Green Synthesis of Barbituric Acid Derivative via Goldsmith Effluent Initiated Gold Nanoparticles and its Molecular Docking Study against Alzheimer Drug Target

A convenient and efficient synthesis of 1,3-dimethyl-5-benzylidenebarbituric acid derivatives via gold nanoparticles is carried out. The gold nanoparticles were initiated from novel and low-cost goldsmith effluent source using green reducing agent D-glucose. By mediating autoclave at 121 ºC and 15 lb/cm2 pressure, these particles were further uniformly synthesized by using microwave radiation. The catalyst was analyzed using UV, IR and scanning electron microscopic techniques. Synthesized 1,3-dimethyl- 5-benzylidene-barbituric acid was assayed to study its inhibitory action against TAU protein.

Chemosensing Test Paper Based on Aggregated Nanoparticles of a Barbituric Acid Derivative

The development of sensitive, cheap, and portable methods for detecting nitroaromatics explosives has a profound significance and value for public health and environmental protection. For this purpose, a new D-π-A barbituric acid derivative CB-CYH with aggregation-induced emission (AIE) behavior was synthesized, which can interact with picric acid through photoinduced electron transfer (PET). Scanning electron microscopy (SEM) and dynamic light scattering (DLS) indicate that the enhanced emission of the compounds is related to the formation of nano-aggregates. It is well known that an important source of mechanochromic fluorescence (MCF) characteristic materials is the compound with AIE characteristics. The chemosensing test paper prepared by aggregated nanoparticles based on AIE properties is often subjected to external friction or squeeze during transportation or storage, resulting in changes of their optical properties, and destruction of test paper followed. Therefore, the development of compounds with AIE properties and stable optical properties in the presence of external stimuli is particularly important for chemosensing test paper. Molecular dynamics simulation (MDS) shows that the presence of hydrophobic cycloalkyl group in CB-CYH, which caused the molecules to be closely interspersed with each other; hence, it is difficult to change the microstructure and stacking mode of molecules by external stimulation simultaneously; the optical properties are not changed by external stimuli. Therefore, the test paper based on the AIE effect of CB-CYH was developed as chemosensing test paper for the detection of nitroaromatics.

Treatment with a New Barbituric Acid Derivative Exerts Antiproliferative and Antimigratory Effects against Sorafenib Resistance in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a common cause of cancer death worldwide. Sorafenib, a multikinase inhibitor, is the first-line drug approved by the Food and Drug Administration (FDA) for the treatment of patients with advanced HCC. However, most patients who continuously receive sorafenib may acquire resistance to this drug. Therefore, it is important to develop a new compound to treat liver cancer and sorafenib-resistant liver cancer. Barbituric acid derivatives have been used as antiasthmatic drugs in the clinic. We previously reported that a novel barbituric acid derivative inhibited carbon tetrachloride-induced liver fibrosis in mice, but its effects on liver cancer remain unknown. Thus, the purpose of this study was to investigate the antitumor effect of barbituric acid derivatives on HCC cells and sorafenib-resistant HCC cells (HCC-SRs). Our findings reveal that one of the barbituric acid derivatives, BA-5, significantly inhibited HCC and HCC-SR cell viability in a dose- and time-dependent manner. Therefore, compound BA-5 was selected for further experiments. Western blot data revealed that BA-5 treatment decreased the phosphorylation of AKT/p70s6k without affecting the MAPK pathway and increased cleaved PARP and cleaved caspase-7 in both HCC and HCC-SR cells. Since epithelial-mesenchymal transition plays a significant role in regulating cancer invasion and migration, we used the wound healing assay to evaluate the antimigratory effect of compound BA-5. The results showed that BA-5 treatment inhibited HCC and HCC-SR cell migration and reduced Vimentin protein expression. These results were confirmed by microarray analysis showing that BA-5 treatment influenced cancer cell motility and growth-related pathways. In the xenograft mouse model experiment, BA-5 administration significantly inhibited HCC cancer cell growth in mice. Furthermore, the combination of BA-5 with a low dose of regorafenib synergistically inhibited HCC-SR cell proliferation. In conclusion, our study showed that the barbituric acid derivative BA-5 is a new candidate for HCC and sorafenib-resistant HCC therapy.

Bactericidal Disruption of Magnesium Metallostasis inMycobacterium tuberculosisIs Counteracted by Mutations in the Metal Ion Transporter CorA

ABSTRACTA defining characteristic of treating tuberculosis is the need for prolonged administration of multiple drugs. This may be due in part to subpopulations of slowly replicating or nonreplicatingMycobacterium tuberculosisbacilli exhibiting phenotypic tolerance to most antibiotics in the standard treatment regimen. Confounding this problem is the increasing incidence of heritable multidrug-resistantM. tuberculosis. A search for new antimycobacterial chemical scaffolds that can kill phenotypically drug-tolerant mycobacteria uncovered tricyclic 4-hydroxyquinolines and a barbituric acid derivative with mycobactericidal activity against both replicating and nonreplicatingM. tuberculosis. Both families of compounds depletedM. tuberculosisof intrabacterial magnesium. Complete or partial resistance to both chemotypes arose from mutations in the putative mycobacterial Mg2+/Co2+ion channel, CorA. Excess extracellular Mg2+, but not other divalent cations, diminished the compounds’ cidality against replicatingM. tuberculosis. These findings establish depletion of intrabacterial magnesium as an antimicrobial mechanism of action and show thatM. tuberculosismagnesium homeostasis is vulnerable to disruption by structurally diverse, nonchelating, drug-like compounds.IMPORTANCEAntimycobacterial agents might shorten the course of treatment by reducing the number of phenotypically tolerant bacteria if they could killM. tuberculosisin diverse metabolic states. Here we report two chemically disparate classes of agents that killM. tuberculosisboth when it is replicating and when it is not. Under replicating conditions, the tricyclic 4-hydroxyquinolines and a barbituric acid analogue deplete intrabacterial magnesium as a mechanism of action, and for both compounds, mutations in CorA, a putative Mg2+/Co2+transporter, conferred resistance to the compounds whenM. tuberculosiswas under replicating conditions but not under nonreplicating conditions, illustrating that a given compound can killM. tuberculosisin different metabolic states by disparate mechanisms. Targeting magnesium metallostasis represents a previously undescribed antimycobacterial mode of action that might crippleM. tuberculosisin a Mg2+-deficient intraphagosomal environment of macrophages.

A new dibenzothiophene-based dual-channel chemosensor for cyanide with aggregation induced emission

A new dibenzothiophene-based barbituric acid derivative (DTB) with an aggregation induced emission (AIE) effect was synthesized as a naked-eye colorimetric and fluorescent probe for CN−.

Benzylidene Barbituric Acid Derivatives Shown Anticonvulsant Activity on Pentylenetetrazole-Induced Seizures in Mice: Involvement of Nitric Oxide Pathway

ABSTRACT Background: Barbituric acid derivatives have long been used as central nervous system (CNS) suppressants, such as sedatives, hypnotics and anticonvulsants. In addition, previous studies have implicated the involvement of nitric oxide (NO) in the anticonvulsive effects of barbiturates in CNS. Therefore, the purpose of this study was to figure out the effects of a novel class of barbituric acid derivatives on pentylenetetrazole (PTZ)-induced seizures in male mice. Methods: Thirteen synthesized barbituric acid derivatives (a-m) and phenobarbital were administered intraperitoneally (i.p.) 30 min before induction of seizures by PTZ administration. The mechanisms of PTZ-induced seizures in the mice was evaluated using a non-selective nitric oxide synthase (NOS) inhibitor, selective inducible NOS (iNOS) inhibitor, a selective neuronal NOS (nNOS) inhibitor, and NO substrate. Results: Administration of most of the above mentioned derivatives significantly increased the seizures threshold (P<0.001). The most potent derivative (compound a), was chosen in order to investigate the mechanism of action involving in anticonvulsant activity. Administration of a non-selective NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) and a selective nNOS inhibitor, 7-nitroindazole (7-NI) reversed anticonvulsant activity of compound a. However, injection of the nitric oxide precursor, L-arginine (L-Arg) and a selective iNOS inhibitor, aminoguanidine (AG), did not change anticonvulsant activity of the mentioned compound. Conclusion: These results indicated that the NO system, specifically nNOS may contribute to the anticonvulsant activity of benzylidene barbituric acid derivative a. Therefore, this compound is a good candidate in order to designing new anticonvulsant medications

Kinetics of Hydrolysis of N-Methyl-2,4-dithiophenobarbital

The rate of hydrolytic degradation of N-methyl-2,4-dithiophenobarbital by spectrophotometric and separation methods was studied. The rate constants, order of reaction, activation energy, and pKa values were calculated based on the measurements of absorbance in the UV range. The changes in the absorbance values ​​over time for solutions of different pH were analysed. Based on the obtained results, it was found that the hydrolysis of N-methyl-2,4-dithiophenobarbital followed the kinetics of a pseudo-first order reaction. Plots illustrating dependences, log k, and pH indicate the catalytic effect of OH– ions on the occurring process. The results show that in an alkaline environment the pyrimidine ring undergoes cleavage in the 1–6 position, and gradual desulfurization. The obtained results were compared with data for phenobarbital, 2-thiophenobarbital, and 2,4-dithiophenobarbital. It can be concluded that the change of an oxygen atom to a sulfur atom in the ring of a barbituric acid derivative causes an easier decomposition of the compound. However, the insertion of a methyl group on the nitrogen atom increases the durability of the compound.