Visible-Light-Driven Method for the Selective Synthesis of Amides and N-Acylureas from Carboxylic Acids and Thioureas.

In this work, we developed a visible-light-driven method for the selective synthesis of amides and N-acylureas from carboxylic acids and thioureas. This protocol was featured as avoidance of additional oxidants and transition metal catalysts, simple manipulations, low cost, broad substrate scope, and good functional group tolerance. As only oxygen serves as the oxidation reagent, this method provides a promising synthesis candidate for the formation of N-aryl amides and N-acylureas, including late-stage functionalization of complex pharmaceutical molecules and biologically active molecules.

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.

Synthesis of Sterically Encumbered Thiourea S-Oxides through Direct Thiourea Oxidation.

Thiourea S-oxides can be viewed as formal analogs of the currently unknown diamino-substituted Criegee intermediates (urea O-oxides). However, the preparation of such S-oxides is rather challenging, and the direct oxidation of thioureas typically only leads to formation of desulfurized products. Employing the accurate revDSD-PBEP86-D4 double hybrid density functional, it was found that the peracid mediated oxidation of thiourea S-oxides exhibits a lower reaction barrier than the oxidation of the corresponding thiourea itself in contrast to most other ordinary thioketones. The undesired overoxidation reactivity, which is associated with strong π-donation from the thiourea's nitrogen atoms, can be partially suppressed by introduction of bulky substituents and the utilization of protic solvents. In this regard, we managed to prepare two sterically encumbered thiourea S-oxides in isolated yields of 35-40 %. The S-oxides are stable in the solid state and in alcoholic solutions at room temperature for extended periods of time, but swiftly decompose in aprotic solvents by disproportionation. A dimesityl-substituted thiourea S-oxide complexed with residual mCBA could be characterized by means of X-ray crystallography, confirming the importance of hydrogen bonding in the stabilization of the amino-substituted C=S+ -O- moiety.

(Thio)urea Containing Chiral Ammonium Salt Catalysts.

(Thio)-urea-containing bifunctional quaternary ammonium salts emerged as powerful non-covalently interacting organocatalysts over the course of the last decade. The most commonly employed catalysts in this field are either based on Cinchona alkaloids, α-amino acids, or trans-cyclohexane-1,2-diamine. Our group has been heavily engaged in the design and use of such catalysts, i. e. trans-cyclohexane-1,2-diamine-based ones for around 10 years now, and it is therefore the intention of this short personal account to provide an overview of the, at least in our opinion, most significant and pioneering achievements in this field by looking on catalyst design and asymmetric method development, with a special focus on our own contributions.

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.

Design, synthesis, biochemical and in silico characterization of novel naphthalene-thiourea conjugates as potential and selective inhibitors of alkaline phosphatase.

Naphthalene ring is present in a number of FDA-approved, commercially available medications, including naphyrone, terbinafine, propranolol, naproxen, duloxetine, lasofoxetine, and bedaquiline. By reacting newly obtained 1-naphthoyl isothiocyanate with properly modified anilines, a library of ten novel naphthalene-thiourea conjugates (5a-5j) were produced with good to exceptional yields and high purity. The newly synthesized compounds were observed for their potential to inhibit alkaline phosphatase (ALP) and scavenge free radicals. All of the investigated compounds displayed a more powerful inhibitory profile than the reference agent, KH2PO4 particularly compound 5h and 5a exhibited strong inhibitory potential against ALP with IC50 value of 0.365 ± 0.011 and 0.436 ± 0.057 µM respectively. In addition, Lineweaver-Burk plots revealed the non-competitive inhibition mode of the most powerful derivative i.e., 5h (ki value 0.5 µM). To investigate the putative binding mode of selective inhibitor interactions, molecular docking was performed. It is recommended that future research will focus on developing selective alkaline phosphatase inhibitors by modifying the structure of the 5h derivative.

Synthesis of novel hybrid pharmacophore of N-((4-sulfamoylphenyl)carbamothioyl)alkanamides as potent carbonic anhydrase-II and 15-lipoxygenase inhibitors.

A series of N-((4-sulfamoylphenyl)carbamothioyl)alkanamides (5a-j) were synthesized by the reaction of sulphanilamide in dry acetone with freshly prepared alkyl and acyl isothiocyanates (5a-j). The structures of products were confirmed by IR, 1 H, and 13 C NMR. The synthesized compounds were screened as inhibitors of the bovine erythrocyte carbonic anhydrase isoform II (bCA II) and 15-lipoxygenase enzyme (15-LOX). Most of the derivatives showed significant activity against bCA-II while only few compounds were found active against 15-LOX. Molecular docking studies of most active compounds were carried out against bCA II as well as 15-LOX to rationalize the binding mode and interactions of compound in the active sites. Additionally, the pharmacokinetic properties of the compounds were predicted through computational tools, which reflect that these compounds possess acceptable pharmacokinetic profile and good drug-likeness.

Synthesis and Identification of New N,N-Disubstituted Thiourea, and Thiazolidinone Scaffolds Based on Quinolone Moiety as Urease Inhibitor.

Synthesis of thiazolidinone based on quinolone moiety was established starting from 4-hydroxyquinol-2-ones. The strategy started with the reaction of ethyl bromoacetate with 4-hydroxyquinoline to give the corresponding ethyl oxoquinolinyl acetates, which reacted with hydrazine hydrate to afford the hydrazide derivatives. Subsequently, hydrazides reacted with isothiocyanate derivatives to give the corresponding N,N-disubstituted thioureas. Finally, on subjecting the N,N-disubstituted thioureas with dialkyl acetylenedicarboxylates, cyclization occurred, and thiazolidinone derivatives were obtained in good yields. The two series based on quinolone moiety, one containing N,N-disubstituted thioureas and the other containing thiazolidinone functionalities, were screened for their in vitro urease inhibition properties using thiourea and acetohydroxamic acid as standard inhibitors. The inhibition values of the synthesized thioureas and thiazolidinones exhibited moderate to good inhibitory effects. The structure-activity relationship revealed that N-methyl quinolonyl moiety exhibited a superior effect, since it was proved to be the most potent inhibitor in the present series achieving (IC50 = 1.83 ± 0.79 µM). The previous compound exhibited relatively much greater activity, being approximately 12-fold more potent than thiourea and acetohydroxamic acid as references. Molecular docking analysis showed a good protein-ligand interaction profile against the urease target (PDBID: 4UBP), emphasizing the electronic and geometric effect of N,N-disubstituted thiourea.

QSAR-Guided Proposition of N-(4-methanesulfonyl)Benzoyl-N'-(Pyrimidin-2-yl)Thioureas as Effective and Safer Herbicides.

Chlorinated agrochemicals play a major role in toxicity due especially to the labile C - Cl bond and high lipophilicity of organochlorines. In turn, urea and thiourea herbicides are widely used for weed control. A series of substituted N-benzoyl-N'-pyrimidin-2-yl thioureas has been recently synthesized and tested against Brassica napus L., demonstrating promising herbicidal activities, particularly for chlorinated derivatives. We have therefore modeled these activities using multivariate image analysis applied to quantitative structure-activity relationships (MIA-QSAR) to find out a significant and reliable correlation between measured and predicted inhibition of B. napus L. root growth (%) and, ultimately, to propose effective, non-chlorinated and/or less lipophilic N-(4-methanesulfonyl)benzoyl-N'-(pyrimidin-2-yl)thiourea candidates. The model was found to be predictive, giving an average r2pred in the external validation of 0.833. The predicted data for the proposed herbicides, interpreted in terms of MIA-plots of the chemical moieties responsible for bioactivity and supported by docking studies towards the photosystem II enzyme, suggest that substituents at both R1 and R2 positions modulate the agrochemical (R1 = Cl increases and R2 = OR decreases bioactivity) and environmental friendship (particularly with R2 = OH) performances of this class of compounds.

Photoredox Generation of Isothiouronyl Radical Cations: A New Platform in Covalent Radical Catalysis.

Thiyl radicals offer unique catalytic patterns for the direct covalent activation of alkenes. However, important limitations in terms of structural diversity and handling have hampered the routine use of thiyl radicals in covalent radical catalysis. Herein, we report a new class of cationic sulfur-centered radicals to achieve covalent radical catalysis. Their generation from highly modular thioureas by photoredox catalysis make their utilization very simple and reliable. The synthetic potential and the versatility of the catalytic system were finally evaluated in a (3+2)-radical cascade between vinylcyclopropanes and olefins.

Exploring Amantadine Derivatives as Urease Inhibitors: Molecular Docking and Structure-Activity Relationship (SAR) Studies.

This article describes the design and synthesis of a series of novel amantadine-thiourea conjugates (3a-j) as Jack bean urease inhibitors. The synthesized hybrids were assayed for their in vitro urease inhibition. Accordingly, N-(adamantan-1-ylcarbamothioyl)octanamide (3j) possessing a 7-carbon alkyl chain showed excellent activity with IC50 value 0.0085 ± 0.0011 µM indicating that the long alkyl chain plays a vital role in enzyme inhibition. Whilst N-(adamantan-1-ylcarbamothioyl)-2-chlorobenzamide (3g) possessing a 2-chlorophenyl substitution was the next most efficient compound belonging to the aryl series with IC50 value of 0.0087 ± 0.001 µM. The kinetic mechanism analyzed by Lineweaver-Burk plots revealed the non-competitive mode of inhibition for compound 3j. Moreover, in silico molecular docking against target protein (PDBID 4H9M) indicated that most of the synthesized compounds exhibit good binding affinity with protein. The compound 3j forms two hydrogen bonds with amino acid residue VAL391 having a binding distance of 1.858 Å and 2.240 Å. The interaction of 3j with amino acid residue located outside the catalytic site showed its non-competitive mode of inhibition. Based upon these results, it is anticipated that compound 3j may serve as a lead structure for the design of more potent urease inhibitors.

Synthesis and Applications of Carbohydrate-Based Organocatalysts.

Organocatalysis is a very useful tool for the asymmetric synthesis of biologically or pharmacologically active compounds because it avoids the use of noxious metals, which are difficult to eliminate from the target products. Moreover, in many cases, the organocatalysed reactions can be performed in benign solvents and do not require anhydrous conditions. It is well-known that most of the above-mentioned reactions are promoted by a simple aminoacid, l-proline, or, to a lesser extent, by the more complex cinchona alkaloids. However, during the past three decades, other enantiopure natural compounds, the carbohydrates, have been employed as organocatalysts. In the present exhaustive review, the detailed preparation of all the sugar-based organocatalysts as well as their catalytic properties are described.

Searching for novel hydrogen sulfide donors: The vascular effects of two thiourea derivatives.

The gasotransmitter hydrogen sulfide (H2S) is involved in the regulation of the vascular tone and an impairment of its endogenous production may play a role in hypertension. Thus, the administration of exogenous H2S may be a possible novel and effective strategy to control blood pressure. Some natural and synthetic sulfur compounds are suitable H2S-donors, exhibiting long-lasting H2S release; however, novel H2S-releasing agents are needed to improve the pharmacological armamentarium for the treatment of cardiovascular diseases. For this purpose, N-phenylthiourea (PTU) and N,N'-diphenylthiourea (DPTU) compounds have been investigated as potential H2S-donors. The thioureas showed long-lasting H2S donation in cell free environment and in human aortic smooth muscle cells (HASMCs). In HASMCs, DPTU caused membrane hyperpolarization, mediated by activation of KATP and Kv7 potassium channels. The thiourea derivatives promoted vasodilation in rat aortic rings, which was abolished by KATP and Kv7 blockers. The vasorelaxing effects were also observed in angiotensin II-constricted coronary vessels. In conclusion, thiourea represents an original H2S-donor functional group, which releases H2S with slow and long lasting kinetic, and promotes typical H2S-mediated vascular effects. Such a moiety will be extremely useful for developing original cardiovascular drugs and new chemical tools for investigating the pharmacological roles of H2S.

Chiral Thioureas-Preparation and Significance in Asymmetric Synthesis and Medicinal Chemistry.

For almost 20 years, thioureas have been experiencing a renaissance of interest with the emerged development of asymmetric organocatalysts. Due to their relatively high acidity and strong hydrogen bond donor capability, they differ significantly from ureas and offer, appropriately modified, great potential as organocatalysts, chelators, drug candidates, etc. The review focuses on the family of chiral thioureas, presenting an overview of the current state of knowledge on their synthesis and selected applications in stereoselective synthesis and drug development.

1,3,5-Triaryl-1,3,5-Triazinane-2,4,6-Trithiones: Synthesis, Electronic Structure and Linear Optical Properties.

The synthesis of four new 1,3,5-triaryl-1,3,5-triazinane-2,4,6-trithione derivatives (thioisocyanurates) and two new partially thionated analogues from the corresponding 1,3,5-triaryl-1,3,5-triazinane-2,4,6-triones (isocyanurates) is reported, together with their spectroscopic properties. DFT calculations and comparison with the corresponding isocyanurates evidence the impact of the oxygen-for-sulfur replacement on the electronic structure and linear optical properties of these heterocycles. A bathochromic shift of the absorption bands and more efficient quenching of the fluorescence was observed.

Synthesis, Structure and Cytotoxicity Testing of Novel 7-(4,5-dihydro-1H-imidazol-2-yl)-2-aryl-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-Imine Derivatives.

The appropriate 1-arylhydrazinecarbonitriles 1a-c are subjected to the reaction with 2-chloro-4,5-dihydro-1H-imidazole (2), yielding 7-(4,5-dihydro-1H-imidazol-2-yl)-2-aryl-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-imines 3a-c, which are subsequently converted into the corresponding amides 4a-e, 8a-c, sulfonamides 5a-n, 9, ureas 6a-I, and thioureas 7a-d. The structures of the newly prepared derivatives 3a-c, 4a-e, 5a-n, 6a-i, 7a-d, 8a-c, and 9 are confirmed by IR, NMR spectroscopic data, as well as single-crystal X-ray analyses of 5e and 8c. The in vitro cytotoxic potency of these compounds is determined on a panel of human cancer cell lines, and the relationships between structure and antitumor activity are discussed. The most active 4-chloro-N-(2-(4-chlorophenyl)-7-(4,5-dihydro-1H-imidazol-2-yl)-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-ylidene)benzamide (4e) and N-(7-(4,5-dihydro-1H-imidazol-2-yl)-2-(p-tolyl)-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-ylidene)-[1,1'-biphenyl]-4-sulfonamide (5l) inhibits the growth of the cervical cancer SISO and bladder cancer RT-112 cell lines with IC50 values in the range of 2.38-3.77 µM. Moreover, N-(7-(4,5-dihydro-1H-imidazol-2-yl)-2-phenyl-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-ylidene)-4-phenoxybenzenesulfonamide (5m) has the best selectivity towards the SISO cell line and induces apoptosis in this cell line.

3-Aminobenzenesulfonamides incorporating acylthiourea moieties selectively inhibit the tumor-associated carbonic anhydrase isoform IX over the off-target isoforms I, II and IV.

We describe the synthesis of a series of novel 1-aroyl/acyl-3-(3-aminosulfonylphenyl) thioureas (4a-k) acting as human carbonic anhydrase (hCA, EC 4.2.1.1) inhibitors. Reaction of alkyl/aryl isothiocyanates with 3-aminobenzenesulfonamide afforded a series of the title compounds incorporating a variety of short as well as highly lipophilic long tails. The newly synthesized sulfonamides were evaluated against 4 physiologically relevant CA isoforms (hCA I, II, IV, and IX). Several compounds showed interesting inhibitory activity. The tumor-associated hCA IX was the most sensitive isoform to inhibition with these compounds, with KIs in the range of 21.5-44.0 nM and selectivity ratios over the major cytosolic isoform hCA II in the range of 3.35-37.3. The sulfonamides incorporating the phenylacetylthioureido and pentadecanoylthioureido moieties were the most hCA IX-selective inhibitors detected in this work, making them of interest for further investigations.

Synthesis, molecular docking and kinetic studies of novel quinolinyl based acyl thioureas as mushroom tyrosinase inhibitors and free radical scavengers.

The enzyme tyrosinase plays a vital role in melanin biosynthesis and enzymatic browning of vegetables and fruits. A series of novel quinolinyl thiourea analogues (11a-j) were synthesized by reaction of 3-aminoquinoline and corresponding isothiocyanates, in moderate to excellent yields with different substitutions and their inhibitory effect on mushroom tyrosinase and free radical scavenging activity were evaluated. The compound N-(quinolin-3-ylcarbamothioyl)hexanamide (11c) exhibited the maximum tyrosinase inhibitory effect (IC50 = 0.0070 ±â€¯0.0098 µM) compared to other derivatives and the reference Kojic acid (IC50 = 16.8320 ±â€¯0.0621 µM). The docking studies were carried out and the compound (11c) showed most negative estimated free energy of -7.2 kcal/mol in mushroom tyrosinase active site. The kinetic analysis revealed that the compound (11c) inhibits the enzyme tyrosinase non-competitively to form the complex of enzyme and inhibitor. The results revealed that 11c could be identified as putative lead compound for the design of efficient tyrosinase inhibitors.

Investigation on the effect of alkyl chain linked mono-thioureas as Jack bean urease inhibitors, SAR, pharmacokinetics ADMET parameters and molecular docking studies.

The increasing resistance of pathogens to common antibiotics, as well as the need to control urease activity to improve the yield of soil nitrogen fertilization in agricultural applications, has stimulated the development of novel classes of molecules that target urease as an enzyme. In this context, the newly developed compounds on the basis of 1-heptanoyl-3-arylthiourea family were evaluated for Jack bean urease enzyme inhibition activity to validate their role as potent inhibitors of this enzyme. 1-Heptanoyl-3-arylthioureas were obtained in excellent yield and characterized through spectral and elemental analysis. All the compounds displayed remarkable potency against urease inhibition as compared to thiourea standard. It was found that novel compounds fulfill the criteria of drug-likeness by obeying Lipinski's rule of five. Particularly compound 4a and 4c can serve as lead molecules in 4D (drug designing discovery and development). Kinetic mechanism and molecular docking studies also carried out to delineate the mode of inhibition and binding affinity of the molecules.

The 1,10-Phenanthroline Ligand Enhances the Antiproliferative Activity of DNA-Intercalating Thiourea-Pd(II) and -Pt(II) Complexes Against Cisplatin-Sensitive and -Resistant Human Ovarian Cancer Cell Lines.

Ovarian cancer is the most lethal gynecological malignancy, often because of the frequent insurgence of chemoresistance to the drugs currently used. Thus, new therapeutical agents are needed. We tested the toxicity of 16 new DNA-intercalating agents to cisplatin (cDDP)-sensitive human ovarian carcinoma cell lines and their resistant counterparts. The compounds were the complexes of Pt(II) or Pd(II) with bipyridyl (bipy) and phenanthrolyl (phen) and with four different thiourea ancillary ligands. Within each of the four series of complexes characterized by the same thiourea ligand, the Pd(phen) drugs invariably showed the highest anti-proliferative efficacy. This paralleled both a higher intracellular drug accumulation and a more efficient DNA intercalation than all the other metal-bidentate ligand combinations. The consequent inhibition of topoisomerase II activity led to the greatest inhibition of DNA metabolism, evidenced by the inhibition of the expression of the folate cycle enzymes and a marked perturbation of cell-cycle distribution in both cell lines. These findings indicate that the particular interaction of Pd(II) with phenanthroline confers the best pharmacokinetic and pharmacodynamic properties that make this class of DNA intercalators remarkable inhibitors, even of the resistant cell growth.