A green, facile, and practical preparation of capsaicin derivatives with thiourea structure.

Capsaicin derivatives with thiourea structure (CDTS) is highly noteworthy owing to its higher analgesic potency in rodent models and higher agonism in vitro. However, the direct synthesis of CDTS remains t one or more shortcomings. In this study, we present reported a green, facile, and practical synthetic method of capsaicin derivatives with thiourea structure is developed by using an automated synthetic system, leading to a series of capsaicin derivatives with various electronic properties and functionalities in good to excellent yields.

Discovery of novel pyrazole based Urea/Thiourea derivatives as multiple targeting VEGFR-2, EGFRWT, EGFRT790M tyrosine kinases and COX-2 Inhibitors, with anti-cancer and anti-inflammatory activities.

A novel series of pyrazole derivatives with urea/thiourea scaffolds 16a-l as hybrid sorafenib/erlotinib/celecoxib analogs was designed, synthesized and tested for its VEGFR-2, EGFRWT, EGFRT790M tyrosine kinases and COX-2, pro-inflammatory cytokines TNF-α and IL-6 inhibitory activities. All the tested compounds showed excellent COX-2 selectivity index in range of 18.04-47.87 compared to celecoxib (S.I. = 26.17) and TNF-α and IL-6 inhibitory activities (IC50 = 5.0-7.50, 6.23-8.93 respectively, compared to celecoxib IC50 = 8.40 and 8.50, respectively). Screening was carried out against 60 human cancer cell lines by National Cancer Institute (NCI), compounds 16a, 16c, 16d and 16 g were the most potent inhibitors with GI% ranges of 100 %, 99.63-87.02 %, 98.98-43.10 % and 98.68-23.62 % respectively, and with GI50 values of 1.76-15.50 µM, 1.60-5.38 µM, 1.68-7.39 µM and 1.81-11.0 µM respectively, in addition, of showing good safety profile against normal cell line (F180). Moreover, compounds 16a, 16c, 16d and 16 g had cell cycle arrest at G2/M phase with induced necrotic percentage compared to sorafenib of 2.06 %, 2.47 %, 1.57 %, 0.88 % and 1.83 % respectively. Amusingly, compounds 16a, 16c, 16d and 16 g inhibited VEGFR-2 with IC50 of 25 nM, 52 nM, 324 nM and 110 nM respectively, compared to sorafenib (IC50 = 85 nM), and had excellent EGFRWT and EGFRT790M kinase inhibitory activities (IC50 = 94 nM, 128 nM, 160 nM, 297 nM), (10 nM, 25 nM, 36 nM and 48 nM) respectively, compared to both erlotinib and osimertinib (IC50 = 114 nM, 56 nM) and (70 nM, 37 nM) respectively and showed (EGFRwt/EGFRT790M S.I.) of (range: 4.44-9.40) compared to erlotinib (2.03) and osmertinib (1.89).

Promoting the Anticancer Activity with Multidentate Furan-2-Carboxamide Functionalized Aroyl Thiourea Chelation in Binuclear Half-Sandwich Ruthenium(II) Complexes.

A new set of binuclear arene ruthenium complexes [Ru2(p-cymene)2(k4-N2OS)(L1-L3)Cl2] (Ru2L1-Ru2L3) encompassing furan-2-carboxamide-based aroylthiourea derivatives (H2L1-H2L3) was synthesized and characterized by various spectral and analytical techniques. Single-crystal XRD analysis unveils the N^O and N^S mixed monobasic bidentate coordination of the ligands constructing N, S, Cl/N, O, and Cl legged piano stool octahedral geometry. DFT analysis demonstrates the predilection for the formation of stable arene ruthenium complexes. In vitro antiproliferative activity of the complexes was examined against human cervical (HeLa), breast (MCF-7), and lung (A549) cancerous and noncancerous monkey kidney epithelial (Vero) cells. All the complexes are more efficacious against HeLa and MCF-7 cells with low inhibitory doses (3.86-11.02 µM). Specifically, Ru2L3 incorporating p-cymene and -OCH3 fragments exhibits high lipophilicity, significant cytotoxicity against cancer cells, and lower toxicity on noncancerous cells. Staining analysis indicates the apoptosis-associated cell morphological changes expressively in MCF-7 cells. Mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) analyses reveal that Ru2L3 can raise ROS levels, reduce MMP, and trigger mitochondrial dysfunction-mediated apoptosis. The catalytic oxidation of glutathione (GSH) to its disulfide form (GSSG) by the complexes may simultaneously increase the ROS levels, alluding to their observed cytotoxicity and apoptosis induction. Flow cytometry determined the quantitative classification of late apoptosis and S-phase arrest in MCF-7 and HeLa cells. Western blotting analysis confirmed that the complexes promote apoptosis by upregulating Caspase-3 and Caspase-9 and downregulating BCL-2. Molecular docking studies unfolded the strong binding affinities of the complexes with VEGFR2, an angiogenic signaling receptor, and BCL2, Cyclin D1, and HER2 proteins typically overexpressed on tumor cells.

Bifunctional iminophosphorane organocatalyst with additional hydrogen bonding: Calculations predict enhanced catalytic performance in a michael addition reaction.

A new iminophosphorane-thiourea superbase was rationally designed and investigated as an organocatalyst for the enantioselective Michael addition reaction of nitromethane to 4-phenylbut-3-en-2-one. Starting from an iminophosphorane-thiourea organocatalyst structure already known, we have used theoretical calculations to determine the structures of transition states involved in the carbon-carbon bond formation step and carried out structural modifications to accelerate the reaction rate and to increase the enantioselectivity. The effective structural modification was adding a rigid hydroxyl group able to make an additional hydrogen bond to the transition state, producing a substantial decrease of the ΔG‡ by 7 kcal mol-1. The enantiomeric excess is predicted to be above of 97% using the reliable M06-2X and ωB97M - V functionals. The determination of the complete reaction mechanism and free energy profile was followed by a detailed microkinetic analysis. The present study points out a new direction for structural modifications on this kind of organocatalyst.

Unsymmetrical thiourea derivatives: synthesis and evaluation as promising antioxidant and enzyme inhibitors.

Background: Unsymmetrical thioureas 1-20 were synthesized and then characterized by various spectroscopy techniques such as UV, IR, fast atom bombardment (FAB)-MS, high-resolution FAB-MS, 1H-NMR and 13C-NMR. Methods: Synthetic compounds 1-20 were tested for their ability for antioxidant, lipoxygenase and xanthine oxidase activities. Results: Compounds 1, 2, 9, 12 and 15 exhibited strong antioxidant potential, whereas compounds 1-3, 9, 12, 15 and 19 showed good to moderate lipoxygenase activity. Ten compounds demonstrated moderate xanthine oxidase inhibition. Conclusion: Compound 15 displayed the highest potency among the series, exhibiting good antioxidant, lipoxygenase and xanthine oxidase activities. Theoretical calculations using density functional theory and molecular docking studies supported the experimental findings, indicating the potential of the synthesized compounds as potent antioxidants, lipoxygenases and xanthine oxidase agents.

Sulfonyl thioureas with a benzo[d]thiazole ring as dual acetylcholinesterase/butyrylcholinesterase and human monoamine oxidase A and B inhibitors: An in vitro and in silico study.

A series of sulfonyl thioureas 6a-q containing a benzo[d]thiazole ring with an ester functional group was synthesized from corresponding substituted 2-aminobenzo[d]thiazoles 3a-q and p-toluenesulfonyl isothiocyanate. They had remarkable inhibitory activity against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), monoamine oxidase (MAO)-A, and MAO-B. Among thioureas, several compounds had notable activity in the order of 6k > 6 h > 6c (AChE), 6j > 6g > 6k (BChE), 6k > 6g > 6f (MAO-A), and 6i > 6k > 6h (MAO-B). Compound 6k was an inhibitor of interest due to its potent or good activity against all studied enzymes, with IC50 values of 0.027 ± 0.008 µM (AChE), 0.043 ± 0.004 µM (BChE), 0.353 ± 0.01 µM (MAO-A), and 0.716 ± 0.02 µM (MAO-B). This inhibitory capacity was comparable to that of the reference drugs for each enzyme. Kinetic studies of two compounds with potential activity, 6k (against AChE) and 6j (against BChE), had shown that both 6k and 6j followed competitive-type enzyme inhibition, with Ki constants of 24.49 and 12.16 nM, respectively. Induced fit docking studies for enzymes 4EY7, 7BO4, 2BXR, and 2BYB showed active interactions between sulfonyl thioureas of benzo[d]thiazoles and the residues in the active pocket with ligands 6k, 6i, and 6j, respectively. The stability of the ligand-protein complexes while each ligand entered the active site of each enzyme (4EY7, 7BO4, 2BXR, or 2BYB) was confirmed by molecular dynamics simulations.

Exploration of newly synthesized amantadine-thiourea conjugates for their DNA binding, anti-elastase, and anti-glioma potentials.

Three newly synthesized amantadine thiourea conjugates namely MS-1 N-(((3 s,5 s,7 s)-adamantan-1-yl)carbamothioyl)benzamide, MS-2 N-(((3 s,5 s,7 s)-adamantan-1-yl)carbamothioyl)-4-methylbenzamide and MS-3 N-((3 s,5 s,7 s)-adamantan-1-ylcarbamothioyl)-4-chlorobenzamide were investigated for their structures, bindings (DNA/ elastase), and for their impact on healthy and cancerous cells. Theoretical (DFT/docking) and experimental {UV-visible (UV-), fluorescence (Flu-), and cyclic voltammetry (CV)} studies indicated binding interactions of each conjugate with DNA and elastase enzyme. Theoretically and experimentally calculated binding parameters for conjugate - DNA interaction revealed MS-3 - DNA to have most significant binding with comparatively greater values of binding parameters {(Kb/M-1: docking, 3.8 × 105; UV-, 5.95 × 103; Flu-,1.55 × 105; CV, 1.52 × 104), (∆G/ kJmol-1: docking, -32.09; UV-, -22.40; Flu-,-30.81; CV, -24.82)}. The docked structures, greater bindings site size values (n), and the trend in DNA viscosity changes in the presence of each conjugate concentration confirmed a mixed binding mode of interaction among them. Conjugate - elastase binding by docking agreed with the experimental anti-elastase findings. Cytotoxicity studies of each tested conjugate demonstrated greater cytotoxicity for cancerous (MG-U87) cells in comparison to control, while for the normal (HEK-293) cells the cytotoxicity was found comparatively low. Overall exploration suggested that MS-3 is the most effective candidate for DNA binding, anti-elastase, and for anti-glioma activities.

Design, synthesis, and biological studies of the new cysteine-N-arylacetamide derivatives as a potent urease inhibitor.

Inhibition of Helicobacter pylori urease is an effective method in the treatment of several gastrointestinal diseases in humans. This bacterium plays an important role in the pathogenesis of gastritis and peptic ulceration. Considering the presence of cysteine and N-arylacetamide derivatives in potent urease inhibitors, here, we designed hybrid derivatives of these pharmacophores. Therefore, cysteine-N-arylacetamide derivatives 5a-l were synthesized through simple nucleophilic reactions with good yield. In vitro urease inhibitory activity assay of these compounds demonstrated that all newly synthesized compounds exhibited high inhibitory activity (IC50 values = 0.35-5.83 µM) when compared with standard drugs (thiourea: IC50 = 21.1 ± 0.11 µM and hydroxyurea: IC50 = 100.0 ± 0.01 µM). Representatively, compound 5e with IC50 = 0.35 µM was 60 times more potent than strong urease inhibitor thiourea. Enzyme kinetic study of this compound revealed that compound 5e is a competitive urease inhibitor. Moreover, a docking study of compound 5e was performed to explore crucial interactions at the urease active site. This study revealed that compound 5e is capable to inhibit urease by interactions with two crucial residues at the active site: Ni and CME592. Furthermore, a molecular dynamics study confirmed the stability of the 5e-urease complex and Ni chelating properties of this compound. It should be considered that, in the following study, the focus was placed on jack bean urease instead of H. pylori urease, and this was acknowledged as a limitation.

Evaluation of synthetic aminoquinoline derivatives as urease inhibitors: in vitro, in silico and kinetic studies.

Background: Quinoline and acyl thiourea scaffolds have major chemical significance in medicinal chemistry. Quinoline-based acyl thiourea derivatives may potentially target the urease enzyme. Materials & methods: Quinoline-based acyl thiourea derivatives 1-26 were synthesized and tested for urease inhibitory activity. Results: 19 derivatives (1-19) showed enhanced urease enzyme inhibitory potential (IC50 = 1.19-18.92 µM) compared with standard thiourea (IC50 = 19.53 ± 0.032 µM), whereas compounds 20-26 were inactive. Compounds with OCH3, OC2H5, Br and CH3 on the aryl ring showed significantly greater inhibitory potential than compounds with hydrocarbon chains of varying length. Molecular docking studies were conducted to investigate ligand interactions with the enzyme's active site. Conclusion: The identified hits can serve as potential leads against the drug target urease in advanced studies.

Rational design and optimization of acylthioureas as novel potent influenza virus non-nucleoside polymerase inhibitors.

Evidence suggests that rapidly evolving virus subvariants risk rendering current vaccines and anti-influenza drugs ineffective. Hence, exploring novel scaffolds or new targets of anti-influenza drugs is of great urgency. Herein, we report the discovery of a series of acylthiourea derivatives produced via a scaffold-hopping strategy as potent antiviral agents against influenza A and B subtypes. The most effective compound 10m displayed subnanomolar activity against H1N1 proliferation (EC50 = 0.8 nM) and exhibited inhibitory activity toward other influenza strains, including influenza B virus and H1N1 variant (H1N1, H274Y). Additionally, druggability evaluation revealed that 10m exhibited favorable pharmacokinetic properties and was metabolically stable in liver microsome preparations from three different species as well as in human plasma. In vitro and in vivo toxicity studies confirmed that 10m demonstrated a high safety profile. Furthermore, 10m exhibited satisfactory antiviral activity in a lethal influenza virus mouse model. Moreover, mechanistic studies indicated that these acylthiourea derivatives inhibited influenza virus proliferation by targeting influenza virus RNA-dependent RNA polymerase. Thus, 10m is a potential lead compound for the further exploration of treatment options for influenza.

Design, in Silico Studies and Biological Evaluation of New Chiral Thiourea and 1,3-Thiazolidine-4,5-dione Derivatives.

In this study, new chiral thiourea and 1,3-thiazolidine-4,5-dione derivatives were synthesized, it was aimed to evaluate the various biological activities and molecular docking of these compounds. Firstly, the new thioureas (1-16) were obtained by reacting 1-naphthylisothiocyanate with different chiral amines. Then, the chiral thioureas were cyclized with oxalyl chloride to obtain 1,3-thiazolidine-4,5-dione derivatives (17-32). All compounds were evaluated with several in vitro antioxidant and enzyme inhibition activities. Compound 30 was the most active compound against AChE, with a value of IC50 =8.09±0.58 µM. On the other hand, all compounds were tested in silico absorption, distribution, metabolism, and excretion (ADME) assays to better understand their bioavailability. These physicochemical properties, pharmacokinetics, and drug-likeness of all compounds were calculated using SwissADME. Furthermore, according to molecular docking analyses compound 30 exhibited significant binding affinities for all enzymes. Based on our overall observations, compound 30 could be recommended as a potential lead for the therapuetic of Alzheimer's.

Green synthesis of nitroaryl thioureas: Towards an improved preparation of guanidinium DNA binders.

We present a general efficient green method for the preparation of nitro N,N'-diaryl thioureas via a one-pot method using cyrene as a solvent with almost quantitative yields. This confirmed the viability of cyrene as a green alternative to THF in the synthesis of thiourea derivatives. After screening different reducing conditions, the nitro N,N'-diaryl thioureas were selectively reduced using Zn dust in the presence of water and acid to the corresponding amino N,N'-diaryl thioureas. These were then used to test the installation of the Boc-protected guanidine group with N,N'-bis-Boc protected pyrazole-1-carboxamidine as a guanidylating reagent not requiring mercury(II) activation. Finally, the TFA salts obtained after Boc-deprotection of two sample compounds were tested for their affinity towards DNA showing no binding.

Investigation of Newly Synthesized Bis-Acyl-Thiourea Derivatives of 4-Nitrobenzene-1,2-Diamine for Their DNA Binding, Urease Inhibition, and Anti-Brain-Tumor Activities.

Bis-acyl-thiourea derivatives, namely N,N'-(((4-nitro-1,2-phenylene)bis(azanediyl)) bis(carbonothioyl))bis(2,4-dichlorobenzamide) (UP-1), N,N'-(((4-nitro-1,2-phenylene) bis(azanediyl))bis(carbonothioyl))diheptanamide (UP-2), and N,N'-(((4-nitro-1,2-phenylene)bis(azanediyl))bis(carbonothioyl))dibutannamide (UP-3), were synthesized in two steps. The structural characterization of the derivatives was carried out by FTIR, 1H-NMR, and 13C-NMR, and then their DNA binding, anti-urease, and anticancer activities were explored. Both theoretical and experimental results, as obtained by density functional theory, molecular docking, UV-visible spectroscopy, fluorescence (Flu-)spectroscopy, cyclic voltammetry (CV), and viscometry, pointed towards compounds' interactions with DNA. However, the values of binding constant (Kb), binding site size (n), and negative Gibbs free energy change (ΔG) (as evaluated by docking, UV-vis, Flu-, and CV) indicated that all the derivatives exhibited binding interactions with the DNA in the order UP-3 > UP-2 > UP-1. The experimental findings from spectral and electrochemical analysis complemented each other and supported the theoretical analysis. The lower diffusion coefficient (Do) values, as obtained from CV responses of each compound after DNA addition at various scan rates, further confirmed the formation of a bulky compound-DNA complex that caused slow diffusion. The mixed binding mode of interaction as seen in docking was further verified by changes in DNA viscosity with varying compound concentrations. All compounds showed strong anti-urease activity, whereas UP-1 was found to have comparatively better inhibitory efficiency, with an IC50 value of 1.55 ± 0.0288 µM. The dose-dependent cytotoxicity of the synthesized derivatives against glioblastoma MG-U87 cells (a human brain cancer cell line) followed by HEK-293 cells (a normal human embryonic kidney cell line) indicated that UP-1 and UP-3 have greater cytotoxicity against both cancerous and healthy cell lines at 400 µM. However, dose-dependent responses of UP-2 showed cytotoxicity against cancerous cells, while it showed no cytotoxicity on the healthy cell line at a low concentration range of 40-120 µM.

Compatible Kinetic Model for Quantitative Description of Dual-Clock Behavior of the Complex Thiourea-Iodate Reaction.

The thiourea-iodate reaction has been investigated simultaneously by ultraviolet-visible spectroscopy and high-performance liquid chromatography (HPLC). Absorbance-time traces measured at the isosbestic point of the iodine-triiodide system have revealed a special dual-clock behavior. During the first kinetic stage of the title reaction, iodine suddenly appears only after a well-defined time lag when thiourea is totally consumed due to the rapid thiourea-iodine system giving rise to a substrate-depletive clock reaction. After this delay, iodine in the system starts to build up suddenly to a certain level, where the system remains for quite a while. During this period, hydrolysis of formamidine disulfide as well as the formamidine disulfide-iodine system along with the Dushman reaction and subsequent reactions of the intermediates governs the parallel formation and disappearance of iodine, resulting in a fairly constant absorbance. The kinetic phase mentioned above is then followed by a more slowly increasing sigmoidally shaped profile that is characteristic of autocatalysis-driven clock reactions. HPLC studies have clearly shown that the thiourea dioxide-iodate system is responsible mainly for the latter characteristics. Of course, depending on the initial concentration ratio of the reactants, the absorbance-time curve may level off or reach a maximum followed by a declining phase. With an excess of thiourea, iodine may completely disappear from the solution as a result of the thiourea dioxide-iodine reaction. In the opposite case, with an excess of iodate, the final absorbance reaches a finite value, and at the same time, iodide ion will disappear completely from the solution due to the well-known Dushman (iodide-iodate) reaction. In addition, we have also shown that in the case of the formamidine disulfide-iodine reaction, unexpectedly the triiodide ion is more reactive toward formamidine disulfide than iodine. This feature can readily be interpreted by the enhancement of the rate of formation of the transition complex containing oppositely charged reactants. A 25-step kinetic model is proposed with just 10 fitted parameters to fit the 68 kinetic traces measured in the thiourea-iodate system and the second, but slower, kinetic phase of the thiourea-iodine reaction. The comprehensive kinetic model is constituted in such a way as to remain coherent in quantitatively describing all of the most important characteristics of the formamidine disulfide-iodine, thiourea dioxide-iodine, and thiourea dioxide-iodate systems.

1,3,4-Thiadiazole and 1,2,4-triazole-5-thione derivatives bearing 2-pentyl-5-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-one ring: Synthesis, molecular docking, urease inhibition, and crystal structure.

Two series of 1,3,4-thiadiazole (40a-o) and 1,2,4-triazole-5-thione (41a-l) derivatives bearing a 2-pentyl-5-phenyl-1,2,4-triazole-3-one ring were synthesized and then studied for their urease inhibitory activities using thiourea as a standard drug. Among the two groups, the first group (40a-o) did not show good activity while the second group (41a-l) showed excellent activity. Compound 41j (1091.24 ± 14.02 µM) of the second series of compounds showed lower activity than thiourea, while the remaining 11 compounds (41a-i, k, and l) showed better activity than thiourea (183.92 ± 13.14 µM). Among the 11 compounds, 41b (15.96 ± 2.28 µM) having the 3-F group on the phenyl ring showed the highest inhibitory activity. Urease kinetic studies of 41b, which is the most active compound, determined it to have an un-competitive inhibition potential. Moreover, in silico analysis against urease from jack bean with 27 new heterocyclic compounds and the reference molecule was carried out to see the necessary interactions responsible for urease activity. The docking calculations of all compounds supported stronger binding to the receptor than the reference molecule, with high inhibition constants. In addition, compound 40m was characterized by single-crystal X-ray diffraction analysis. X-ray analysis reveals that the structures of the compound 40m crystallize in the monoclinic P21/c space group with the cell parameters: a = 10.2155(9) Å, b = 22.1709(18) Å, c = 21.4858(17) Å, ß = 99.677(8)°, V = 4797.0(7) Å3 . X-ray diffraction analyses were also performed to gain insights into the role of weak intermolecular interactions and C-H…X (halogen) interactions in compound 40m that influence the crystal packing.

Synthesis, antileishmanial activity and molecular modeling of new 1-aryl/alkyl-3-benzoyl/cyclopropanoyl thiourea derivatives.

Due to the lack of effective vaccine(s) against leishmania and also pharmacokinetics issues of current drugs, it is necessary to discover new antileishmanial agents. Within this particular study, a series of novel 1-aryl/alkyl-3-benzoyl/cyclopropanoyl thiourea derivatives were synthesized (yields 69-84%) and evaluated as antileishmanial compounds (1-11). Synthetic derivatives were subjected to in vitro antileishmanial assessment against Leishmania major promastigotes by colorimetric MTT assay. Compounds 3 (IC50 38.54 µg/mL), 5 (IC50 84.75 µg/mL) and 10 (IC50 70.31 µg/mL) exhibited higher activities after 48 h but were less potent than amphotericin B (IC50 0.19 µg/mL). Antileishmanial activities indicated priority of 5-methyl-4-phenyl thiazole over furyl methyl substituents and 4-phenyl thiazole on thiourea nitrogen. N-myristoyltransferase (NMT) was selected as a validated L. major target for molecular docking studies. In silico results indicated the contribution of hydrophobic, π-stacking and H-bond interactions in binding to target. Most of the synthesized derivatives had lower binding affinities to human NMT (hNMT) than leishmanial enzyme. Docking conformations of top-ranked selective binders (compounds 3 and 5) were subjected to 50 ns MD simulations inside L. major HMT (LmNMT) active site. MD trajectories were used to extract RMSD, RMSF, Rg and durability of intramolecular/intermolecular H-bonds of the complex. It was observed that compound 3 escaped from LmNMT binding site during simulation period and no stable complex could be envisaged. Unlike 3, compound 5 attained stable binding conformation with converged stability parameters. Although mechanistic details for antileishmanial effects of synthesized derivatives are to be explored, current results may be implicated in further structure-guided approach toward potent antileishmanial agents.

Synthesis, Structural Characterization and Biological Activity Evaluation of Novel Cu(II) Complexes with 3-(trifluoromethyl)phenylthiourea Derivatives.

Copper complexes with 1,3-disubstituted thiourea derivatives, all containing 3-(trifluoromethyl)phenyl tail and 1-alkyl/halogen-phenyl substituent, were synthesized. The experimental spectroscopic studies and theoretical calculation revealed that two ligands coordinate to Cu(II) in a bidentate fashion via thiocarbonyl S and deprotonated N atoms of thiourea moiety. Such monomers are characteristic of alkylphenylthiourea complexes, whereas the formation of a sandwich-type dimer is observed for halogeno derivatives. For the first time, the structural identifications of CuN2S2-based complexes using experimental and theoretical X-ray absorption near edge structure are demonstrated. The dimeric halogeno derivatives showed higher antimicrobial activity in comparison with alkylphenylthiourea complexes. The Cu(II) complex of 1-(4-chloro-3-nitrophenyl)-3-[3-(trifluoromethyl)phenyl]thiourea was active against 19 strains of methicillin-resistant Staphylococci (MIC = 2 µg/mL). This derivative acted as a dual inhibitor of DNA gyrase and topoisomerase IV isolated from Staphylococcus aureus. Additionally, complexes of halogenphenylthiourea strongly inhibited the growth of mycobacteria isolated from tuberculosis patients, even fourfold stronger than the reference isoniazid. The complexes exerted weak to moderate antitumor activity (towards SW480, SW620, and PC3) being non-toxic towards normal HaCaT cells.

Intramolecular H-Bonds in an Organocatalyst Enabled an Asymmetric Michael/Alkylation Cascade Reaction to Construct Spirooxindoles Incorporating a Densely Substituted Cyclopropane Motif.

A cascade Michael addition/alkylation reaction between 3-chlorooxindoles and α-cyano chalcones catalyzed using a multifunctional quinine-derived aminoindanol-thiourea substance was investigated. A series of spirooxindoles incorporating a densely substituted cyclopropane motif were efficiently obtained with moderate to excellent diastereo- and enantioselectivity and further transformed to products with versatile structural diversity. Density functional theory (DFT) calculations indicated that the tentative intramolecular hydrogen bonds in the chiral catalyst were crucial for the stereocontrol.

Analysis of 1-Aroyl-3-[3-chloro-2-methylphenyl] Thiourea Hybrids as Potent Urease Inhibitors: Synthesis, Biochemical Evaluation and Computational Approach.

Urease is an amidohydrolase enzyme that is responsible for fatal morbidities in the human body, such as catheter encrustation, encephalopathy, peptic ulcers, hepatic coma, kidney stone formation, and many others. In recent years, scientists have devoted considerable efforts to the quest for efficient urease inhibitors. In the pharmaceutical chemistry, the thiourea skeleton plays a vital role. Thus, the present work focused on the development and discovery of novel urease inhibitors and reported the synthesis of a set of 1-aroyl-3-[3-chloro-2-methylphenyl] thiourea hybrids with aliphatic and aromatic side chains 4a-j. The compounds were characterized by different analytical techniques including FT-IR, 1H-NMR, and 13C-NMR, and were evaluated for in-vitro enzyme inhibitory activity against jack bean urease (JBU), where they were found to be potent anti-urease inhibitors and the inhibitory activity IC50 was found in the range of 0.0019 ± 0.0011 to 0.0532 ± 0.9951 µM as compared to the standard thiourea (IC50 = 4.7455 ± 0.0545 µM). Other studies included density functional theory (DFT), antioxidant radical scavenging assay, physicochemical properties (ADMET properties), molecular docking and molecular dynamics simulations. All compounds were found to be more active than the standard, with compound 4i exhibiting the greatest JBU enzyme inhibition (IC50 value of 0.0019 ± 0.0011 µM). The kinetics of enzyme inhibition revealed that compound 4i exhibited non-competitive inhibition with a Ki value of 0.0003 µM. The correlation between DFT experiments with a modest HOMO-LUMO energy gap and biological data was optimal. These recently identified urease enzyme inhibitors may serve as a starting point for future research and development.

Design, Synthesis, Crystal Structure, In Vitro and In Silico Evaluation of New N'-Benzylidene-4-tert-butylbenzohydrazide Derivatives as Potent Urease Inhibitors.

BACKGROUND: Hydrazides play a vital role in making biologically active compounds in various fields of chemistry. These determine antioxidant, antidepressant, antimalarial, anti-inflammatory, antiglycating, and antimicrobial activity. In the present study, twenty-three new N' benzylidene-4-(tert-butyl)benzohydrazide derivatives (4-26) were synthesized by the condensation of aromatic aldehydes and commercially available 4-(tert-butyl)benzoic acid. All the target compounds were successfully synthesized from good to excellent yield; all synthesized derivatives were characterized via spectroscopic techniques such as HREI-MS and 1H-NMR. Synthesized compounds were evaluated for in vitro urease inhibition. All synthesized derivatives demonstrated good inhibitory activities in the range of IC50 = 13.33 ± 0.58-251.74 ± 6.82 µM as compared with standard thiourea having IC50 = 21.14 ± 0.425 µM. Two compounds, 6 and 25, were found to be more active than standard. SAR revealed that electron donating groups in phenyl ring have more influence on enzyme inhibition. However, to gain insight into the participation of different substituents in synthesized derivatives on the binding interactions with urease enzyme, in silico (computer simulation) molecular modeling analysis was carried out.