Infrared spectra of thiourea and its inclusion compounds. 3. Conformational studies of halocyclohexanes trapped in thiourea.
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Cyclohexanes↗
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Infrared spectra of thiourea and its inclusion compounds. V. Use of thiourea-d4 as a host molecule.
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Infrared Rays↗
[Studies on chemotherapeutic agents against Mycobacterium tuberculosis. XXVII. Synthesis and antituberculous activity of 1-alkyl-3-(3'-hydroxy-4'-alkoxycarbonylphenyl)-2-thiourea and 1-aryl-3-(3'-hydroxy-4'-alkoxycarbonylphenyl)-2-thiourea].
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Aminosalicylic Acids↗
Crystal structures of N,N'-(m-tolyl)thiourea and N,N'-(p-tolyl)thiourea.
C15H16N2S is monoclinic [orthorhombic], P2(1)/c [Pbcn]. Unit-cell dimensions at 293 K are a = 9.506(1), b = 7.629(1), c = 20.077(1)A, beta = 99.93(1) degrees, V= 1434.2(2)A(3), D(x) = 1.187 g/cm3, and Z = 4 [a = 11.806(2), b = 13.954(2), c = 8.466(1)A, V = 1394.7(3)A(3), D(x) = 1.221 g/cm3, and Z = 8]. The R value is 0.049 [0.045] for 1620 [1229] observed reflections. The dihedral angle between the tolyl rings is 53.6(1) degrees [47.9(1)degrees]. The crystal structures are stabilized by N-H...S hydrogen bonds and van der Waals forces.
Chelating Agents↗
Study of the orientation of thiourea adsorbed on aluminum oxide by tunneling spectroscopy. I. Determination of partial charges from molecular electrostatic potential calculations for thiourea and urea.
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Journal Article↗
NTP Toxicology and Carcinogenesis Studies of Ethylene Thiourea (CAS: 96-45-7) in F344 Rats and B6C3F1 Mice (Feed Studies).
Ethylene thiourea is a white crystalline solid used extensively in the rubber industry as an accelerator in the vulcanization of elastomers. It is also a trace contaminant and metabolic degradation product of a widely used class of ethylene bisdithiocarbamate fungicides. Ethylene thiourea is known to produce thyroid neoplasms in rats and liver neoplasms in mice following long-term administration; thus, it was chosen by the National Toxicology Program in an investigation of the potential value of perinatal exposures in assessing chemical carcinogenicity. Chronic toxicity and carcinogenicity studies of ethylene thiourea, 99% pure, were conducted in F344/N rats and B6C3F1 mice of each sex. The studies were designed to determine 1) the effects of ethylene thiourea in rats and mice receiving adult exposure only (a typical carcinogenicity study), 2) the toxic and carcinogenic effects of ethylene thiourea on rats and mice receiving perinatal exposure only (dietary exposure of dams prior to breeding and throughout gestation and lactation), and 3) the effects of combined perinatal and adult exposure to ethylene thiourea. STUDIES IN F344/N RATS: In a preliminary study to determine the perinatal dietary concentrations for the 2-year studies, female F344/N rats were fed 0, 8, 25, 83, or 250 ppm ethylene thiourea in the feed beginning 2 weeks prior to breeding and continuing throughout gestation and lactation, and the pups were fed at these same concentrations up to 9 weeks postweaning. Based on decreased survival of rat pups between postnatal days 0 to 4 and reduction in body weight gains in male weanling rats receiving 250 ppm, dietary concentrations of 0, 9, 30, and 90 ppm were selected for the perinatal (F0) exposure levels in the 2-year studies. Groups of 10 male and 10 female rats, 8 to 9 weeks of age, were fed diets containing 0, 60, 125, 250, 500, or 750 ppm ethylene thiourea for 13 weeks to determine the adult dietary concentrations. Because of reduced weight gains and decreased feed consumption in rats receiving 500 or 750 ppm ethylene thiourea, dietary concentrations of 0, 25, 83, and 250 ppm were selected for the adult (F1) exposure during the 2-year studies. In the 2-year studies, perinatal and adult exposures to ethylene thiourea were applied separately and together to groups of male or female rats as shown in the following table. The principal toxic effects of ethylene thiourea involved the thyroid gland. Serum levels of thyroxine (T4) and/or triiodothyronine (T3) were significantly decreased in rats receiving adult concentrations of 83 or 250 ppm, and thyrotropin (thyroid-stimulating hormone, TSH) was significantly increased at these concentrations. In male and female rats receiving adult-only exposure of 83 or 250 ppm, the incidences of follicular cell hyperplasia or follicular cell adenoma of the thyroid gland were significantly increased relative to the controls. The incidences of follicular cell carcinoma were significantly increased in the 250 ppm groups, and carcinomas occurred more frequently in males than in females. Exposure Groups of Rats in the 2-Year Feed Studies of Ethylene Thiourea a F1 Concentration (ppm)b F0(ppm)c 0 25 83 250 0 60 -- 60 60 9 -- 60 -- -- 30 -- -- 60 -- 90 60 -- 60 60 a Ten rats from each group were sacrificed and evaluated at 9 months b Concentration of ethylene thiourea in feed given to rats beginning at 8 weeks of age for 24 months c Concentration of ethylene thiourea in feed through breeding, gestation, and lactation until pups were 8 weeks of age Perinatal-only exposure to 90 ppm had no effect on the incidence of thyroid neoplasms in these studies, although there was a marginal increase in follicular cell hyperplasia relative to the controls. However, for groups of rats receiving combined perinatal and adult exposure (F0:F1), males and females receiving concentrations of 90:250 ppm ethylene thiourea had significantly increased incidences of thyroid follicular cell neoplasms relative to those receiving adult-only exposure to 250 ppm. Further, groups of male rats receiving 90:83 ppm 83 ppm showed a significantly increased incidence of follicular cell hyperplasia. Final mean body weights of males and survival of males and females receiving combined perinatal (90 ppm) and adult (250 ppm) exposure were lower than those receiving adult-only exposure of 250 ppm. Thus, in rats, combined perinatal and adult exposure slightly enhanced the toxicity and proliferative effects on the thyroid gland observed with adult-only exposure to ethylene thiourea. Neoplasms of the Zymbal's gland were marginally increased in rats receiving 90:250 ppm (males - 0:0, 1/50; 90:250, 5/50; females - 0:0, 1/50; 90:250, 4/50). Mononuclear cell leukemia occurred with a significant trend in groups of male and female rats receiving perinatal exposure of 90 ppm and increasing adult concentrations (90:0, 90:83, and 90:250 ppm), and for female rats without perinatal exposure (0:0, 0:83, and 0:250 ppm). The incidences of mononuclear cell leukemia in males receiving 90:83 ppm and males and females receiving 90:250 ppm were statistically significant relative to the respective 0:0 ppm groups. Low incidences of renal tubule cell adenomas occurred in most dose groups of male rats, but not in the highest dose group or the controls. STUDIES IN B6C3F1 MICE: In a preliminary study to determine the perinatal dietary concentrations for the 2-year studies, adult female C57BL/6N mice were fed 0, 33, 100, 330, or 1,000 ppm ethylene thiourea in the feed beginning 2 weeks prior to breeding and continuing throughout gestation and lactation and up to 9 weeks postweaning. Because of reduced survival of mouse pups at postnatal day 28 and lower final mean body weights in weanlings receiving perinatal exposure of 1,000 ppm, dietary concentrations of 0, 33, 110, and 330 ppm were selected for the perinatal exposure levels in the 2-year studies. Groups of 10 male and 10 female mice, 8 to 9 weeks of age, were fed diets containing 0, 125, 250, 500, 1,000, or 2,000 ppm ethylene thiourea for 13 weeks to determine the adult dietary concentrations. Moderately severe diffuse follicular cell hyperplasia in the thyroid gland and centrilobular cytomegaly of the liver occurred in mice receiving 2,000 ppm. Because the severity of the thyroid lesion (and degree of hypothyroidism) at this concentration was considered potentially life threatening in 2-year studies, dietary concentrations of 0, 100, 330, and 1,000 ppm ethylene thiourea were selected for adult exposure during the 2-year studies. In the 2-year studies, perinatal and adult exposures to ethylene thiourea were applied separately and together to groups of male or female mice as shown in the following table. Exposure Groups of Mice in the 2-Year Feed Studies of Ethylene Thiourea a F1 Concentration (ppm)b F0(ppm)c 0 100 330 1,000 0 69 -- 60 60 33 -- 34/29d -- -- 110 -- -- 60 -- 330 60 -- 60 60 a Ten mice from each group except the 33:100 ppm group were sacrificed and evaluated at 9 months b Concentration of ethylene thiourea in feed given to mice beginning at 8 weeks of age for 24 months c Concentration of ethylene thiourea in feed through breeding, gestation, and lactation until pups were 8 weeks of age d 34 males and 29 females assigned to group The principal toxic effects of ethylene thiourea in mice occurred in the thyroid gland, liver, and pituitary gland. Serum levels of T3 were significantly decreased in groups of mice receiving adult concentrations of 1,000 ppm; TSH was significantly increased in mice receiving 330 and 1,000 ppm. The incidences of follicular cell hyperplasia and neoplasia increased principally in males receiving 1,000 ppm and in females receiving 330 or 1,000 ppm. Follicular cell carcinomas were significantly increased in mice receiving 1,000 ppm. Incidences of centrilobular hepatocellular cytomegaly (males and females), hepatocellular adenoma (females), hepatocellular carcinoma (males and females), and adenoma or carcinoma combined (males and females) also were significantly increased in mice receiving F1 concentrations of 330 or 1,000 ppm. In the pituitary gland, incidences of focal hyperplasia (males) or adenoma (males and females) of the pars distalis were significantly increased in groups of mice receiving 1,000 ppm ethylene thiourea. Perinatal exposure to concentrations of 330 ppm had no effect on the incidences of nonneoplastic lesions or neoplasms in mice. For groups of mice receiving combined perinatal and adult exposure, females receiving F0:F1 concentrations of 330:330 ppm had significantly increased incidences of follicular cell adenoma relative to those receiving adult-only exposure to 330 ppm. Similarly, male mice receiving F0:F1 concentrations of 330:330 ppm had significantly increased incidences of follicular cell hyperplasia. Thus, in mice, perinatal exposure slightly enhanced the proliferative effects on the thyroid gland of adult exposure. There were no effects of perinatal exposure in mice at sites other than in the thyroid gland. CONCLUSIONS: 2-Year Adult-Only Exposure:Under the conditions of these 2-year adult-only dietary exposures, there was clear evidence of carcinogenic activity of ethylene thiourea in male and female F344/N rats, as shown by increased incidences of thyroid follicular cell neoplasms. There was clear evidence of carcinogenic activity of ethylene thiourea in male and female B6C3F1 mice as shown by increased incidences of thyroid follicular cell neoplasms, hepatocellular neoplasms, and adenomas of the pars distalis of the pituitary gland. Nonneoplastic lesions associated with the administration of ethylene thiourea included follicular cell hyperplasia in rats and mice and follicular cell cytoplasmic vacuolation, centrilobular hepatocellular cytomegaly, and focal hyperplasia of the pars distalis of the pituitary gland in mice. Other effects associated with the administration of ethylene thiourea included decreased serum levels of T4 and/or T3 in rats and increased serum levels of TSH in rats and mice. Perinatal-Only Exposure:Perinatal exposure alone had no effect on the incidences of neoplasms in rats or mice after 2 years. Animals may have been able to tolerate higher perinatal exposure concentrations. Combined Perinatal and 2-Year Adult Exposures:Combined perinatal and 2-year adult dietary exposure to ethylene thiourea confirmed the findings of the 2-year adult-only exposures for the incidences of neoplasms in the thyroid gland of rats and mice and the liver and pituitary gland of mice. In male and female rats, combined perinatal and adult exposure to 90:250 ppm was associated with marginal increases, relative to the untreated (0:0 ppm) controls, in Zymbal's gland neoplasms and mononuclear cell leukemia, which may have been related to chemical administration. In rats receiving adult exposure to 250 ppm ethylene thiourea, perinatal exposure to 90 ppm was associated with a slightly enhanced incidence of thyroid neoplasms compared to adult-only exposure. However, increasing perinatal exposure from 0 to 90 ppm had no effect on incidences of thyroid neoplasms in rats receiving adult exposure to 83 ppm. Increasing perinatal exposure from 0 to 330 ppm was associated with a marginally increased incidence of thyroid neoplasms in female mice receiving adult exposure to 330 ppm, but there were no enhancing effects of perinatal exposure in mice receiving adult exposure to 1,000 ppm. Synonyms: 2-Imidazolidinethione; Imidazoline-2-thiol; 2-mercaptoimidazoline; N,N'-ethylenethiourea; 1,3-ethylenethiourea; 2-imadazoline-2-thiol
Journal Article↗
Piperidinylethyl, phenoxyethyl and fluoroethyl bromopyridyl thiourea compounds with potent anti-HIV activity.
Derivatives of piperidinylethyl, phenoxyethyl and fluoroethyl bromopyridyl thioureas were designed and synthesized as non-nucleoside reverse transcriptase inhibitors (NNRTIs) of HIV-1 reverse transcriptase (RT). The anti-HIV activity of these compounds was examined by determining their ability to inhibit the replication of the HIV-1 strain HTLV(IIIB) in human peripheral blood mononuclear cells. The unsubstituted parent pyridyl thiourea compound N-[2-(1-piperidine)ethyl]-N'-[2-(pyridyl)] thiourea (1) exhibited no anti-HIV activity, even at 100 microM. However, the thiourea derivatives that contain a bromo- or chloro-substituted pyridyl group, compounds 2 and 5, inhibited HIV-1 replication at nanomolar concentrations. The addition of a methyl group onto the piperidine ring significantly altered the potency of these compounds; while methyl substitution at the 3-position of the piperidine ring reduced the activity, methyl substitution at the 2-position enhanced the anti-HIV activity. The IC50 value of the lead piperidinyl compound, N-[2-(2-methylpiperidinylethyl)]-N'-[2-(5-bromopyridyl)] thiourea (4) was <0.001 microM. All three phenoxyethyl derivatives, including the unsubstituted parent phenoxyethyl pyridyl thiourea compound N-[2-(phenoxy)ethyl]-N'-[2-(pyridyl)]thiourea (8) and the bromo-/chloro-substituted phenoxyethyl halopyridyl thiourea compounds N-[2-(phenoxy)ethyl]-N'-[2-(5-chloropyridyl)]thiourea (9) and N-[2-(phenoxy)ethyl]-N'-[2-(5-bromopyridyl)]thiourea (10) exhibited potent anti-HIV activity with nanomolar IC values. The corresponding fluoroethyl halopyridyl thiourea compounds beta-fluoro[2-phenethyl]-N'[2-(5-chloropyridyl)]thiourea (11) and beta-fluoro[2-phenethyl]-N'[2-(5-bromopyridyl)]thiourea (12) inhibited HIV-1 replication in PBMC with subnanomolar IC50 values and selectivity indices >30000. Compared to the corresponding phenoxyethyl thiourea compounds 9 and 10, these compounds were >4-5-fold more active as anti-HIV agents. Notably, the lead fluorothiourea compounds 11 and 12 were both substantially more active against the NNRTI-resistant HIV strains RT-MDR (V106A) and A17 (Y181C) than nevirapine or delavirdine. Taken together, our results provide additional experimental evidence that the structural features of the 'linker unit' between the pyridyl and phenyl moieties and changes in the phenyl group of PETT-related thiourea compounds significantly affects their biological activity as NNRTIs of HIV-1 RT.
Anti-HIV Agents↗
Substituted heterocyclic thiourea compounds as a new class of anti-allergic agents inhibiting IgE/Fc epsilon RI receptor mediated mast cell leukotriene release.
Mast cell derived leukotrienes (LT's) play a vital role in pathophysiology of allergy and asthma. We synthesized various analogues of indolyl, naphthyl and phenylethyl substituted halopyridyl, thiazolyl and benzothiazolyl thioureas and examined their in vitro effects on the high affinity IgE receptor/Fc epsilon RI-mediated mast cell leukotriene release. Of the 22 naphthylethyl thiourea compounds tested, there were 7 active compounds and N-[1-(1-naphthyl)ethyl]-N'-[2-(ethyl-4-acetylthiazolyl)]thiourea (17 and 16) (IC(50)=0.002 microM) and N-[1-(1R)-naphthylethyl]-N'-[2-(5-methylpyridyl)]thiourea (compound 5) (IC(50)=0.005 microM) were identified as the lead compounds. Among the 11 indolylethyl thiourea compounds tested, there were seven active compounds and the halopyridyl compounds N-[2-(3-indolylethyl)]-N'-[2-(5-chloropyridyl)]thiourea (24) and N-[2-(3-indolylethyl)]-N'-[2-(5-bromopyridyl)]thiourea (25) were the most active agents and inhibited the LTC(4) release with low micromolar IC(50) values of 4.9 and 6.1 microM, respectively. The hydroxylphenyl substituted compounds N-[2-(4-hydroxyphenyl)ethyl]-N'-[2-(5-chloropyridyl)]thiourea (37; IC(50)=12.6 microM), N-[2-(4-hydroxyphenyl)ethyl]-N'-[2-(5-bromopyridyl)]thiourea (50; IC(50)=16.8 microM) and N-[2-(4-hydroxyphenyl)ethyl]-N'-[2-(pyridyl)]thiourea (35; IC(50)=8.5 microM) were the most active pyridyl thiourea agents. Notably, the introduction of electron withdrawing or donating groups had a marked impact on the biological activity of these thiourea derivatives and the Hammett sigma values of their substituents were identified as predictors of their potency. In contrast, experimentally determined partition coefficient values did not correlate with the biological activity of the thiourea compounds which demonstrates that their liphophilicity is not an important factor controlling their mast cell inhibitory effects. These results establish the substituted halopyridyl, indolyl and naphthyl thiourea compounds as a new chemical class of anti-allergic agents inhibiting IgE receptor/Fc epsilon RI-mediated mast cell LTC(4) release. Further lead optimization efforts may provide the basis for new and effective treatment as well as prevention programs for allergic asthma in clinical settings.
Animals↗
Inhibition of mast cell leukotriene release by thiourea derivatives.
Mast cell derived leukotrienes (LT's) play a vital role in pathophysiology of allergy and asthma. We synthesized various analogues of indolyl, naphthyl and phenylethyl substituted halopyridyl, thiazolyl and benzothiazolyl thioureas and examined their in vitro effects on the high affinity IgE receptor/FcERI-mediated mast cell leukotriene release. Of the 22 naphthylethyl thiourea compounds tested, there were seven active compounds and N-[1-(1-naphthyl)ethyl]-N'-[2-(ethyl-4-acetylthiazolyl)]thiourea (17 and 16) (IC(50)=0.002 microM) and N-[1-(1R)-naphthylethyl]-N'-[2-(5-methylpyridyl)]thiourea (5) (IC(50)=0.005 microM) were identified as the lead compounds. Among the 11 indolylethyl thiourea compounds tested, there were seven active compounds and the halopyridyl compounds N-[2-(3-indolylethyl)]-N'-[2-(5-chloropyridyl)]thiourea and N-[2-(3-indolylethyl)]-N'-[2-(5-bromopyridyl)]thiourea were the most active agents and inhibited the LTC(4) release with low micromolar IC(50) values of 4.9 microM and 6.1 microM, respectively. The hydroxylphenyl substituted compounds N-[2-(4-hydroxyphenyl)ethyl]-N'-[2-(5-chloropyridyl)]thiourea (IC(50)=12.6 microM), N-[2-(4-hydroxyphenyl)ethyl]-N'-[2-(5-bromopyridyl)]thiourea (IC(50)=16.8 microM) and N-[2-(4-hydroxyphenyl)ethyl]-N'-[2-(pyridyl)]thiourea (IC(50)=8.5 microM) were the most active pyridyl thiourea agents. Notably, the introduction of electron withdrawing or donating groups had a marked impact on the biological activity of these thiourea derivatives and the Hammett sigma values of their substituents were identified as predictors of their potency. In contrast, experimentally determined partition coefficient values did not correlate with the biological activity of the thiourea compounds which demonstrates that their liphophilicity is not an important factor controlling their mast cell inhibitory effects.
Animals↗
Comparative cytotoxicity of N-substituted N'-(4-imidazole-ethyl)thiourea in precision-cut rat liver slices.
In order to more rationally design thiourea-containing drugs and drug candidates, specifically thiourea-containing histamine H3 receptor antagonists, it is necessary to develop structure-toxicity relationships (STRs). For this purpose, the cytotoxicity of a series of thiourea-containing compounds was tested in precision-cut rat liver slices. A concentration of 1000 microM of N-p-bromophenyl, N'-(4-imidazole-ethyl)thiourea (8) or N-p-nitrophenyl, N'-(4-imidazole-ethyl)thiourea (9) was found to cause cytotoxicity, evidenced as LDH leakage, resulting in more than 95% LDH leakage after 6h. N-p-Methoxyphenyl, N'-(4-imidazole-ethyl)thiourea (6) caused 40.6 +/- 19.7% LDH leakage after 6h. Control levels of cell death (1% methanol as control vehicle) were below 20% in 6h. After 6h of exposure, N-p-chlorophenyl, N'-(4-imidazole-ethyl)thiourea (7), 8, and 9 were already found to cause significant cytotoxicity at a concentration of 100 microM. At 200 microM, 9 was found to cause significantly more cytotoxicity than 7 and 8. N-Naphthyl, N'-(4-imidazole-ethyl)thiourea (12) was found to cause significant cytotoxicity towards precision-cut rat liver slices after 6h of exposure to a concentration of 500 microM. All other N-substituted, N'-(4-imidazole-ethyl)thiourea tested in this study were not found to be cytotoxic towards precision-cut rat liver slices within the 6h of exposure up to a concentration of 1000 microM. Intracellular glutathione (GSH) content and mitochondrial MTT reduction activity were also examined after exposure of slices to N-substituted, N'-(4-imidazole-ethyl)thiourea. Both of these markers, however, were not found to provide additional information regarding the possible mechanisms of cytotoxicity, i.e. GSH depletion or reduced mitochondrial activity since these markers did not clearly precede LDH leakage. A correlation was found between cytotoxicity towards precision-cut rat liver slices and Vmax/Km values for the formation of sulfenic acids from N-substituted N'-(4-imidazole-ethyl)thiourea by hepatic rat flavin-containing monooxygenases (FMO). The compound with the highest Vmax/Km value for the formation of sulfenic acids, 9, was also the most cytotoxic. Compounds with a significantly lower Vmax/Km value, 7, 8, and 12, were less cytotoxic than 9. Compounds with a Vmax/Km value for the formation of sulfenic acids lower than 0.0788 ml/(minmg) were found not to be cytotoxic towards precision-cut rat liver slices for concentrations up to 1000 microM at an exposure time of 6h. It is concluded, from this study, that N-phenyl substituted N'-(4-imidazole-ethyl)thiourea-containing electron-withdrawing p-substituents are cytotoxic towards precision-cut rat liver slices. Cytotoxicity is increased with increasing electron-withdrawing capacity of the p-substituent. A correlation was found to exist between Vmax/Km value for the formation of sulfenic acids by rat liver FMO enzymes and cytotoxicity.
Animals↗
Activation of microsomal glutathione S-transferase and inhibition of cytochrome P450 1A1 activity as a model system for detecting protein alkylation by thiourea-containing compounds in rat liver microsomes.
The recent development of several promising new thiourea-containing drugs has renewed interest in the thiourea functionality as a potential toxicophore. Most adverse reactions of thiourea-containing compounds are attributed to the thionocarbonyl moiety. Oxidation of these thionocarbonyl compounds by flavin-containing monooxygenases (FMO) and cytochrome P450 isoenzymes (P450) to reactive sulfenic, sulfinic, or sulfonic acids leads to alkylation of essential macromolecules. To more rationally design thiourea-containing drugs, structure-toxicity relationships (STRs) must be derived. Since for the development of STRs a large number of thiourea-containing compounds must be investigated, it is important to develop rapid in vitro assays for alkylating potential. In this study, the utility of activation of microsomal glutathione S-transferase (mGST) and inactivation of P450 1A1 as markers of the alkylating potential of metabolites of thiourea-containing compounds was investigated. It was found that metabolites of thiourea-containing compounds inactivate P450 1A1 in a time-dependent manner, as evidenced by a decrease in 7-ethoxyresorufin O-dealkylation (EROD) activity. An extent of inactivation of P450 1A1 by 100 microM N-phenylthiourea (PTU) of 64% was found after 10 min. This inactivation was dependent on the presence of NADPH and the presence of the thionosulfur, since the carbonyl analogue of PTU was not found to inactivate P450 1A1, and was partially prevented by heat treatment of the microsomes which is known to selectively inactivate FMO enzymes. Inactivation of P450 1A1 could be reversed by treatment with dithiothreitol, indicating the formation of disulfide bonds. However, thiourea-containing compounds also inhibited the EROD activity of P450 1A1 in a competitive manner. This property complicates the usefulness of the EROD activity of P450 1A1 as a marker for the alkylating potential of thiourea-containing compounds. It was found that metabolites of thiourea-containing compounds could transiently activate the mGST. A maximal level of activation by 100 microM PTU of 162+/-16% was found after 10 min. Activation of mGST by 100 microM PTU was dependent on the presence of NADPH and the presence of the thionosulfur, since the carbonyl analogue of PTU was not found to activate mGST. Activation was completely prevented by heat treatment of the microsomes, indicating involvement of FMO in the bioactivation process. Finally, a series of structurally diverse thiourea-containing compounds were tested for their ability to activate mGST. It appeared that their potency in alkylating mGST was inversely related to their Vmax/Km value for the FMO enzyme. From this study, it is concluded that, whereas activation of mGST in rat liver microsomes may be a useful system with which to investigate the relationship between structure and alkylating potential of thiourea-containing compounds in vitro, inactivation of P450 1A1 is not.
Alkylation↗
Novel thiourea compounds as dual-function microbicides.
Sexually active women represent the fastest growing human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome risk group. In an effort to develop a vaginal microbicidal contraceptive potentially capable of preventing HIV transmission as well as providing fertility control, we previously reported the synthesis of novel nonnucleoside inhibitors (NNIs) of HIV-1 reverse transcriptase with sperm-immobilizing activity (SIA). To gain further insight into the structure-function relationship controlling these two properties of NNIs, we have rationally designed and synthesized 30 novel thiourea compounds and examined them for dual-function, anti-HIV and spermicidal activity. Twelve of the 30 thiourea compounds exhibited potent anti-HIV activity in the nanomolar range (IC(50) = <1-9 nM). Nine of the 30 thiourea derivatives exhibited both anti-HIV and spermicidal activity. Among the phenyl ring-containing thioureas, the 2-fluoro (HI-240) -substituted and 2-chloro (HI-253) -substituted derivatives exhibited potent anti-HIV activity (IC(50) = <1 nM) with SIA (EC(50) = 70 microM and 147 microM). Among the alicyclic ring-containing thioureas, the 5-bromo (HI-346) and 5-chloro (HI-445) functionalized cyclohexenyl ring-substituted thioureas were the most potent dual-function spermicides (EC(50) = 42 and 57 microM), with anti-HIV activity at nanomolar range (IC(50) = 3 nM). Unlike nonoxynol-9 (N-9), none of the potent dual-function thiourea compounds were cytotoxic to normal human vaginal, ectocervical, and endocervical epithelial cells at spermicidal concentrations. We conclude that as potent anti-HIV agents with SIA and reduced cytotoxicity when compared with N-9, the phenyl-substituted and cyclohexenyl-substituted thiourea derivatives, especially compounds HI-253 (N-[2-(2-chlorophenethyl)]-N'-[2-(5-bromopyridyl)-thiourea), HI-346 (N-[2-(5-bromopyridinyl)]-N'-[2-(1-cyclohexenyl)ethyl-thiourea), and HI-445 (N-[2-(5-chloropyridinyl)]-N'-[2-(1-cyclohexenyl)ethyl-thiourea) show unique clinical potential to become the active ingredients of a vaginal contraceptive for women who are at high risk for acquiring HIV by heterosexual vaginal transmission.
Anti-HIV Agents↗
Potent dual anti-HIV and spermicidal activities of novel oxovanadium(V) complexes with thiourea non-nucleoside inhibitors of HIV-1 reverse transcriptase.
We have previously demonstrated that tetrahedral bis(cyclopentadienyl)vanadium(IV) complexes and square pyramidal oxovanadium(IV) complexes of vanadium are rapid and selective spermicidal agents at low micromolar concentrations. This study investigated the potential utility of oxovanadium in combination with thiourea non-nucleoside inhibitors (NNIs) of HIV-1 reverse transcriptase (RT) for the development of an effective dual-function anti-HIV spermicide. Two rationally designed substituted phenyl-ring containing pyridyl thiourea NNIs, N-[2-(2-chlorophenethyl)]-N(')-[2-(5-bromopyridyl)-thiourea) [1] and N-[2-(2-methoxyphenethyl)]-N(')-[2-(pyridyl)-thiourea [2] that exhibited subnanomolar IC(50) values against the drug-sensitive, drug-resistant, and multidrug-resistant strains of HIV-1, were complexed with oxovanadium. The oxovanadium-thiourea [OVT] NNIs, C(29)H(27)Br(2)Cl(2)N(6)O(2)S(2)V [3], and C(31)H(35)N(6)O(4)S(2)V [4], were synthesized by reacting VOSO(4), a V(IV) compound, with the corresponding deprotonated thiourea NNI compounds as ligands. Elemental analysis showed that each OVT-NNI used two thiourea molecules as ligands. The existence of the Vz.dbnd6;O bond (968cm(-1)) was confirmed by IR spectroscopy. No d-d bands were observed in the visible spectra of OVT-NNIs and their EPR spectra were featureless, indicating that the vanadium centers were oxidized to V(V). The new OVT-NNIs as well as their thiourea NNI ligands were evaluated for (i) anti-HIV activity using the cell-free recombinant RT inhibition assays, (ii) cellular HIV replication assays, (iii) spermicidal activity against human sperm by computer-assisted sperm analysis (CASA), and (iv) cytotoxicity against normal human female genital tract epithelial cell using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) dye-reduction assays. Similar to thiourea NNIs 1 and 2, the OVT-NNIs 3 and 4, exhibited potent anti-HIV activity with submicromolar IC(50[p24]) values (0.08 and 0.128 microM, respectively) and submicromolar IC(50[RT]) values (2.1 and 0.87 microM, respectively). Notably, OVT-NNIs were spermicidal against human sperm at low micromolar concentrations (IC(50)=34 and 55 microM, respectively) and induced rapid sperm immobilization (T(1/2)=12 and 240s) when compared with their respective thiourea NNI ligands (EC(50)=>400 microM and T(1/2)=>180min). Moreover, OVT-NNIs displayed high selectivity indices against normal female genital tract epithelial cells (IC(50) values >250 microM) when compared to the detergent-type spermicide, nonoxynol-9, which was cytotoxic at spermicidal concentrations (IC(50) values 32-64 microM). This is the first report on the dual anti-HIV and spermicidal activities of a vanadium/oxovanadium complex. Our discovery of potent anti-HIV and rapid spermicidal activities of OVT-NNIs may be useful for the development of an effective and safe vaginal anti-HIV spermicide for women who are at high risk for acquiring HIV/AIDS by heterosexual transmission.
Anti-HIV Agents↗
Cytotoxicity of a series of mono- and di-substituted thiourea in freshly isolated rat hepatocytes: a preliminary structure-toxicity relationship study.
The cytotoxicity of a series of 12 mono- and 4 di-substituted thiourea containing compounds in freshly isolated rat hepatocytes was investigated. It was found that thiourea toxicity, as evidenced by an increase in LDH-leakage from the cells, was accompanied by a depletion of intracellular glutathione (GSH). No increase in lipid peroxidation was observed with any of the thiourea. Burimamide and thioperamide, thiourea-containing histamine receptor ligands, were also found to deplete intracellular GSH. A clear structure-toxicity relationship was uncovered among a homologous series of N-phenylalkylthiourea. N-benzylthiourea (BTU) and N-phenylethylthiourea (PETU) were found to be non-toxic at a concentration of 1 mM, while N-phenylpropylthiourea (PPTU) and N-phenylbutylthiourea (PBTU) were found to cause significant LDH-leakage from the cells, accompanied by a depletion of intracellular GSH. This structure-toxicity relationship was further investigated using hepatocytes of differentially induced rats, however, no significantly different results were obtained when using hepatocytes of rats induced with phenobarbital (PB) or beta-naphthoflavone (BNF). Oxidation of the thiourea moiety is thought to be the first step in the bioactivation of thiourea containing compounds. The oxidation of thiocholine sulfenic acids, produced by FMO-mediated oxidation of the thiourea moiety, was used to determine whether the compounds examined are substrates for the FMO enzymes in rat liver. No clear relationship was found between cytotoxicity of the mono-substituted thiourea and lipophilicity of the N-substituent, nor with the FMO-mediated oxidation of the thionosulfur atom of the mono-substituted thiourea. It is concluded from this study, that thiourea toxicity in rat hepatocytes is structure-dependent and manifests itself as LDH-leakage and as a depletion of intracellular non-protein sulfhydryls, notably GSH, most likely followed by alkylation of vital macromolecular structures.
Animals↗
Remediation of methyl iodide in aqueous solution and soils amended with thiourea.
Methyl iodide (MeI) is considered a very promising fumigant alternative to methyl bromide (MeBr) for controlling soil-borne pests. Because atmospheric emission of highly volatile fumigants contributes to air pollution, feasible strategies to reduce emissions are urgently needed. In this study, thiourea (a nitrification inhibitor) was shown to accelerate the degradation of MeI in soil and water. In aqueous solution, the reaction between MeI and thiourea was independent of pH, although the rate of MeI hydrolysis increased in alkaline solution. Substantial increases in the rate of MeI dissipation were observed in thiourea-amended soils. Transformation of MeI by thiourea in aqueous solution was by a single chemical reaction process, while MeI degradation in thiourea-amended soil apparently involved a catalytic mechanism. The electron delocalization between the thiourea molecule and the surfaces of soil particles is energetically favorable and would increase the nucleophilic reactivity of the thiono group toward MeI, resulting in an enhancement of the dissipation rate. The soil half-life for MeI was reduced from >300 h for unamended soils to only a few hours in soil or sand amended with thiourea at a 2:1 molar ratio (thiourea:MeI). The MeI transformation rate in thiourea-amended soil increased with increasing soil temperature and decreasing soil moisture. Therefore, spraying thiourea on the soil surface to form a "reactive surface barrier" may be an effective and innovative strategy for controlling fumigant emissions to the atmosphere and for improving environmental protection.
Air Pollution↗
Occupational allergic contact dermatitis caused by thiourea compounds.
Thiourea compounds are mainly used as accelerators in the rubber industry, but also in other industries, e.g., as antioxidants in the graphics industry. Thiourea compounds may provoke allergic contact dermatitis, although the number of reported cases is relatively low. During 1985-1991, we had 5 patients with allergic patch test reactions caused by thiourea compounds. 1 of our patients had to use a knee brace after an occupational accident. He developed allergic contact dermatitis caused by the knee brace, probably because he had become sensitized to diethylthiourea. 2 patients were probably sensitized by diphenylthiourea in neoprene gloves. A florist had an allergic patch test reaction to diphenylthiourea and might have been sensitized by fungicides or pesticides, which break down into thioureas. It is often difficult, however, to detect the source of thiourea compound sensitization. If the patient has contact dermatitis and has been exposed to products that may contain thiourea compounds (or compounds that break down into thiourea compounds), such as rubber, PVC plastic or adhesive, diazo paper, paints or glue remover, anticorrosive agents, fungicides or pesticides, patch testing with a series of thiourea compounds needs to be performed. If patch testing with thiourea compounds is not performed, allergic contact dermatitis caused by thiourea compounds is not likely to be diagnosed.
Adult↗
Patch-test reactions to thioureas are frequently relevant.
BACKGROUND: Thioureas are used as antioxidants in the manufacture of rubber (especially neoprene) and as fixatives in photography and photocopy paper. The number of reported cases of allergic contact dermatitis from thioureas is relatively low, and standard patch test series often do not contain thiourea allergens. Thioureas are included in our institution's standard patch test series. OBJECTIVE: To examine the occurrence and relevance of patch-test reactions to thioureas. METHODS: We retrospectively analyzed patch-test data for patients evaluated between January 1999 and June 2001. Patients included in the study underwent testing with a standard screening series of allergens and a standardized patch testing technique. Our standard patch test series includes mixed dialkyl thioureas at a concentration of 1% in petrolatum. RESULTS: Of 1,368 patients tested with our standard series, 33 patients (2.4%) had patch-test reactions to mixed dialkyl thioureas at day 5. Reactions in 14 (42%) of those patients were of definite clinical relevance, indicating a confirmed exposure to thioureas in many different settings. CONCLUSION: Patch-test reactions to thioureas occur as often as do reactions to many other allergens in the standard series and are often relevant. Institutions should consider including mixed dialkyl thioureas in their standard patch test screening series.
Dermatitis, Allergic Contact↗
[Inhibition and inactivation of horseradish peroxidase by thiourea].
The kinetics of horseradish peroxidase (EC 1.11.1.7)-catalyzed oxidation of o-dianisidine by hydrogen peroxide in the presence of thiourea were studied. At the first, fast step of this process thiourea acts as a competitive reversible inhibitor with respect to o-dianisidine (Ki = 0.22 mM). The formation of a thiourea-peroxidase complex was determined by the increase in the absorbance at A495 and A638 of the enzyme. The dissociation constant for the peroxidase-thiourea complex is equal to 2.0-2.7 mM. Thiourea is not a specific substrate of peroxidase during the oxidation reaction by H2O2, but is an oxidase substrate (although not a very active one) of peroxidase. The irreversible inactivation of the enzyme during its incubation with thiourea was studied. The first-order inactivation rate constant (kin) was shown to increase with a fall in the enzyme concentration. The curve of the dependence of kin on the initial concentration of thiourea shows a maximum at 5-7 mM. The enzyme inactivation is due to its modification by intermediate free radical products of thiourea oxidation. The inhibitors of the free radical reactions (o-dianisidine) protect the enzyme against inactivation. The degree of inactivation depends on concentrations and ratio of thiourea and peroxidase. A possible mechanism of peroxidase interaction with thiourea is discussed.
Horseradish Peroxidase↗