Biological Activity of Hexaazaisowurtzitane Derivatives.

Biologically active compounds of natural or synthetic origin have a complex structure and generally contain various structural groups among which polycyclic cage amines are found. Hexaazaisowurtzitanes are representatives of these amines and studies on their biological activity began less than two decades ago, starting with research on the environmental impact of CL-20. This research helped to evaluate the risks of potential pollution in the habitat environments of living organisms and determine whether the chemical compounds in question could be utilized in pesticides, herbicides, fungicides, or medicinal drugs. The nomenclature of hexaazaisowurtzitane compounds has recently been expanded significantly, and some of them have demonstrated promise in the design of medicinal drugs. This paper review studies the pharmacological activity of the acyl derivatives of hexaazaisowurtzitane. Most of the compounds have been found to possess a high analgesic activity, providing a solution to the pressing issue of pain management in current pharmacology. Analgesic drugs currently used in the clinical practice do not meet all of the efficacy and safety requirements (gastro-, nephro-, hepato-, haematotoxicity, etc.). The material presented in the seven sections of this paper highlights information about hexaazaisowurtzitane derivatives. Furthermore, they have been observed to exhibit anti-inflammatory, anticonvulsant, antihypoxic, and antimetastatic activities, which render them highly promising for evaluation in various fields of medicinal practice.

A Comparative Study of the Synthesis and Hydrolysis of sym-Triaminobenzene Homologues.

Here, we investigated the synthetic processes for the methyl derivatives of sym-triaminobenzene and phloroglucinol, the essential chemical reactants coming into use in the production of dyes and pigments, and medicinal drugs for different purposes. The most eco-benign process for the synthesis of triamino derivatives involves the catalytic hydrogenation of corresponding nitroarenes. The present study investigated the hydrogenation of 2,4,6-trinitrotoluene, 2,4,6-trinitroxylene, and 2,4,6-trinitromesitylene over a Pd catalyst. A 1% Pd/Sibunit catalyst was found to be preferable to the 5% analogue with a preserved palladium loading because it shortens the reaction time and provides a higher yield of the target product. The hydrogenation in methanol (or mixed methanol/toluene) at 50-55 °C and 0.5 MPa pressure produced 2,4,6-triaminotoluene, 2,4,6-triaminoxylene, and 2,4,6-triaminomesitylene, which were isolated as sulfuric acid salts in 98, 91, and 97% yields, respectively. The hydrolysis process of the resultant salts was examined, and conditions leading to mono-, di-, and trimethyl derivatives of phloroglucinol (90, 77, and 82%, respectively,) were identified. The hydrogenation of the trinitrobenzene homologues in mixed 7:1 (v/v) acetone/water, followed by hydrolysis to the respective polyphenols, was explored. A successful result was achieved only for 2,4,6-trinitrotoluene. The catalyst activity was shown to decline negligibly throughout 10 cycles of reuse. 2-Methylphloroglucinol was synthesized in a high yield ranging from 85 to 91% calculated as 2,4,6-trinitrotoluene.

Nitration of 2,6,8,12-Tetraacetyl-2,4,6,8,10,12-Hexaazaisowurtzitane Derivatives.

The nitration of novel bioactive derivatives of 2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazaisowurtzitane in different nitrating systems was examined. The yield of CL-20, the known product from the nitration of hexaazaisowurtzitane compounds, was found to depend on the nature of substituents at the 4,1 positions and on the composition of the nitrating mixture.

Condensation of 4-Tert-butyl-2,6-dimethylbenzenesulfonamide with Glyoxal and Reaction Features: A New Process for Symmetric and Asymmetric Aromatic Sulfones.

The synthesis of substituted aza- and oxaazaisowurtzitanes via direct condensation is challenging. The selection of starting ammonia derivatives is very limited. The important step in developing alternative synthetic routes to these compounds is a detailed study on their formation process. Here, we explored an acid-catalyzed condensation between 4-tert-butyl-2,6-dimethylbenzenesulfonamide and glyoxal in aqueous H2SO4, aqueous acetonitrile and acetone, and established some new processes hindering the condensation. In particular, an irreversible rearrangement of the condensation intermediate was found to proceed and be accompanied by the 1,2-hydride shift and by the formation of symmetric disulfanes and sulfanes. It has been shown for the first time that aldehydes may act as a reducing agent when disulfanes are generated from aromatic sulfonamides, as is experimentally proved. The condensation between 4-tert-butyl-2,6-dimethylbenzenesulfonamide and formaldehyde resulted in 1,3,5-tris((4-(tert-butyl)-2,6-dimethylphenyl)sulfonyl)-1,3,5-triazinane. It was examined if diimine could be synthesized from 4-tert-butyl-2,6-dimethylbenzenesulfonamide and glyoxal by the most common synthetic procedures for structurally similar imines. It has been discovered for the first time that the Friedel-Crafts reaction takes place between sulfonamide and the aromatic compound. A new synthetic strategy has been suggested herein that can reduce the stages in the synthesis of in-demand organic compounds of symmetric and asymmetric aromatic sulfones via the Brønsted acid-catalyzed Friedel-Crafts reaction, starting from aromatic sulfonamides and arenes activated towards an electrophilic attack.

Synthesis of Diaminoacetic Acid Derivatives as a Promising Scaffold for the Synthesis of Polyheterocyclic Cage Compounds.

Here, we explored in detail an acid-catalyzed condensation of glyoxylic acid or its ethyl ester with several carboxamides of different basicity, or with mesyl amide, to furnish diaminoacetic acid derivatives. The most suitable synthesis conditions and the reaction catalysts were identified. Properties such as structure and basicity of the starting amides were demonstrated to influence the condensation process. Elemental iodine was used for the first time herein as an acid catalyst for the condensation of glyoxylic acid or its ester, which gave access to diaminoacetic acid derivatives in higher yields in most cases, as opposed to p-toluenesulfonic acid (PTSA). An abnormally high activity of mesyl amide when condensed with ethyl glyoxylate was noticed, which may evidence a special impact of the sulfonyl moiety in the amide molecule on the condensation.

Discovery of a Novel Non-Narcotic Analgesic Derived from the CL-20 Explosive: Synthesis, Pharmacology, and Target Identification of Thiowurtzine, a Potent Inhibitor of the Opioid Receptors and the Ion Channels.

The number of candidate molecules for new non-narcotic analgesics is extremely limited. Here, we report the identification of thiowurtzine, a new potent analgesic molecule with promising application in chronic pain treatment. We describe the chemical synthesis of this unique compound derived from the hexaazaisowurtzitane (CL-20) explosive molecule. Then, we use animal experiments to assess its analgesic activity in vivo upon chemical, thermal, and mechanical exposures, compared to the effect of several reference drugs. Finally, we investigate the potential receptors of thiowurtzine in order to better understand its complex mechanism of action. We use docking, molecular modeling, and molecular dynamics simulations to identify and characterize the potential targets of the drug and confirm the results of the animal experiments. Our findings finally indicate that thiowurtzine may have a complex mechanism of action by essentially targeting the mu opioid receptor, the TRPA1 ion channel, and the Cav voltage-gated calcium channel.

Neuroprotective effects of p-tyrosol after the global cerebral ischemia in rats.

BACKGROUND: Salidroside is a biologically active compound derived from Rhodiola rosea L. Studies showed that salidroside after i.v. injection is extensively metabolized to p-tyrosol and only trace amounts of salidroside are found in the brain tissue. OBJECTIVE: The aim of the study was to investigate the neuroprotective effects of p-tyrosol in the global cerebral ischemia-reperfusion (GCI) model. STUDY DESIGN: A total of 103 Wistar rats were assigned to groups of sham-operated (n=10), control (n=42), p-tyrosol-treated (n=36), and pentoxifylline-treated (n=15) animals. The rats of control, p-tyrosol-treated, and pentoxifylline-treated groups received intravenously 0.9% NaCl solution, 2% solution of p-tyrosol in doses of 5mg/kg, 10mg/kg, and 20mg/kg, and pentoxifylline in a dose of 100mg/kg, respectively, daily for 5 days. Rats were examined at days 1, 3, and 5 after GCI. After evaluation of neurological deficit, animals were euthanized for morphological and biochemical characterization. METHODS: Rats of control, p-tyrosol-treated, and pentoxifylline-treated groups were exposed to three-vessel model of GCI. Neurological deficit, numeric density of neurons in hippocampal CA1 region, and percentage of neurons with focal and total chromatolysis were studied. Biochemical study assessed contents of conjugated dienes and fluorescent products in brain homogenate. RESULTS: In control group, only 50.0% of rats survived by day 5 after the GCI; 38.1% of survived animals had severe neurologic deficit. In brain tissue of PTX-treated rats, the levels of diene conjugates and fluorescent products were 79% and 73%, respectivley, at day 5 compared with control. Differences in diene conjugates were statistically significant compared with control. The survival rate of animals treated with 20mg/kg p-tyrosol was 82.3% at day 5 after GCI. In p-tyrosol-treated GCI rats, the numeric density of neurons in the hippocampal CA1 region was higher by 31% compared with control. The percentage of neurons with focal and total chromatolysis decreased by 27% and 43%, respectively. At day 5 after GCI, the levels of conjugated dienes and fluorescent products were significantly lower (by 37% and 45%, respectively) in group of animals treated with 20mg/kg p-tyrosol compared with control. Moderate neuroprotective effects of 5mg/kg p-tyrosol administration were documented only at day 5 after GCI. In case of 10mg/kg p-tyrosol administration, neuroprotection was documented sooner: at day 1 or 3 after GCI. However, administration of 5 and 10mg/kg p-tyrosol did not affect animal survival. CONCLUSION: Course administration of intravenous p-tyrosol in a dose of 20mg/kg increased survival, reduced neurological deficit after GCI, attenuated neuronal damage in the hippocampus, and attenuated lipid peroxidation in brain tissue in animals subject to GCI with reperfusion.

Shikimic acid: review of its analytical, isolation, and purification techniques from plant and microbial sources.

Shikimic acid properties and its available analytical techniques are discussed. Plants having the highest content of shikimic acid are shown. The existing isolation methods are analyzed and the most optimal approaches to extracting this acid from natural sources (plants and microorganisms) are considered.