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Biomedicine & Pharmacotherapy =... Aug 20232-Azabicycloalkanes: 2-azabicyclo[2.2.1]heptane and 2-azabicyclo[3.2.1]octane were used as a chiral platform for the construction of a set of 1,2,3-triazole, thiourea,...
2-Azabicycloalkanes: 2-azabicyclo[2.2.1]heptane and 2-azabicyclo[3.2.1]octane were used as a chiral platform for the construction of a set of 1,2,3-triazole, thiourea, and ebselen derivatives. Cytotoxicity and antiviral activity studies revealed the most promising potency for selected thioureas.
Topics: Thiourea; Triazoles; Organoselenium Compounds; Antiviral Agents; Structure-Activity Relationship
PubMed: 37224757
DOI: 10.1016/j.biopha.2023.114908 -
Bioorganic & Medicinal Chemistry Jan 2022Tuberculosis (TB) remains a serious public health problem and one of the main concern is the emergence of multidrug-resistant and extensively resistant TB....
Tuberculosis (TB) remains a serious public health problem and one of the main concern is the emergence of multidrug-resistant and extensively resistant TB. Hyper-reactive patients develop inflammatory necrotic lung lesions that aggravate the pathology and facilitate transmission of mycobacteria. Treatment of severe TB is a major clinical challenge that has few effective solutions and patients face a poor prognosis, years of treatment and different adverse drug reactions. In this work, fifteen novel and thirty-one unusual thiourea derivatives were synthesized and evaluated in vitro for their antimycobacterial and anti-inflammatory potential and, in silico for ADMET parameters and for structure-activity relationship (SAR). Thioureas derivatives 10, 15, 16, 28 and 29 that had shown low cytotoxicity and high activities were selected for further investigation, after SAR study. These five thioureas derivatives inhibited Mtb H37Rv growth in bacterial culture and in infected macrophages, highlighting thiourea derivative 28 (MIC 2.0 ± 1.1 and 2.3 ± 1.1 µM, respectively). Moreover, these compounds were active against the hypervirulent clinical Mtb strain M299, in bacterial culture, especially 16, 28 and 29, and in extracellular clumps, highlighting 29, with MIC 5.6 ± 1.2 µM. Regarding inflammation, they inhibited NO through the suppression of iNOS expression, and also inhibited the production of TNF-α and IL-1β. In silico studies were carried out suggesting that these five compounds could be administered by oral route and have low toxicological effects when compared to rifampicin. In conclusion, our data show that, at least, thiourea derivatives 16, 28 and 29 are promising antimycobacterial and anti-inflammatory agents, and candidates for further prospective studies aiming new anti-TB drugs, that can be used on a dual approach for the treatment of severe TB cases associated with exacerbated inflammation.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Antitubercular Agents; Dose-Response Relationship, Drug; Humans; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Severity of Illness Index; Structure-Activity Relationship; Thiourea; Tuberculosis, Pulmonary
PubMed: 34890996
DOI: 10.1016/j.bmc.2021.116506 -
Chemical & Pharmaceutical Bulletin 2021Novel innovative catalytic systems such as hydrogen-bond donors and thiourea hybrid catalysts have been developed for the asymmetric synthesis of biologically important... (Review)
Review
Novel innovative catalytic systems such as hydrogen-bond donors and thiourea hybrid catalysts have been developed for the asymmetric synthesis of biologically important pharmaceuticals and natural products. Benzothiadiazines possess a stronger hydrogen-bond donor ability compared to thioureas and exhibit remarkable catalytic performance for the activation of α,β-unsaturated amides. Hybrid thioureas (bearing an arylboronic acid and an ammonium salt) efficiently promote the hetero-Michael addition to α,β-unsaturated carboxylic acids and the O-alkylation of keto enols with 5-chlorofuran-2(5H)-one. These hybrid catalysts enable the first total synthesis of non-racemic avenaol, a noncanonical strigolactone, as well as the asymmetric synthesis of several pharmaceuticals. In addition, this study discovers unique chemical phenomena (i.e., the dual role of benzoic acid as a boron ligand and a proton shuttle, the chirality switch of products by solvent used, and the dynamic kinetic resolution of a racemic electrophile in an S2-type reaction).
Topics: Benzoic Acid; Boron; Bridged Bicyclo Compounds; Catalysis; Cyclopropanes; Hydrogen Bonding; Kinetics; Ligands; Molecular Structure; Thiourea
PubMed: 34470946
DOI: 10.1248/cpb.c21-00390 -
Molecules (Basel, Switzerland) Nov 2021In this work, two thiourea ligands bearing a phosphine group in one arm and in the other a phenyl group () or 3,5-di-CF substituted phenyl ring () have been prepared and...
In this work, two thiourea ligands bearing a phosphine group in one arm and in the other a phenyl group () or 3,5-di-CF substituted phenyl ring () have been prepared and their coordination to Au and Ag has been studied. A different behavior is observed for gold complexes, a linear geometry with coordination only to the phosphorus atom or an equilibrium between the linear and three-coordinated species is present, whereas for silver complexes the coordination of the ligand as P^S chelate is found. The thiourea ligands and their complexes were explored against different cancer cell lines (HeLa, A549, and Jurkat). The thiourea ligands do not exhibit relevant cytotoxicity in the tested cell lines and the coordination of a metal triggers excellent cytotoxic values in all cases. In general, data showed that gold complexes are more cytotoxic than the silver compounds with , in particular the complexes [Au(PPh)]OTf, the bis(thiourea) [Au()]OTf and the gold-thiolate species [Au(SR)]. In contrast, with better results are obtained with silver species [Ag(PPh)]OTf and the [Ag()]OTf. The role played by the ancillary ligand bound to the metal is important since it strongly affects the cytotoxic activity, being the bis(thiourea) complex the most active species. This study demonstrates that metal complexes derived from thiourea can be biologically active and these compounds are promising leads for further development as potential anticancer agents.
Topics: A549 Cells; Antineoplastic Agents; Coordination Complexes; Gold; HeLa Cells; Humans; Models, Molecular; Silver; Thiourea
PubMed: 34833983
DOI: 10.3390/molecules26226891 -
Journal of the American Chemical Society Aug 2022The mechanism of chiral hydrogen-bond donor (HBD) and hydrogen chloride (HCl) co-catalyzed Prins cyclizations was analyzed through a combination of experimental and...
The mechanism of chiral hydrogen-bond donor (HBD) and hydrogen chloride (HCl) co-catalyzed Prins cyclizations was analyzed through a combination of experimental and computational methods and revealed to involve an unexpected and previously unrecognized mode of alkene activation. Kinetic and spectroscopic studies support the participation of a catalytically active HCl·HBD complex that displays reduced Brønsted acidity relative to HCl alone. Nevertheless, rate acceleration relative to the HCl-catalyzed background reaction as well as high levels of enantioselectivity are achieved. This inverse Brønsted correlation is ascribed to chloride-mediated substrate activation in the rate-limiting and enantiodetermining cyclization transition state. Density functional theory (DFT) calculations, distortion-interaction analysis, and quasiclassical dynamics simulations support a stepwise mechanism in which rate acceleration and enantioselectivity are achieved through the precise positioning of the chloride anion within the active site of the chiral thiourea to enhance the nucleophilicity of the alkene and provide transition-state stabilization through local electric field effects. This mode of selective catalysis through anion positioning likely has general implications for the design of enantioselective Brønsted acid-catalyzed reactions involving π-nucleophiles.
Topics: Alkenes; Anions; Catalysis; Chlorides; Cyclization; Halogens; Hydrochloric Acid; Stereoisomerism; Thiourea
PubMed: 35994741
DOI: 10.1021/jacs.2c06688 -
Science (New York, N.Y.) Nov 2021A strategy that facilitates the construction of a wide variety of trisubstituted stereocenters through a catalytically accessed common chiral intermediate could prove...
A strategy that facilitates the construction of a wide variety of trisubstituted stereocenters through a catalytically accessed common chiral intermediate could prove highly enabling for the field of synthetic chemistry. We report the discovery of enantioselective, catalytic 1,2-boronate rearrangements for the synthesis of α-chloro pinacol boronic esters from readily available boronic esters and dichloromethane. The chiral building blocks produced in these reactions can undergo two sequential stereospecific elaborations to generate a wide assortment of trisubstituted stereocenters. The enantioselective reaction is catalyzed by a lithium-isothiourea-boronate complex, which is proposed to promote rearrangement through a dual–lithium-induced chloride abstraction orchestrated by Lewis basic functionality on the catalyst scaffold.
Topics: Boronic Acids; Catalysis; Chemistry Techniques, Synthetic; Esters; Lithium; Molecular Structure; Stereoisomerism; Thiourea
PubMed: 34735250
DOI: 10.1126/science.abm0386 -
British Medical Journal Jun 1977
Topics: Humans; Noxythiolin; Peritonitis; Thiourea; Tissue Adhesions
PubMed: 871723
DOI: 10.1136/bmj.1.6077.1664-d -
Molecules (Basel, Switzerland) Oct 2022Synthesis of thiazolidinone based on quinolone moiety was established starting from 4-hydroxyquinol-2-ones. The strategy started with the reaction of ethyl bromoacetate...
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 ,-disubstituted thioureas. Finally, on subjecting the ,-disubstituted thioureas with dialkyl acetylenedicarboxylates, cyclization occurred, and thiazolidinone derivatives were obtained in good yields. The two series based on quinolone moiety, one containing ,-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 -methyl quinolonyl moiety exhibited a superior effect, since it was proved to be the most potent inhibitor in the present series achieving (IC = 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 ,-disubstituted thiourea.
Topics: Urease; Thiourea; Molecular Docking Simulation; Quinolones; Ligands; Enzyme Inhibitors; Structure-Activity Relationship; Anti-Bacterial Agents; Hydrazines; Isothiocyanates; Molecular Structure
PubMed: 36296723
DOI: 10.3390/molecules27207126 -
Molecules (Basel, Switzerland) Jun 2022Reaction of two equivalents of the bulky 1,3-bis(2,6-diethylphenyl)thiourea ligand () with MX (being M = Cu, Ag+; and X = Cl, Br, I) in acetonitrile afforded neutral...
Mononuclear Tricoordinate Copper(I) and Silver(I) Halide Complexes of a Sterically Bulky Thiourea Ligand and a Computational Insight of Their Interaction with Human Insulin.
Reaction of two equivalents of the bulky 1,3-bis(2,6-diethylphenyl)thiourea ligand () with MX (being M = Cu, Ag+; and X = Cl, Br, I) in acetonitrile afforded neutral complexes of the type [MXL] [CuClL].2CHCN (); [CuBrL].2CHCN (); [CuIL] (): [AgClL] (); [AgBrL] () and [AgIL] (). The two aromatic groups in free ligand were found to be with respect to the thiourea unit, which was a reason to link the ligand molecules via intermolecular hydrogen bonding. Intramolecular hydrogen bonding was observed in all metal complexes. The copper complexes and are acetonitrile solvated and show not only intra- but also intermolecular hydrogen bonding between the coordinated thiourea and the solvated acetonitrile molecules. Silver complexes reported here are the first examples of structurally characterized tricoordinated thiourea-stabilized monomeric silver(I) halides. Molecular docking studies were carried out to analyze the binding modes of the metal complexes inside the active site of the human insulin (HI) protein. Analysis of the docked conformations revealed that the electrostatic and aromatic interactions of the protein -terminal residues (i.e., Phe and His) may assist in anchoring and stabilizing the metal complexes inside the active site. According to the results of docking studies, the silver complexes exhibited the strongest inhibitory capability against the HI protein, which possesses a deactivating group, directly bonded to silver. All compounds were fully characterized by elemental analysis, NMR spectroscopy, and molecular structures of the ligand, and five out of six metal complexes were also confirmed by single-crystal X-ray diffraction.
Topics: Acetonitriles; Coordination Complexes; Copper; Crystallography, X-Ray; Humans; Insulins; Ligands; Molecular Docking Simulation; Silver; Thiourea
PubMed: 35807475
DOI: 10.3390/molecules27134231 -
Report on Carcinogens : Carcinogen... 2011
Topics: Animals; Antithyroid Agents; Carcinogens; Free Radical Scavengers; Humans; Neoplasms; Thiourea
PubMed: 21863107
DOI: No ID Found