Targeting kinases with anilinopyrimidines: Discovery of N-phenyl-N'-[4-(pyrimidin-4-ylamino)phenyl]urea derivatives as selective inhibitors of class III receptor tyrosine kinase subfamily

Kinase inhibitors are attractive drugs/drug candidates for the treatment of cancer. The most recent literature has highlighted the importance of multi target kinase inhibitors, although a correct balance between specificity and non-specificity is required. In this view, the discovery of multityrosine kinase inhibitors with subfamily selectivity is a challenging goal. Herein we present the synthesis and the preliminary kinase profiling of a set of novel 4-anilinopyrimidines. Among the synthesized compounds, the N-phenyl-N\u2019-[4-(pyrimidin-4-ylamino)phenyl]urea derivatives selectively targeted some members of class III receptor tyrosine kinase family. Starting from the structure of hit compound 19 we synthesized a further compound with an improved affinity toward the class III receptor tyrosine kinase members and endowed with a promising antitumor activity both in vitro and in vivo in a murine solid tumor model. Molecular modeling simulations were used in order to rationalize the behavior of the title compounds

Attenuation of Mycobacterium species through direct and macrophage mediated pathway by unsymmetrical diaryl urea

Tuberculosis is a major threat for mankind and the emergence of resistance strain of Mycobacterium tuberculosis (Mtb) against first line antibiotics makes it lethal for human civilization. In this study, we have synthesized different diaryl urea derivatives targeting the inhibition of mycolic acid biosynthesis. Among the 39 synthesized molecules, compounds 46, 57, 58 and 86 showed MIC values ≤ 10 μg/ml against H37Rv and mc26030 strains. The best molecule with a methyl at ortho position of the first aromatic ring and prenyl group at the meta position of the second aromatic ring showed the MIC value of 5.2 μg/ml and 1 μg/ml against H37Rv and mc26030 respectively, with mammalian cytotoxicity of 163.4 μg/ml. The effective compounds showed selective inhibitory effect on mycolic acid (epoxy mycolate) biosynthesis in14C-radiolabelled assay. At the same time these molecules also executed their potent immunomodulatory activity by up-regulation of IFN-γ and IL-12 and down-regulation of IL-10.Fil: Velappan, Anand Babu. Sastra University; IndiaFil: Charan Raja, Mamilla R.. Sastra University; IndiaFil: Datta, Dhrubajyoti. Indian Institute of Science Education and Research Pune; IndiaFil: Tsai, Yi Ting. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Halloum, Iman. Université de Montpellier; Francia. Centre National de la Recherche Scientifique; FranciaFil: Wan, Baojie. University of Illinois; Estados UnidosFil: Kremer, Laurent. Université de Montpellier; Francia. Inserm; Francia. Centre National de la Recherche Scientifique; FranciaFil: Gramajo, Hugo Cesar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Franzblau, Scott G.. University of Illinois; Estados UnidosFil: Kar Mahapatra, Santanu. Sastra University; IndiaFil: Debnath, Joy. Sastra University; Indi

Emerging Investigators Series: Pyrolysis Removes Common Microconstituents Triclocarban, Triclosan, and Nonylphenol from Biosolids

Reusing biosolids is vital for the sustainability of wastewater management. Pyrolysis is an anoxic thermal degradation process that can be used to convert biosolids into energy rich py-gas and py-oil, and a beneficial soil amendment, biochar. Batch biosolids pyrolysis (60 minutes) revealed that triclocarban and triclosan were removed (to below quantification limit) at 200 °C and 300 °C, respectively. Substantial removal (\u3e90%) of nonylphenol was achieved at 300 °C as well, but 600 °C was required to remove nonylphenol to below the quantification limit. At 500 °C, the pyrolysis reaction time to remove \u3e90% of microconstituents was less than 5 minutes. Fate studies revealed that microconstituents were both volatilized and thermochemically transformed during pyrolysis; microconstituents with higher vapor pressures were more likely to volatilize and leave the pyrolysis reactor before being transformed than compounds with lower vapor pressures. Reductive dehalogenation products of triclocarban and suspected dehalogenation products of triclosan were identified in py-gas. Application of biosolids-derived biochar to soil in place of biosolids has potential to minimize organic microconstituents discharged to the environment provided appropriate management of py-gas and py-oil

Metabolic and cometabolic degradation of herbicides in the fine material of railway ballast

Microbial degradation of 3-(3,4-dichlorophenyl)-1,1-dimethylurea (diuron) and mineralization of 4-chloro-2-methylphenoxyacetic acid (MCPA) were studied in soil samples taken from the ballast layers of three Swedish railway embankments. The degradation of diuron followed first-order kinetics and half-lives ranged between 122 and 365 days. The half-lives correlated strongly with microbial biomass estimated by substrate-induced respiration (SIR; R=-0.85; p<0.05) and with the amount of organic matter measured as loss on ignition (R=-0.87; p<0.05). Accumulation of the metabolites 1-(3,4-dichlorophenyl)-3-methyl urea (DCPMU) and 1-(3,4-dichlorophenyl) urea (DCPU) was observed in all samples and these were only detectably degraded in the sample with the highest SIR. Addition of ground lucerne straw to the ballast samples stimulated microbial activity and led to increased formation of metabolites, but further transformation of DCPMU and DCPU was not enhanced. Mineralization of MCPA followed growth-linked kinetics and the time for 50% mineralization was 44.5±7.1 days in samples of previously untreated ballast. In samples of ballast that had been previously treated with the herbicide formulation MCPA 750, the time for 50% mineralization was reduced to 13.7±11.3 days. The number of MCPA degraders, quantified using an MPN technique, was clearly increased but highly variable. An average yield of 0.18 cells pg−1 of MCPA was estimated from the kinetic data. The yield estimates correlated with the amount of nitrogen in the ballast, indicating that mineralization of MCPA was nitrogen-limited in the railway embankments studied. This has practical implications for weed control using herbicides on railways

Excretion balance, metabolic fate, and tissue residues of N-Phenyl-N'-1,2,5-Thiadiazol-3-Ylurea (Photothidiazuron) in rats

"December, 1978""Thidiazuron (DROPP[copyright]) or N-phenyl-N'-1,2,3-thiadiazol-5-ylurea is a promising new cotton defoliant currently being developed by NOR-AM Agricultural Products, Incorporated. In addition to its defoliating activity, thidiazuron demonstrates strong inhibition of regrowth with no adverse effect on the opening or quality of fiber of mature bolls not open at the time of application (Anonymous, 1975). These attributes indicate this could be a useful product. With the possibility of widespread use of thidiazuron in cotton growing regions, it is necessary to consider the result of its photodegradation. The major thidiazuron conversion product, which occurs on the plant surface, is photothidiazuron or N-phenyl-N'-1,2,5-thiadiazol-3-ylurea (Anonymous, 1976). This new compound is the result of a rearrangement in the thiadiazol moiety (Anonymous, 1976). Thidiazuron and photothidiazuron are classified chemically as substituted ureas. This includes a broad group of compounds varying greatly in their molecular substituents and commercial uses. However, most substituted ureas are herbicides, and therefore, the orientation of research has been directed to plant and soil situations. Research data pertaining to the effects of substituted ureas upon mammalian and other animal systems is very limited (Geissbuhler, et al., 1975). Since it is possible that leaves and other parts of a thidiazuron treated cotton plant may be incorporated into livestock feed or eaten by other animals, it is essential to examine certain of the properties of photothidiazuron in relation to mammalian systems. The purpose of this study was to determine the excretion balance, metabolic fate, and tissue residues of photothidiazuron in rats. Specifically, the objectives were: 1. To determine the excretion balance, metabolic fate, and tissue residues after the administration of a single oral dose of photothidiazuron-14 aniline- C to male rats, 2. To investigate the degradation of photothidiazuron by rat liver subcellular fractions and by a model hydroxylation system, and 3. To identify major photothidiazuron metabolites."--Introduction

Quantitative determination of urea, thiourea, and certain of their substitution products by spectrophotometric techniques

Call number: LD2668 .T4 1960 H5

N-(4-Bromo­phen­yl)urea

In the title compound, C7H7BrN2O, both the urea moiety [maximum deviation 0.003 (2) Å] and the benzene ring are essentially planar [maximum deviation 0.003 (2) Å] but are rotated with respect to each other by a dihedral angle of 47.8 (1)°. The crystal assembly is stabilized by N—H⋯O hydrogen bonds between all NH protons as conventional hydrogen bond donors and the C=O oxygen as a trifurcated hydrogen-bond acceptor. Both the overall mol­ecular geometry and the crystal packing of the title compound are very similar to those of N-phenyl­urea, which is underscored by a practically isostructural relationship between these two urea derivatives

Relationships between lipophilicity and root uptake and translocation of non-ionized chemicals by barley

The uptake by roots from solution, and subsequent translocation to shoots in barley, of two series of non‐ionised chemicals, O‐methylcarbamoyloximes and substituted phenylureas, were measured, Uptake of the chemicals by roots was greater the more lipophilic the chemical, and fell to a lower limiting value for polar chemicals. Translocation to the shoots was a passive process, and was most efficient for compounds of intermediate polarity. Both processes had reached equilibrium within 24h of treatment. The reported behaviour of many pesticides in various plant species agrees with the derived relationships, but the detailed mechanisms of these processes are unknown.&nbsp

Synergistic Degradation of Linuron by a Bacterial Consortium and Isolation of a Single Linuron-Degrading Variovorax Strain

The bacterial community composition of a linuron-degrading enrichment culture and the role of the individual strains in linuron degradation have been determined by a combination of methods, such as denaturing gradient gel electrophoresis of the total 16S rRNA gene pool, isolation and identification of strains, and biodegradation assays. Three strains, Variovorax sp. strain WDL1, Delftia acidovorans WDL34, and Pseudomonas sp. strain WDL5, were isolated directly from the linuron-degrading culture. In addition, subculture of this enrichment culture on potential intermediates in the degradation pathway of linuron (i.e., N,O-dimethylhydroxylamine and 3-chloroaniline) resulted in the isolation of, respectively, Hyphomicrobium sulfonivorans WDL6 and Comamonas testosteroni WDL7. Of these five strains, only Variovorax sp. strain WDL1 was able to use linuron as the sole source of C, N, and energy. WDL1 first converted linuron to 3,4-dichloroaniline (3,4-DCA), which transiently accumulated in the medium but was subsequently degraded. To the best of our knowledge, this is the first report of a strain that degrades linuron further than the aromatic intermediates. Interestingly, the rate of linuron degradation by strain WDL1 was lower than that for the consortium, but was clearly increased when WDL1 was coinoculated with each of the other four strains. D. acidovorans WDL34 and C. testosteroni WDL7 were found to be responsible for degradation of the intermediate 3,4-DCA, and H. sulfonivorans WDL6 was the only strain able to degrade N,O-dimethylhydroxylamine. The role of Pseudomonas sp. strain WDL5 needs to be further elucidated. The degradation of linuron can thus be performed by a single isolate, Variovorax sp. strain WDL1, but is stimulated by a synergistic interaction with the other strains isolated from the same linuron-degrading culture