Phenylurea Derivatives Research Articles

Synthesis and activity evaluation of phenylurea derivatives as potent antitumor agents

We have discovered several tubulin-active compounds in our previous studies. In the establishment of a compound library of small molecule weight tubulin ligands, 14 new N-3-haloacylaminophenyl- N′-(alkyl/aryl) urea analogs were designed and synthesized. The structure–activity relationship (SAR) analysis revealed that (i) the order of anticancer potency for the 3-haloacylamino chain was following –CH 2Br > –CHBrCH 3; (ii) the N′-substituent moiety was not essential for the anticancer activity, and a proper alkyl substitution might enhance the anticancer activity. Among these analogs, the compounds 16j bearing bromoacetyl at the N′-end exhibited a potent activity against eight human tumor cell lines, including CEM (leukemia), Daudi (lymphoma), MCF-7 (breast cancer), Bel-7402 (hepatoma), DU-145 (prostate cancer), DND-1A (melanoma), LOVO (colon cancer) and MIA Paca (pancreatic cancer), with the IC 50 values between 0.38 and 4.07 μM. Interestingly, compound 16j killed cancer cells with a mechanism independent of the tubulin-based mechanism, indicating a significant change of the action mode after the structure modification.

Application of Gold Nanoparticles to Spectrophotometric Sensing of Hydrophilic Anions Based on Molecular Recognition by Urea Derivative

We have prepared gold nanoparticles (GNPs) modified with a thiol compound that possesses a phenylurea moiety for the spectrophotometric sensing of hydrophilic anions, such as dihydrogen phosphate, based on changes in the surface plasmon absorption of the GNP. We examined the spectral change of phenylurea-modified GNP in dichloromethane upon the addition of various anions as tetrabutylammonium salts to the solution. The GNP showed increasing plasmon intensity with the concentration of dihydrogen phosphate. For a control experiment with an inactive hexanethiolate-modified GNP, such an ion-selective change in the plasmon band was not observed. Furthermore, in order to realize the spectrophotometric detection of hydrophilic anions in water using GNP with the urea functionality, we attempted to prepare bifunctional GNP modified with both the phenylurea derivative and a water-soluble thiol (e.g., L-cysteine). The resulting bifunctional GNP showed anion-selective changes in the plasmon band accompanied by increasing absorbance at a longer wavelength due to GNPs aggregation.

Salicylate–urea-based soluble epoxide hydrolase inhibitors with high metabolic and chemical stabilities

We investigated N-adamantyl- N′-phenyl urea derivatives as simple sEH inhibitors. Salicylate ester derivatives have high inhibitory activities against human sEH, while the free benzoic acids are less active. The methyl salicylate derivative is a potent sEH inhibitor, which also has high metabolic and chemical stabilities; suggesting that such inhibitors are potential lead molecule for bioactive compounds acting in vivo.

Reduced toxicity of diuron to the freshwater green alga Pseudokirchneriella subcapitata in the presence of black carbon

Black carbon (BC) is known to act as supersorbent for many organic contaminants. Its presence in surface waters at a level of a few mg/L, which may occur, e.g., after storm events in urban areas, might result in a reduced bioavailability of many contaminants and thus greatly impact their potential toxicity. Photosynthesis-inhibiting phenyl urea derivatives, such as diuron, are widely used as herbicides and diuron is regularly measured in European freshwater systems. In this study, the toxicity of diuron to the freshwater green alga Pseudokirchneriella subcapitata was investigated in the presence of BC in its native and combusted form. As a toxicity endpoint, the in vivo chlorophyll fluorescence was determined and used to indicate the bioavailability of diuron. Fifty milligrams native BC/L reduced effects of 5 μg diuron/L on photosynthesis by 10 ± 2%, whereas photosynthesis was completely restored in the presence of the same concentration of combusted BC, suggesting a significantly enhanced adsorption of diuron to the BC fraction compared to the organic carbon fraction. Assuming an environmentally realistic concentration of approximately 1.5 mg of combusted BC/L, diuron toxicity would be reduced by approximately 20% in surface waters due to the presence of BC. Higher BC concentrations after storm events might reduce the toxicity even further. A calculation of the Freundlich sorption coefficient K F,BC,tox via the toxicity endpoint, resulted in a log K F,BC,tox of the combusted BC of 5.7, which is comparable to values obtained by classical sorption experiments. This study contributes to a refined risk assessment of micropollutants in surface waters taking into account the presence of potentially relevant sorbents and, consequently, reduced bioavailability.

Genetic instability in calamondin (Citrus madurensis Lour.) plants derived from somatic embryogenesis induced by diphenylurea derivatives

Somatic embryos were regenerated in vitro from calamondin style-stigma explants cultured in the presence of N (6)-benzylaminopurine (BAP) cytokinin and three synthetic phenylurea derivatives, N-(2-chloro-4-pyridyl)-N-phenylurea (4-CPPU), N-phenyl-N'-benzothiazol-6-ylurea (PBU) and N,N'-bis-(2,3-methilendioxyphenyl)urea (2,3-MDPU). The phenylurea derivative compounds tested at micromolar level (12 muM) were able to induce a percentage of responsive explants significantly higher from that obtained with BAP and hormone-free (HF) conditions. In order to verify the genetic stability of the regenerants, 27 plants coming from different embryogenic events were randomly selected from each different culture condition and evaluated for somaclonal variations using inter-simple sequence repeat and random amplified polymorphic DNA analyses. We observed that 2,3-MDPU and PBU gave 3.7% of somaclonal mutants, whereas 4-CPPU gave 7.4% of mutants. No somaclonal variability was observed when plantlets were regenerated in BAP or HF medium. Although diphenylurea derivatives show a higher embryogenic potential as compared to BAP, they induce higher levels of somaclonal variability. This finding should be taken in consideration when new protocols for clonal propagation are being developed.

Phenyl urea derivatives as organic stabilizers for rigid poly(vinyl chloride) against photo‐degradation

AbstractPhenyl urea derivatives have been prepared and investigated as photostabilizers for rigid PVC by measuring the extent of weight loss (%), the amount of gel formation as well as the intrinsic viscosity of the soluble fractions of the degraded polymer. Moreover, the efficiency of these stabilizers was evaluated from the extent of discoloration of the degraded polymer in their presence. The results indicated a reasonable stabilizing effect of these derivatives when compared with the commercially used UV stabilizers: phenyl salicylate (Salol) and methanone, 2‐hydroxy‐4‐(octyloxy)‐phenyl‐benzophenone. A synergistic effect is achieved when the phenyl urea derivatives are mixed with the UV absorbers in the ratio (75 : 25%), respectively. A radical mechanism is proposed to account for the stabilizing action of the products investigated. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 103: 2217–2226, 2007

Diphenylurea Derivatives Induce Somatic Embryogenesis in Citrus

The present research investigates the possibility that three diphenylurea (DPU) deriva- tives, N-phenyl-N¢-benzothiazol-6-ylurea (PBU), N,N¢-bis-(2,3-methilendioxyphenyl)urea (2,3- MDPU) and N,N¢-bis-(3,4-methilendioxyphe- nyl)urea (3,4-MDPU), stimulate the induction of somatic embryogenesis in three Citrus species. The hypothetical embryogenic activity was assessed using stigma and styles of Citrus myrtifolia Raf., Citrus madurensis Lour. and Citrus limon (L.) Burm. The three compounds influenced the pro- duction of somatic embryos differently as regards the concentrations tested and the citrus species. PBU was able to induce somatic embryogenesis at all the concentrations tested and in all the three species with percentages that ranged from 44 (C. limon) to 85% (C. myrtifolia). 2,3-MDPU and 3,4-MDPU were completely unable to induce the production of somatic embryos in C. myrtifolia while both the compounds at the higher concentration (12 lM) acted positively in both C. madurensis and C. limon (68% of embryogenic explants). The phenylurea derivatives, used for the first time in this study to induce somatic embryo- genesis in plant, showed a higher embriogenic performance when compared with 6-benzylamin- opurine (BAP), a classical adenine-cytokinin, and with N-(2-chloro-4-pyridyl)-N¢-phenylurea (CPPU), a classical DPU derivative.

Adeninic and ureidic cytokinins: Primary response events in in vitro tomato caulogenesis

Among the molecules showing cytokinin activity, phenylurea derivatives have been long discussed as regards their direct or indirect action in cytokinin-mediated processes. This paper considers the activity of three cytokinins, an adenine and two phenylurea derivatives, on the caulogenesis onset. Caulogenesis is composed of sequential stages involving peculiar hormonal requirements and the differential activation of genes that can be considered markers of the steps leading to shoot production. Our study shows that the expression of LESK1, marker of caulogenic competence acquisition, is induced by both adeninic and ureidic derivatives, indicating that morphogenesis is induced by these molecules through the activation of common components of response pathway. The detailed analysis on morphogenesis in a system deprived of endogenous cytokinins strengthen the hypothesis of a proper cytokinin activity for the two phenylurea derivatives, 1-phenyl-3-(1,2,3-thiadiazol-5-yl)urea (thidiazuron TDZ) and N-phenyl- N′-benzothiazol-6-ylurea (PBU). A different behaviour of zeatin riboside (ZR), TDZ and PBU, emerges when the growth regulator supply is preceded by a 3-day pre-culture which positively affects the caulogenesis obtained with TDZ, while it strongly inhibits the action of ZR. PBU activity instead resulted more similar to that of the cytokinin/auxin treatment, supporting the idea of an interaction of diphenylurea derivatives with auxin metabolism. The synergistic effect of auxin on shoot production emerges from both the higher rate of caulogenic competence acquisition, marked by a sharper peak of LESK1 expression, which leads to a strong increase in shoot number produced per explant when cytokinin and auxin are supplied together.

Biomimetic Approach to Biomembrane Models Studies: Medium Influence on the Interaction Kinetics of Some Phenylurea Derivatives Herbicides

The ability of herbicides to interact with cell membranes outer lipid layer and subsequently to penetrate inside cells can be a prerequisite for exhibiting a toxic activity for both the directly exposed workers and the end consumers as the herbicides are present in the soil and water. The effect exerted by fenuron, chlorotoluron, metobromuron, monolinuron, and chlorbromuron, five structurally similar phenylurea herbicides, on the thermotropic behavior of model membranes, represented by dimyristoylphosphatidylcholine (DMPC) vesicles, was investigated by differential scanning calorimetry. The examined compounds, when dispersed in liposomes during their preparation, exerted a different action on the gel-to-liquid crystal phase transition of DMPC multilamellar vesicles. The ability of phenylurea herbicides, as a finely powdered solid, to migrate through an aqueous medium and interact with biomembrane models was also studied. This transfer process was compared with these compounds intermembrane transfer from herbicide-loaded liposomes to empty ones. These processes can mimic absorption kinetics mediated by hydrophilic or lipophilic media. Different rate and entity of interaction occurred between model membranes and solid phenylurea herbicides. Different behavior was observed by considering the time-dependent studies carried out by contacting, for increasing times, equivalent amounts of empty DMPC vesicles with phenylurea herbicide-loaded ones; all compounds were able to migrate from loaded to empty DMPC vesicles. Thus, phenylurea herbicides are able to reach and penetrate biological membranes when dispersed in a lipophilic or hydrophilic medium; these processes are related to the substituents present on the compounds backbone. The obtained experimental results seem to validate the employed strategy to study the ability of bioactive compounds to both interact with biological membranes and be adsorbed inside a membrane mimicking a biological cell when dispersed in a lipophilic or hydrophilic medium.

EFFECT OF THIDIAZURON ON SENESCENCE OF FLOWERS IN CUT INFLORESCENCES OF LUPINUS DENSIFLORUS BENTH

EFFECT OF THIDIAZURON ON SENESCENCE OF FLOWERS IN CUT INFLORESCENCES OF LUPINUS DENSIFLORUS BENTH

Time-Dependent Absorption Evidence of Phenylurea-Derived Herbicides on Model Biomembranes: A DSC Study

Environmental Context. The need to improve the quality of agricultural cultivation and to control the weed growth of non-cultivated area has brought herbicides to wide-scale use. Unfortunately, these compounds have been proved to be toxic for many organisms, humans included. With an aim to a better knowledge of the mobility and fate of environmental pollutants, it becomes very important to have an exact knowledge of the role that the medium in which these products are dissolved or dispersed plays on the absorption of these products by biological membranes as a complement to information on the interaction between these compounds and cells. Abstract. Phenylurea derivatives are used as herbicides that inhibit photosynthesis. These materials enter plants via their roots and are employed for selective control of germinating grass and broad-leaved weeds in many crops as well as for total weed control of non-cultivated areas such as roads, railways, and parks. The study of the interaction between the herbicide and lipid membrane is interesting in assessing the relevance of the dispersing medium in the absorption processes. Differential scanning calorimetry (DSC), which detects the effect of foreign molecules on the phase transition from an ordered to a disordered lipid structure when submitted to heating, was employed to study such an interaction. Effects exerted by four phenylurea herbicides (difenoxuron, diuron, metoxuron, and linuron) on the thermotropic behavior of model membranes were here investigated. Aqueous dispersions of dimyristoylphosphatidylcholine (DMPC) were used as model membranes to study herbicide–membrane interactions. Experiments carried out by leaving herbicides, in a powdered form, in contact with DMPC-based multilamellar or unilamellar vesicles show that all the examined herbicides are able, but in different ways, to migrate through the aqueous medium and interact with model membranes. Experiments on herbicide-loaded liposomes in contact with empty ones indicate that the compounds are able to migrate from a loaded membrane to an empty one. The obtained data seem to validate the use of the DSC in demonstrating that bioactive and potentially toxic compounds not only to interact with biological membranes but also adsorb into a cell when dispersed in a lipophilic medium.

Synthesis and Biological Activity of Urea and Thiourea Derivatives from 2-Aminoheterocyclic Compounds

Thirty-eight N-substituted-N′-(2-thiazolyl and furfuryl)ureas and thioureas were prepared by reaction of 2-aminothiazole and 2-furfurylamine with the appropriate iso(thio)cyanate. All compounds were tested for herbicidal activity and selectivity on seedlings of wheat (a monocotyledonous plant) and cucumber (a dicotyledonous plant). Only one compound (1) out of 14 ureas was characterized by considerable herbicidal activity against the wheat seedlings and two compounds (1 and 2) - towards the cucumber seedlings. The phenylurea derivative of 2-aminothiazole (1) was 1.7-fold more and the 3-chlorophenylurea derivative of 2-furfurylamine (23) was equally as active as the standard diuron with respect to selective herbicidal activity. Among 24 thioureas, four compounds (15,16,17, and 18) to displayed the highest selective herbicidal activity and two other compounds (19 and 33) were almost equal to diuron activity. Selective herbicidal ratio (SHR) represents the degree of herbicidal effect of the investigated compounds compared to diuron at both test objects. Four compounds (16,17,18, and 23) possessed SHR > 100. Therefore these compounds were substantially more active herbicides to the wheat seedlings as compared to diuron. The cytokinin-like activity of the synthesized compounds was also investigated in terms of betacyanin synthesis and radish cotyledon enlargement. The urea derivatives exhibited mostly high cytokinin-like activity but their activity remained lower than those of kinetin and N-phenyl-N′-(4-pyridyl)urea. The N-(3-fluorophenyl)-N′-(2-thiazolyl)urea (2) possessed the greatest activity at 10 μM while the corresponding compound with 3-chlorophenyl (4) was the most active cytokinin-like substance in the whole concentration range tested. Attention was also given to structure-activity relationships for the screened compounds. In general, the ureas and thioureas containing a 2-thiazole ring were more active than those containing a 2-furfuryl residue.

1H NMR study of inclusion compounds of phenylurea derivatives in β-cyclodextrin

Proton nuclear magnetic resonance spectroscopy ( 1H NMR), which has become an important tool for the study “in situ” of β-cyclodextrin (β-CD) complexes, was used to study and structurally characterize the inclusion complexes formed between β-CD and isoproturon, fenuron, monuron and diuron. The high variation of the chemical shifts from the proton located inside the cavity (H-3, H-5 and H-6) coupled with the non variation of the one located outer sphere of the β-CD (H-1, H-2 and H-4) provided clear evidence of the inclusion phenomena. Two-dimensional rotating frame Overhauser effect spectroscopy (ROESY) experiments were carried out to further support the proposed inclusion mode.

Octanol/Water Partition Coefficient of Selected Herbicides: Determination Using Shake-Flask Method and Reversed-Phase High-Performance Liquid Chromatography

For some triazines and phenylurea derivatives no reliable KOW values were available from literature. The log KOW values were determined directly with the shake-flask procedure and also indirectly using the reversed-phase high-performance liquid chromatography (RP-HPLC) method in the isocratic and gradient elution mode, respectively. Atrazine, as a well-investigated substance, and two herbicides of different chemical structures (acid amides) were included in this study. Both RP-HPLC methods yield log KOW values comparable among themselves and identical with the shake-flask results for methabenzthiazuron (2.5), chloroxuron (3.8), sebutylazine (3.2), and atrazine (2.6). For the atrazine metabolites investigated, the RP-HPLC-derived log KOW values are significantly less than those directly measured (1.0 for desethylatrazine and 1.5 for desisopropylatrazine). In contrast to these findings, considerably higher log KOW values were obtained for the two acid amides propachlor and metazachlor with both RP-HPLC methods compared to the shake-flask values (2.2 for both compounds). Because of the still complicated choice of reliable reference compounds/data for the RP-HPLC methods, the shake-flask technique should be preferred for determination of octanol/water partition coefficients with high accuracy in the range of log KOW < 4. Finally, the directly measured KOW values were compared with estimates obtained with two widely applied group-contribution methods (CLOGP and LOGKOW).

Synthesis and Morphine Enhancement Activity of N‐[5‐(2‐Phenoxyphenyl)‐1,3,4‐oxadiazole‐2‐yl]‐N′‐phenylurea Derivatives.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis and morphine enhancement activity of N-[5-(2-phenoxyphenyl)-1, 3, 4-oxadiazole-2-yl]-N'-phenylurea derivatives.

The synthesis of N-[5-(2-phenoxyphenyl)-1, 3, 4-oxadiazole-2-yl]-N'-phenylurea derivatives is reported. The structures of these compounds are supported by their IR, (1)H-NMR and mass spectra. Conformational analysis and superimposition of energy minima conformers of these compounds on L-365, 260, a known 3-ureido-1, 4-benzodiazepine CCK-B antagonist, showed that the aromatic rings fell in the same contour. Morphine analgesia enhancement evaluation of the synthesized compounds in comparison with a control group showed that compounds 8a, 8c, 8h-8j, 8l, 8o have significant effects.

Alkaloid production by somatic embryo cultures of Corydalis ambigua

Somatic embryos of Corydalis ambigua (Papaveraceae), which were cultured in liquid Linsmaier and Skoog medium supplemented with 0.1 mM IAA and 3% sucrose, produced two tetrahydroprotoberberine alkaloids, corydaline (0.03% of dry cell weight) and cavidine (1.09%). Among various plant growth regulators tested, two phenylurea derivatives, thidiazuron and N-(2-chloro-4-pyridyl)-N� -phenylurea enhanced the alkaloid production. Addition of 1 mM thidiazuron to the medium gave the maximum alkaloid content, 0.12% corydaline and 1.91% cavidine, after 21 days incubation. These results were compared with those from callus cultures and various intact organs. Corydaline and cavidine were accumulated in leaf, tuber and somatic embryos, whereas corybulbine was detected only in tubers. Callus cultures and immature seeds, which lack embryos, contained only trace amounts of these alkaloids, suggesting the necessity for organ differentiation for alkaloid production in C. ambigua.

Versatile access to benzhydryl-phenylureas through an unexpected rearrangement during microwave-enhanced synthesis of hydantoins.

[reaction: see text] A new access to benzhydryl-phenylureas is described. These new interesting urea derivatives were obtained by reaction of substituted benzils with substituted phenylureas under microwave irradiation. Phenylthiourea, when reacted with benzil, gave 3-phenyl-thiohydantoin. Moreover, benzylurea, as phenethylurea, gave the corresponding 3-substituted hydantoin derivatives, demonstrating that only phenylurea derivatives can result in benzhydryl-phenylureas under the applied conditions. This new reaction proved to be an easy access to substituted 1-benzhydryl-3-phenyl-ureas.

Robotized time‐lapse imaging to assess in‐planta uptake of phenylurea herbicides and their microbial degradation

Two key physiological parameters of plant leaves, photosynthesis and transpiration, can be continuously monitored by, respectively, chlorophyll a fluorescence imaging and thermography. These non‐contact techniques immediately visualize any local stress or treatment affecting either photosynthetic efficiency or water status. Photosystem II‐inhibiting herbicides, including the phenylurea derivatives diuron and linuron, cause a marked increase in chlorophyll a fluorescence several days before appearance of chlorosis. Here, bioprotection through microbial degradation of linuron in the feeding solution of common bean plants (Phaseolus vulgaris L.) was monitored by the absence of an increase in chlorophyll a fluorescence in primary leaves. The different treatments and repeats were imaged sequentially at 2 h intervals using a robotized system with thermal, fluorescence and video cameras. Chlorophyll fluorescence imaging visualized the effect of linuron transported by the transpiration stream earlier than thermography. In addition, local effects and transport after topical application of diuron were recorded presymptomatically in tobacco (Nicotiana tabacum L.) and Arabidopsis thaliana (L.) Heynh. Thermal imaging clearly monitored localized stomatal closure, coinciding with the first increase in chlorophyll fluorescence, at the sites of diuron treatment. In conclusion, the robotized chlorophyll a fluorescence set‐up permits fully reliable, early high‐contrast visualization for bioremediation purposes.

Induction of multiple shoots by thidiazuron from caryopsis cultures of minor millet ( Paspalum scrobiculatum L.) and its effect on the regeneration of embryogenic callus cultures

Caryopsis culture of a minor millet (Paspalum scrobiculatum L. cv. PSC 1) on N6 medium supplemented with high concentrations of thidiazuron (TDZ, 11.25 µM and 22.5 µM), a phenylurea derivative known to simulate cytokinin action, resulted in the formation of multiple shoots from the base of the seedling. This is the first time that multiple-shoot formation by a seedling cultured on TDZ without a callus interphase has been reported in graminaceous crop plants. The presence of a cytokinin, 6-benzylaminopurine (BAP), at low or high concentrations failed to evoke any morphogenic response. The presence of the auxin 2,4-dichlorophenoxyacetic acid (2,4-D, 4.5 µM) either alone or with BAP (4.5 µM) resulted in the formation of embryogenic callus from the base of the seedlings, which subsequently differentiated into somatic embryos. The combination of TDZ and the auxin (4.5 µM, 2,4-D) in the medium stimulated the differentiation of shoot buds in embryogenic callus cultures. This effect of TDZ, noted for the first time in a monocotyledonous plant, was evident in terms of a significant increase in the frequency of shoot-bud formation in embryogenic callus cultures and occurred only at a high concentration of TDZ (11.25 µM). This requirement for a high concentration of TDZ for the induction of multiple shoots from cultured seedlings or shoot buds in an embryogenic callus culture of a monocot is contrary to its effect at low concentrations in dicotyledonous plants. Complete plantlets, derived either from somatic embryos or shoot buds, could be regenerated on hormone-free basal medium or on basal medium fortified with activated charcoal (0.5%). Following a gradual acclimatization in a culture room, these regenerants survived on transfer to soil and ultimately set seed.