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At least 199 records · Page 11Linked to original sources
PubMed2001

Some 3-thioxo/alkylthio-1,2,4-triazoles with a substituted thiourea moiety as possible antimycobacterials.

A series of novel N-alkyl/aryl-N'-[4-(4-alkyl/aryl-2,4-dihydro-3H-1,2,4-triazole-3-thione-5-yl)phenyl]thioureas 1-19 and three S-alkylated representatives of the former, N-alkyl/aryl-N'-[4-(3-aralkylthio-4-alkyl/aryl-4H-1,2,4-triazole-5-yl)phenyl]thioureas 20-22, were synthesized and tested for antimycobacterial activity against Mycobacterium tuberculosis H37Rv as well as Mycobacterium fortuitum ATCC 6841 which is a rapid growing opportunistic pathogen. Compounds 4 and 9-11 were found to possess the same MIC value with that of Tobramycin against M. fortuitum ATCC 6841 whereas 1-3 and 21 had positive response against M. tuberculosis H37Rv at varying degrees. Compound 21 was identified as the most potent derivative of the 1-22 series by an MIC value of 6.25 microg/mL and selectivity index of 1.6.

Animals↗
PubMed1999

Rational design of N-[2-(2,5-dimethoxyphenylethyl)]-N'-[2-(5-bromopyridyl)]-thiourea (HI-236) as a potent non-nucleoside inhibitor of drug-resistant human immunodeficiency virus.

The novel thiourea compound N-[2-(2,5-dimethoxyphenylethyl)]-N'-[2-(5-bromopyridyl)]-thi ourea (HI-236) targeting the non-nucleoside inhibitor (NNI) binding pocket of HIV-1 reverse transcriptase (RT) was rationally designed using a computer model of the NNI binding pocket. The NNI binding pocket model takes into consideration changes in binding pocket size, shape, and changes in residue character that result from clinically-observed NNI resistance-associated mutations of HIV RT. RT assays revealed that HI-236 was not only more potent than trovirdine, MKC-442, and AZT against the drug-sensitive HIV-1 strain HTLV(IIIB), it was also 50-100 times more effective than delavirdine or nevirapine and twice as effective as our recently reported lead compound N-[2-(2-fluorophenethyl)]-N'-[2-(5-bromopyridyl)]-thiourea (HI-240) against the NNI-resistant Y181C mutant HIV-1 strain A17. Most importantly, HI-236 was highly effective against the multidrug-resistant HIV-1 strain RT-MDR with multiple mutations involving the RT residues 74V, 41L, 106A, and 215Y. The activity of HI-236 against RT-MDR was superior to that of other anti-HIV agents tested, which are listed in the following order: HI-236 (IC50: 5 nM) > HI-240 (IC50: 6 nM) > trovirdine (IC50: 20 nM) > AZT (IC50: 150 nM) > MKC-442 (IC50: 300 nM) > delavirdine (IC50: 400 nM) > nevirapine (IC50: 5 microM).

Anti-HIV Agents↗
PubMed2001

N-(3-Acyloxy-2-benzylpropyl)-N'-(4-hydroxy-3-methoxybenzyl) thiourea derivatives as potent vanilloid receptor agonists and analgesics.

A series of N-(3-acyloxy-2-benzylpropyl)-N'-(4-hydroxy-3-methoxybenzyl) thiourea derivatives were investigated as vanilloid receptor ligands in an effort to discover a novel class of analgesics. The proposed pharmacophore model of resiniferatoxin. which includes the C20 homovanillic moiety, the C3-carbonyl and the orthoester phenyl ring as key pharmacophoric groups, was utilized as a guide for drug design. The compounds were synthesized after several steps from diethylmalonate and evaluated in vitro in a receptor binding assay and in a capsaicin-activated channel assay. Additional evaluation of analgesic activity, anti-inflammatory activity and pungency was conducted in animal models by the writhing test, the ear edema assay, and the eye-wiping test, respectively. Among the new compounds, 23 and 28 were found to be the most potent receptor agonists of the series with Ki values of 19 nM and 11 nM, respectively. Their strong in vitro potencies were also reflected by an excellent analgesic profile in animal tests with ED50 values of 0.5 microg kg for 23 and 1.0 microg/kg for 28. Relative to capsaicin these compounds appear to be ca. 600 and 300 times more potent. Both 23 and 28 were found to be less pungent than capsaicin based on the eye-wiping test. However, the compounds did not show significant anti-inflammatory activity. A molecular modeling study comparing the energy-minimized structures of resiniferatoxin and 35 demonstrated a good correlation in the spatial disposition of the corresponding key pharmacophores. The thioureas described in this investigation, which were designed as simplified resiniferatoxin surrogates, represent a novel class of potent vanilloid receptor agonists endowed with potent analgesic activity and reduced pungency.

Analgesics↗
PubMed2002

3-D-QSAR analysis of N-(3-acyloxy-2-benzylpropyl)-N'-dihydroxytetrahydrobenzazepine and tetrahydroisoquinoline and N-(3-acyloxy-2-benzylpropyl)-N'-(4-hydroxy-3-methoxybenzyl) thioureas analogues as potent vanilloid receptor ligands.

3-D-Quantitative structure--activity relationships of N-(3-acyloxy-2-benzylpropyl)-N'-dihydroxytetrahydro-benzazepine and tetrahydroisoquinoline and N-(3-acyloxy-2-benzylpropyl)-N'-(4-hydroxy-3-methoxybenzyl) thiourea analogues as potent vanilloid receptor ligands were investigated using the CoMFA and the COMSIA methods. The best CoMFA model obtained in this study from 29 substituted thiourea analogues is a two-component model with the following statistics. R(2)((cv))=0.407 and RMSE((cv))=0.532 for the cross-validation, and R(2)=0.705 and RMSE=0.375 for the fitted. The best COMSIA model obtained from the same 29 compounds is a two-component model with the following statistics: R(2)((cv))=0.336 and RMSE((cv))=0.563 for the cross-validation, and R(2)=0.693 and RMSE=0.382 for the fitted.

Analgesics↗
PubMed2002

Infrared spectra of new Re(III) complexes with thiourea derivatives.

Complexes of the type [Re(III)L6]X3, with L = thiourea, N-methylthiourea, N-ethylthiourea or N,N'-dimethytlthiourea and X = Cl- or PF6-, were prepared as suitable precursors for the synthesis of new rhenium complexes potentially useful in nuclear medicine. The infrared (IR) spectra of these complexes were recorded and analyzed and a general vibrational pattern for Re(III) complexes with thiourea derivatives could be established. Approximate assignments for N-allylthiourea and N-ethylthiourea are also proposed for the first time. The synthesis of the new complex [Re(III)(N-allylthiourea)6](PF6)3 is also reported, and information about its structural characteristics was obtained comparing its IR spectrum with those of the other complexes of the investigated series.

Radioisotopes↗
PubMed2005

Thiourea-catalyzed enantioselective cyanosilylation of ketones.

The new chiral amino thiourea catalyst 3d promotes the highly enantioselective cyanosilylation of a wide variety of ketones. The hindered tertiary amine substituent plays a crucial role with regard to both stereoinduction and reactivity, suggesting a cooperative mechanism involving electrophile activation by thiourea and nucleophile activation by the amine.

Catalysis↗
PubMed2005

Thiourea-based bifunctional organocatalysis: supramolecular recognition for living polymerization.

A versatile, metal-free, organocatalytic approach to the living ring-opening polymerization of lactide using a bifunctional thiourea-tertiary amine catalyst is described. Mild and highly selective polymerization conditions produced poly(lactides) with predictable molecular weights and extremely narrow polydispersities ( approximately 1.05), characteristic of a living polymerization. The extraordinary selectivity of this catalyst system for polymerization relative to transesterification is remarkably unusual. The low polydispersities and exceptional control observed are a consequence of selective transesterification of lactide relative to the open chain esters. Presumably, the ring strain of lactide provides both a driving force for the polymerization and a kinetic preference for polymerization relative to transesterification with catalyst. We postulate that the initiating/propagating alcohol is activated by acid-base interaction with the tertiary amine moiety and the carbonyl of the lactide monomer is simultaneously activated by hydrogen bonding to the thiourea moiety of the catalyst.

Amines↗
PubMed2006

Highly enantioselective direct conjugate addition of ketones to nitroalkenes promoted by a chiral primary amine-thiourea catalyst.

Primary amine-thiourea derivative 1 is an active and highly enantioselective catalyst for the conjugate addition of ketones to nitroalkenes. Broad substrate scope is described, with nitroalkenes bearing either aromatic or aliphatic substituents and a wide variety of ketones shown to be useful reacting partners. Ethyl ketones react preferentially, generating anti products with methyl-bearing stereocenters with good-to-excellent diastereoselectivity. An enamine mechanism is indicated, with cooperative activation of the electrophile by the thiourea and of the ketone by the primary amine.

Alkenes↗
PubMed1983

Pyridazinones. 2. Synthesis and antisecretory and antiulcer activities of thiourea and 2-cyanoguanidine derivatives.

In an effort to develop new types of antiulcer agents, we synthesized a series of novel 2-[omega-(thioureido)alkyl]- and 2-[omega-(cyanoguanidino)alkyl]-3(2H)-pyridazinone derivatives. All target compounds were evaluated for gastric antisecretory activity in the pylorus-lygated rat by the method of Shay, and selected compounds were evaluated in the stress-induced ulcer test in rats. Structure-activity relationships were established. Two series of the compounds had significant activity in antisecretory and/or antiulcer tests. The molecular features essential for the activities are a thiourea group or a 2-cyanoguanidine group, a phenyl group in the C-6 position of the 3(2H)-pyridazinone ring, a four-carbon chain length between the 3(2H)-pyridazinone ring and the functional group, and a methyl group at the N-3 position of the functional group. Among them, the three thiourea derivatives (24, 26, and 38) and the six 2-cyanoguanidine derivatives (61, 62, 65, 75, 85, and 86) had the most potent antisecretory and/or antiulcer activities. These compounds are not histamine H2-receptor antagonists.

Acetylcholine↗
PubMed1996

Synthesis and antihypertensive activity of N-(alkyl/alkenyl/aryl)-N-heterocyclic ureas and thioureas.

A variety of N-(alkyl/alkenyl/aryl-N-heterocyclic ureas and thioureas were synthesized as potential antihypertensives. The selected heterocyclic nuclei were the 6-substituted quinoline and the pyridine. Eleven synthesized compounds and seven related compounds in the series were evaluated orally at a dose of 100 mg/kg in conscious deoxycorticosterone acetate/saline-treated hypertensive rats by the tail-cuff method. Seventeen out of the eighteen tested compounds possessed significant antihypertensive activity (p < 0.05). 1-n-Propyl-3-[2'-(6-methoxy)quinolyl]urea (9), showing 29.1% reduction in systolic blood pressure, was the most active compound in the series. Two other compounds producing a fall in systolic blood pressure of the same magnitude were 1-allyl-3-[2'-(6-methyl)quinolyl]thiourea (4) and 1-n-propyl-3-[(2'-pyridyl)methyl]urea (17). Compound 17 with rapid onset caused significant relaxation (p < 0.01) of isolated rabbit femoral artery and guinea pig atrium but had no effect on heart rate. However, none of these exhibited higher potency than prazosin (5 mg/kg). The potency, onset, and duration of action improved when the heterocyclic nucleus was pyridine.

Animals↗
PubMed2005

A highly efficient synthesis of the FGH ring of micrandilactone A. Application of thioureas as ligands in the Co-catalyzed Pauson-Khand reaction and Pd-catalyzed carbonylative annulation.

The functionalized FGH ring system of micrandilactone A was successfully constructed in high selectivity and good yields. The key reactions in our strategy are the Co-thiourea-catalyzed stereoselective, intramolecular Pauson-Khand reaction and Pd-thiourea-catalyzed stereoselective, intramolecular annulation. [structure: see text]

Catalysis↗
PubMed2004

Hydrogen bonding patterns of calix[4]arenes with thiourea functionalities in solution and in the solid state.

[structure: see text] We have synthesized a number of calix[4]arene derivatives presenting thiourea functional groups at their upper rims by the condensation of a 1,3-di(p-amino)calix[4]arene with alkyl isothiocyanates. Mono- and dithiourea-substituted calix[4]arenes were prepared selectively in good yields, and homocoupling of the former led to calix[4]arene dimers with a thiourea linker. X-ray crystallography revealed interesting intra- and intermolecular hydrogen bonding patterns. (1)H NMR data and computational studies also provided some insight into the hydrogen bonding patterns.

Calixarenes↗
PubMed2005

Chiral binaphthyl-derived amine-thiourea organocatalyst-promoted asymmetric Morita-Baylis-Hillman reaction.

[reaction: see text] A new bifunctional binaphthyl-derived amine thiourea organocatalyst has been developed to promote enantioselective Morita-Baylis-Hillman reaction of cyclohexenone with a wide range of aldehydes. The process, catalyzed by the amine thiourea, affords synthetically valuable chiral allylic alcohol building blocks in high yields and high enantioselectivities.

Aldehydes↗
PubMedDate not supplied

Characterization of isothiocyanates, thioureas, and other lysine adduction products in carbon disulfide-treated peptides and protein.

Carbon disulfide (CS2) is an industrial solvent used in rayon production and as an organic synthetic precursor. It is also a member of the class of neuropathy-inducing xenobiotics known as the "neurofilament (NF) neurotoxicants". Current hypotheses propose direct reaction of CS2 with NF lysine epsilon-amine moieties as a step in the mechanism of this neuropathy. In this study, covalent CS2 binding in a lysine-containing dipeptide and in bovine serum albumin (BSA) in vitro was characterized. Dipeptide and BSA, incubated with 14CS2, exhibited stable incorporation of radioactivity after removal of unbound CS2 and reincubation in physiological buffer for up to 10 days. In contrast, free thiol levels decreased from a maximum immediately following CS2 exposure to near-base-line levels after 10 days, consistent with time-dependent conversion of initially formed N-substituted dithiocarbamate adducts into secondary products. HPLC/thermospray-MS and HPLC/UV photodiode-array analysis of CS2-dipeptide adducts confirmed dithiocarbamate formation and demonstrated their conversion into N-alkylisothiocyanates and, ultimately, N,N'-disubstituted thioureas and ureas. The results of UV spectrophotometry of CS2-treated BSA were also consistent with loss of dithiocarbamate and appearance of thioureas. Similar time-dependent formation of these products, in addition to N,N'-disubstituted thiuram disulfides, was demonstrated in CS2-treated BSA by means of 13C-NMR spectroscopy. SDS-PAGE analysis of adducted protein revealed a discrete, higher mobility band, likely representing a specific intramolecular cross-link. In contrast, no evidence for intermolecular protein cross-linking was obtained. Identical results were obtained with cysteinyl-blocked BSA, indicating the lack of formation of N,S-dialkyldithiocarbamate (dithiourethane) cross-links in these preparations.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding Sites↗
PubMed2004

Synthesis and photophysical evaluation of charge neutral thiourea or urea based fluorescent PET sensors for bis-carboxylates and pyrophosphate.

The synthesis of the fluorescent photoinduced electron transfer (PET) chemosensors 1-3 for bis-anions such as bis-carboxylates and pyrophosphate in organic solvents is described herein. These sensors are based on the receptor-spacer-fluorophore-spacer-receptor motif where the receptors are charge neutral aromatic thiourea or urea receptors and the fluorophore is anthracene. The anion recognition was evaluated using 1H NMR as well as absorption and fluorescence spectroscopy in DMSO. For simple anions such as acetate or fluoride, the recognition was shown to be through hydrogen bonding of the corresponding anion to the receptors. This gave rise to only minor changes in the absorption spectra, but significant changes in the fluorescence emission spectra, which was substantially (70-95%) quenched. Analysis of these recognition events implied a 1 : 2 (sensor : anion) binding and ideal PET behaviour for ions such as AcO- and H2PO4-. For F-, the luminescent quenching indicated a 1 : 1 binding, but we deduced that this was due more to complete quenching of the excited state after the addition of one equivalent of the anion. For all of the anions, the quenching contributed to enhanced efficiency of PET from the receptors to the excited state of the fluorophore. In the case of the bis-anions (ambient), such as di-carboxylates, similar fluorescence quenching was observed. However, here either a 1 : 1 or a 1 : 2 binding was observed depending on the length of the spacer separating the two carboxylate moieties and the nature of the receptor. Whereas both pyrophosphate and malonate gave rise to a 1 : 1 binding, glutarate gave rise to approximately 1 : 2 binding for the thiourea sensors 1 and 2. However, for the urea based sensor 3, the binding was found to be 1 : 1 for all the bis-anions. For such a 1 : 1 binding we propose that the anion most likely bridges the fluorophore moiety. This was also evident from the 1H NMR (DMSO-d6) spectrum where the anthracene resonances were significantly affected. By simply modifying the electronic structure of the receptor, the sensitivity of the recognition process could also be modified; e.g. compound 1, bearing the trifluoromethyl substituent, showed stronger binding to the bis-anions than 2, which possessed a simple phenyl moiety.

Chemical Phenomena↗
PubMed1974

Reactions of L-ergothioneine and some other aminothiones with2,2'-and 4,4'-dipyridyl disulphides and of L-ergothioneine with iodoacetamide. 2-Mercaptoimidazoles, 2- and 4-thiopyridones, thiourea and thioacetamide as highly reactive neutral sulphur nucleophils.

1. The reactions of 2,2'- and 4,4'-dipyridyl disulphide (2-Py-S-S-2-Py and 4-Py-S-S-4-Py) with l-ergothioneine (2-mercapto-l-histidine betaine), 2-mercaptoimidazole, 1-methyl-2-mercaptoimidazole, thiourea, thioacetamide, 2-thiopyridone (Py-2-SH) and 4-thiopyridone (Py-4-SH) were investigated spectrophotometrically in the pH range approx. 1-9. 2. These reactions involve two sequential reversible thiol-disulphide interchanges. 3. The reaction of l-ergothioneine with 2-Py-S-S-2-Py and/or with the l-ergothioneine-Py-2-SH mixed disulphide, both of which provide Py-2-SH, is characterized by at least three reactive protonic states. This provides definitive evidence that neutral l-ergothioneine is a reactive nucleophile, particularly towards the highly electrophilic protonated disulphides. 4. A similar situation appears to obtain in the reactions of l-ergothioneine and Py-2-SH with 4-Py-S-S-4-Py and in the reactions of the other 2-mercaptoimidazoles, thiourea and Py-4-SH with 2-Py-S-S-2-Py. The nucleophilic reactivity of Py-4-SH suggests that general base catalysis provided by the disulphide in a cyclic or quasi-cyclic transition state is not necessary to generate nucleophilic reactivity in the other amino-thiones whose geometry could permit such catalysis. 5. The existence of a positive deuterium isotope effect in the l-ergothioneine-2-Py-S-S-2-Py system at pH6-7 provides no evidence for general base catalysis but is in accord with a mechanism involving specific acid catalysis and post-transition-state proton transfer. 6. The pH-dependences of the overall equilibrium positions of the various thiol-disulphide interchanges are described. 7. Reaction of thioacetamide with a stoicheiometric quantity of 2-Py-S-S-2-Py at pH1 provides 2 molecules of Py-2-SH per molecule of thioacetamide and elemental sulphur; these findings can be accounted for by thiol-disulphide interchange to provide a thioacetamide-Py-2-SH mixed disulphide followed by fragmentation to provide CH(3)CN, S and Py-2-SH. 8. Provision of high reactivity in the neutral forms of the members of this series of sulphur nucleophiles by electron donation by the amino group is compared with the well known alpha effect that provides enhanced nucleophilicity in compounds containing an electronegative atom adjacent to the nucleophilic atom. 9. The decrease in the u.v. absorption of l-ergothioneine at 257nm consequent on transformation of its aminothione moiety into an S-alkyl-2-mercaptoimidazole moiety provides a convenient method of following the alkylation of l-ergothioneine by iodoacetamide. 10. The pH dependence of the extinction coefficient of l-ergothioneine at 257nm is described by epsilon(257)={8x10(3)/(1+K(a)/[H(+)]} +6x10(3)m(-1).cm(-1) in which pK(a)=10.8. 11. In the pH range 3-11 the reaction is characterized by two reactive protonic states (X and XH). 12. The X state, reaction of the ionized 2-mercaptoimidazole moiety of the l-ergothioneine dianion with neutral iodoacetamide, is characterized by the second-order rate constant 4.0m(-1).s(-1) (25.0 degrees C, I=0.05). The XH state, characterized by the second-order rate constant 0.03m(-1).s(-1), is interpreted as reaction of the thione form of the neutral 2-mercaptoimidazole moiety of the l-ergothioneine monoanion with neutral iodoacetamide. 13. The XH state of the alkylation reaction does not exhibit a deuterium isotope effect.

2,2'-Dipyridyl↗