cysteines. We chose the main protease of SARS-CoV-2 harboring Cys145 at the active site that is a structurally characterized and clinically validated target of covalent inhibitors. We screened an in-house, cysteine-targeting covalent inhibitor library which resulted in several covalent fragment hits with benzoxazole, benzothiazole and benzimidazole cores. Thione derivatives and Michael acceptors were selected for further investigations with the objective of exploring the mechanism of inhibition of the thiones and using the thoroughly characterized Michael acceptors for benchmarking our studies. Classical and hybrid quantum mechanical/molecular mechanical (QM/MM) molecular dynamics simulations were carried out that revealed a new mechanism of covalent cysteine labelling by thione derivatives, which was supported by QM and free energy calculations and by a wide range of experimental results. Our study shows that the molecular recognition step plays a crucial role in the overall binding of both sets of molecules.

Reaction of Tetrahydropyrimidine-2(1H)-thione Derivatives with Thiolated Acid Hydrazides as a Method of Synthesis of Biologically Active Ligands for Glyco-Gold Nanoparticles

Reaction of Tetrahydropyrimidine-2(1H)-thione Derivatives with Thiolated Acid Hydrazides as a Method of Synthesis of Biologically Active Ligands for Glyco-Gold Nanoparticles

Novel 1,2,4-triazolethiol–thiophen Hybrids: Facile Synthesis, Characterization, ADMET Prediction and Molecular Docking

In the present contribution, novel 1,2,4-triazolethiol–thiophene hybrids, namely 4-ethyl-5-(thiophen-2-yl)-4H-1,2,4-triazole-3-thiol (1) and 4-phenyl-5-(thiophen-2-yl)-4H-1,2,4-triazole-3-thiol (2), which were readily fabricated from addition of isothiocyanatoethane or isothiocyanatobenzene, respectively, to thiophene-2-carbohydrazide followed by addition a KOH solution to provoke the cyclization to the 1,2,4-triazole ring. The formation of compounds 1 and 2 was firmly confirmed by the means of elemental analysis, IR, 1H and 13C{1H} NMR spectroscopy. The DFT-based computations in gas phase were additionally applied to shed light on the structure and electronic features of the title compounds. Theoretical calculations revealed that for both molecules their corresponding thione derivatives, namely 4-ethyl-5-(thiophen-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (1') and 4-phenyl-5-(thiophen-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (2'), are 15.00 and 11.96 kcal/mol, respectively, more energetically favorable in gas phase. However, a comparison of the experimental and calculated IR and NMR spectra testify to the thiol tautomers of compounds 1 and 2 for both compounds in solid state and in DMSO-d 6. The chemical activity of 1 and 2 was estimated by reactivity descriptors and MEP surface. ADMET properties of the reported compounds were predicted in silico using online services. Potential inhibition of a series of the tick-borne encephalitis (TBE) proteins by compounds 1 and 2 was studied using molecular docking, which, in turn, allowed to reveal the ligand efficiency scores for the resulting protein–ligand complexes. It was established that compound 1 exhibits the best activity against the tick-borne encephalitis virus Serine protease NS3, while compound 2 is preferable for the RNA-stimulated ATPase activity of tick-borne encephalitis virus helicase.

Thiadiazine thione derivatives as anti-leishmanial agents: synthesis, biological evaluation, structure activity relationship, ADMET, molecular docking and molecular dynamics simulation studies

During last decades, 3,5-disubstituted-tetrahydro-2H-thiadiazine-2-thione scaffold remains the center of interest due to their ease of preparation, diverse range substituents at N-3 and N-5 positions, and profound biological activities. In the current study, a series of 3,5-disubstituted-tetrahydro-2H-thiadiazine-2-thiones were synthesized in good to excellent yield, and the structure of the compounds were confirmed by various spectroscopic techniques such as FTIR, 1H-NMR, 13C-NMR and Mass spectrometry, and finally evaluated against Leishmania major. Whereas, all the evaluated compounds (1-33), demonstrate potential leishmanicidal activities with IC50 values in the range of (1.30- 149.98 uM). Among the evaluated compounds such as 3, 4, 6, and 10 exhibited excellent leishmanicidal activities with IC50 values of (2.17 μM), (2.39 μM), (2.00 μM), and (1.39 μM), respectively even better than the standard amphotericin B (IC50 = 0.50) and pentamidine (IC50 = 7.52). In order to investigate binding interaction of the most active compounds, molecular docking study was conducted with Leishmania major. Further molecular dynamic simulation study was also carried out to assess the stability and correct binding of the most active compound 10, within active site of the Leishamania major. Likewise, the physiochemical properties, drug likeness, and ADMET of the most active compounds were investigated, it was found that none of the compounds violate Lipiniski’s rule of five, which show that this class of compounds had enough potential to be used as drug candidate in near future. Communicated by Ramaswamy H. Sarma

Synthesis of 3, 5-Disubstituted-Tetrahydro-2h-1, 3, 5-Thiadiazine2-Thiones Derivatives and their Metal Complexes as Potential Bioactive Agents

Thiadiazine thione derivatives (2-(5-(2-.hydroxyethyl)-2-thioxo-1,3,5-thiadiazinane-3-yl) Acetic acid, 2-(5-.butyl-6-thioxo.-1, 3, 5-thiadiazinane-3-yl) Acetic acid, 2, 1 and 2 were synthesized by the reaction of alkyl primary amines (glycine, butylamine) with carbon disulfide and potassium hydroxide followed by addition of formaldehyde and various primary amines (ethanolamine, glycine) in phosphate buffer medium. The synthesized compounds were transformed into organometallic complexes (3-12) Ni (II), Co (II), Cu (II), Zn (II) and Fe (II) using their metal salts. The structure determinations of these compounds were elucidated by spectral methods such as IR, NMR spectroscopy and Mass spectrometry. All the synthesized compounds were screened for their anti-microbia++l activities. Their structure activity relationship showed that the potential of tested compounds enhanced with metal complexes against evaluated activities.

Antimicrobial Activity Studies of 3-Substituted Indole-2-one and -thione derivatives and Molecular Docking and ADME Evaluations

Increasing antibiotic resistance is an important problem for public health therefore new antimicrobial compounds are needed. In this study, the antimicrobial effects of 3-Substituted Indole-2-one and -thione derivatives were investigated. Antimicrobial effects of previously synthesized 18 different 3-substituted indole-2-one and 2-thione derivatives against 5 different microorganisms were investigated and the structure-activity relationships and drug-like properties of compounds were analyzed by molecular docking and in silico prediction studies. The in vitro antimicrobial activities of compounds were tested by microdilution method. The most active compounds were found as 2, 3, 4, 5, 6, 7, 8 at 125 μg/mL of MIC value. Compounds 2 and 3 were found to be active against S. enterica and compounds 4, 5, 6, 7, and 8 were found to be active against methicillin-resistant S. aureus. According to molecular docking studies, all compounds presented weaker binding properties than ciprofloxacin, ampicillin and gentamicin. The predicted values for molecular weight, log P, PSA, crossing the BBB, GI absorption properties and type of CYPP450 inhibition data of compounds were found promising for drug-like properties. 3-Substituted Indole-2-one and -thione derivatives can proivide an important contribution to develop alternative antimicrobial agents.

EMIM]AlCl4‐ionic liquid catalyzed mechanochemically assisted synthesis of 3,4‐dihydropyrimidin‐2‐(1H)‐one and thione derivatives

Abstract[EMIM]AlCl4 (1‐ethyl‐3‐methylimidazolium tetrachloroaluminate) ionic liquid catalyzed mechanochemically assisted methodology for the Biginelli reaction has been developed successfully. One‐pot, multicomponent reaction between ethyl/methyl acetoacetate, urea/thiourea, and various aromatic/aliphatic and heterocyclic aldehydes in presence of catalytic amount of [EMIM]AlCl4 under grinding conditions in ethanol affords 3,4‐dihydropyrimidin‐2‐(1H)‐one and its thione derivatives. Short reaction time, inclusion of eco‐friendly solvent, moderate to high yield of the product, and operational simplicity are some of the noteworthy features of this protocol. In consequence, the described procedure finds an alternative way to existing methods for the synthesis of the titled compounds.

Synthesis, spectroscopic, crystallographic, quantum and molecular docking investigations of cis-4,5-diphenylimidazolidine-2-thione

We present the synthesis and characterization of stereoselective thione. The synthetic procedure includes readily available starting materials and minimum side products. The reaction of meso‑stilbenediamine with carbon disulphide in the presence of strong base gave cis-4,5-diphenylimidazolidine-2-thione (DPIT) in an excellent yield. The thione compound was characterized via FT-IR and mass spectroscopy. In addition, the crystal structure of it was determined by single crystal X-rays diffraction analysis which inferred that the molecular configuration was stabilized by intramolecular π⋯π stacking interaction. The crystal packing was mainly stabilized by N-H⋯S bonding. Hirshfeld surface analysis was performed for the exploration of the intermolecular interactions. Void analysis was carried out to predict the mechanical stability. Interaction energy between the molecular pairs is calculated which showed that the dispersion energy played a dominant role in the stabilization of the crystal packing. Moreover, the quantum computational methods were used to study the molecular structure and electronic properties of entitled compound. The molecular geometries were optimized for possible thione and thiole tautomeric structures. A comparison of total energy of molecular tautomers indicates that thione tautomer possesses lower total energy which is about 20.18 Kcal/mol lower than thiole tautomer. The electronic properties of thione derivative were studied including 3-D wavefunction delocalization of highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) orbitals and their orbital energy gap. The HOMO-LUMO energy gap for DPIT was found to be 4.874 eV. The delocalization of wavefunction indicates the probable presence of HOMO and HOMO-1 are mainly localized over C-S bond owing to the presence of lone pair of electrons in the sulfur atom. Additionally, the molecular docking study was also carried out for main protease (Mpro) of SARS-CoV-2. The binding energy calculation and investigation of intermolecular interactions highlighted the probable inhibition tendency of DPIT for SARS-CoV-2. The present experimental and computational studies indicate a significant potential of entitled molecule for electronic and biological perspectives.

Design, synthesis and antifungal evaluation of phenylthiazole-1,3,4-oxadiazole thione (ketone) derivatives inspired by natural thiasporine A.

Plant pathogenic fungal infections have become a severe threat to the yield and quality of agricultural products, and new green antifungal agents with high-efficiency and low-toxicity are needed. In this study, a series of thiasporine A derivatives containing phenylthiazole-1,3,4-oxadiazole thione (ketone) structures were designed and synthesized, and their antifungal activities against six invasive and highly destructive phytopathogenic fungi were evaluated. The results showed that all compounds showed moderate to potent antifungal activity against six phytopathogenic fungi, and most of E the series compounds showed remarkable antifungal activity against S. sclerotiorum and C. camelliaet. In particular, compounds E1 - E5, E7, E8, E13, E14, E17, and E22 showed more significant antifungal activity against S. sclerotiorum, with EC50 values of 0.22，0.48, 0.56, 0.65, 0.51, 0.39, 0.60, 0.56, 0.60, 0.63, and 0.45 μg/mL, respectively, which were superior to that of carbendazim (0.70 μg/mL). Further activity studies showed that compound E1 showed superior curative activities against S. sclerotiorum in vivo and better inhibitory effects on sclerotia germination and formation of S. sclerotiorum compared to those of carbendazim. Therefore, this study indicates that these thiasporine A derivatives containing phenylthiazole-1,3,4-oxadiazole thione structures might be applied as antifungal agents against S. sclerotiorum. This article is protected by copyright. All rights reserved.

In-vitro Antioxidant and Antitumor Activity of Dihydropyrimidine-2(1-H)-thione Derivatives with Carbazole Moiety

Aim: Prepared a series of molecules called Dihydropyrimidine-2(1-H)-thione of carbazole to evaluate antioxidant and antitumor activity. Materials and Methods: Compounds from DTP-1 to DTP-11 were prepared and subjected for Spectral analysis like infrared, 1H NMR, and Mass spectroscopy. Further evaluated antioxidant property of molecules using DPPH free radical scavenging method and analyzed the antitumor activity by MTT assay. Results: The molecule DTP-4 (4-(9H-carbazol-9-yl)-6-(3-hydroxyphenyl)-5,6-dihydropyrimidine-2(1H)-thione) exhibit the spectral values i.e, Mass, m/z: 371.08, 166.45; IR (KBr) νmax, cm−1: 3420 (NH Str), 3567(O-H); 1H NMR (MHz, δ): (15H, Ar-H) 8.003-7.019, (1H, N-H) 11.129, (1H, O-H) 10.03 and DTP-6: 4-(9H-carbazol-9-yl)-6-(4-Dimethylamino-phenyl)-5,6-dihydropyrimidine-2(1H)-thione Mass value of m/z: 398.03, 166.09; IR (KBr)vmax, cm−1: 3419 (NH Str), (Ar C=S); 1H NMR (MHz, δ): (15H, Ar-H) 8.128-7.121, (1H, N-H) 11.290, (6H, -N-(CH3)2)3.491-2.791. Conclusion: Among all of those prepared molecules, DTP-4, which includes the functional group (3-OH) ortho-hydroxy, has an IC50 value of 2.32 μm against the Jurkat T cell line while compound DTP-06, which contains the functional group 4-dimethylamino, exhibits an IC50 value of 05.39 μm against the HeLa cell line.

A novel, simple, and facile synthesis of 3-(3-benzyl-2,3-dihydrobenzo[d]thiazol-2-yl)benzo[d]oxazole-2(3H)-thione derivatives

Novel 3-(3-benzyl-2,3-dihydrobenzo[ d]thiazol-2-yl)benzo[ d]oxazole-2(3 H)-thione derivatives are efficiently synthesized in excellent yields by reactions of benzothiazoles, benzyl bromides, and 2-mercaptobenzoxazole in acetone under catalyst-free conditions in the presence of triethylamine. The structures of the products are confirmed by nuclear magnetic resonance spectroscopy, infrared spectroscopy, electron ionization mass spectrometry, and elemental analyses.

Design, Synthesis and Molecular Docking of 1,3,4-Oxadiazole-2(3H)-thione Derivatives Containing 1,4-Benzodioxane Skeleton as Potential FabH Inhibitors.

Fatty acid biosynthesis is essential for bacterial survival. Of these promising targets, β-ketoacyl-acyl carrier protein (ACP) synthase III (FabH) is the most attractive target. A series of novel 1,3,4-oxadiazole-2(3H)-thione derivatives containing 1,4-benzodioxane skeleton targeting FabH were designed and synthesized. These compounds were determined by 1 H-NMR, 13 C-NMR, MS and further confirmed by crystallographic diffraction study for compound 7m and 7n. Most of the compounds exhibited good inhibitory activity against bacteria by computer-assisted screening, antibacterial activity test and E. coli FabH inhibitory activity test, wherein compounds 7e and 7q exhibited the most significant inhibitory activities. Besides, compound 7q showed the best E. coli FabH inhibitory activity (IC50 =2.45 μΜ). Computational docking studies also showed that compound 7q interacts with FabH critical residues in the active site.