Synthesis and Evaluation of Antioxidant Properties of 2-Substituted Quinazolin-4(3H)-ones

Quinazolinones represent an important scaffold in medicinal chemistry with diverse biological activities. Here, two series of 2-substituted quinazolin-4(3H)-ones were synthesized and evaluated for their antioxidant properties using three different methods, namely DPPH, ABTS and TEACCUPRAC, to obtain key information about the structure–antioxidant activity relationships of a diverse set of substituents at position 2 of the main quinazolinone scaffold. Regarding the antioxidant activity, ABTS and TEACCUPRAC assays were more sensitive and gave more reliable results than the DPPH assay. To obtain antioxidant activity of 2-phenylquinazolin-4(3H)-one, the presence of at least one hydroxyl group in addition to the methoxy substituent or the second hydroxyl on the phenyl ring in the ortho or para positions is required. An additional ethylene linker between quinazolinone ring and phenolic substituent, present in the second series (compounds 25a and 25b), leads to increased antioxidant activity. Furthermore, in addition to antioxidant activity, the derivatives with two hydroxyl groups in the ortho position on the phenyl ring exhibited metal-chelating properties. Our study represents a successful use of three different antioxidant activity evaluation methods to define 2-(2,3-dihydroxyphenyl)quinazolin-4(3H)-one 21e as a potent antioxidant with promising metal-chelating properties.

8-Hydroxy-6-methoxy-7-(3-methylbut-2-enyloxy)coumarin (capensine)

The title coumarin derivative, C15H16O5, was isolated from the roots of Sophora japonica. The coumarin (2H-chromen-2-one) fragment is almost planar, with an r.m.s. deviation of 0.0356 Å. The carbon atom of the methoxy substituent is coplanar with the benzopyran oxa-heterocycle. The 3-methylbut-2-enyloxy group is disordered over two sets of sites with occupation factors of 0.920 (3) and 0.080 (3). In the crystal, molecules are linked by O—H...O and C—H...O hydrogen bonds into chains propagating along the [101] direction.

Syntheses and structures of two benzoyl amides: 2-chloro-4-ethoxy-3,5-dimethoxy-N-(3-oxocyclohex-1-en-1-yl)benzamide and 2-chloro-N-(5,5-dimethyl-3-oxocyclohex-1-en-1-yl)-4-ethoxy-3,5-dimethoxybenzamide

The first title benzoyl amide, C17H20ClNO5 (3a), crystallizes in the monoclinic space group P21/c with Z = 4 and the second, C19H24ClNO5 (3b), also crystallizes in P21/c with Z = 8 (Z′ = 2), thus there are two independent molecules in the asymmetric unit. In 3a, the phenyl ring makes a dihedral angle of 50.8 (3)° with the amide moiety with the C=O group on the same side of the molecule as the C—Cl group. One methoxy group is almost in the plane of the benzene ring, while the ethoxy and other methoxy substituent are arranged on opposite sides of the ring with the ethoxy group occupying the same side of the ring as the C=O group in the amide moiety. For one of the two molecules in 3b, both the amide and 5,5-dimethyl-3-oxocyclohex-1-en-1-yl moieties are disordered over two sets of sites with occupancies of 0.551 (2)/0.449 (2) with the major difference between the two conformers being due to the conformation adopted by the cyclohex-2-en-1-one ring. The three molecules in 3b (i.e., the undisordered molecule and the two disorder components) differ in the arrangement of the subsituents on the phenyl ring and the conformation adopted by their 5,5-dimethyl-3-oxocyclohex-1-en-1-yl moieties. In the crystal of 3a, N—H...O hydrogen bonds link the molecules into a zigzag chain propagating in the [001] direction. For 3b a combination of C—H...O and N—H...O intermolecular interactions link the molecules into a zigzag ribbon propagating in the [001] direction.

Effect of Additional Donor on Decene Formation in Ethylene Oligomerization Catalyzed by Cr/PCCP System: A Combined Experimental and DFT Study

A two-carbon bridged diphosphine (PCCP) ligand bearing an ortho-methoxy substituent in the phosphine phenyl group has been synthesised and applied in Cr-catalysed ethylene tri-/tetramerization. Compared to previous catalysts, the Cr...

Indole C6 Functionalization of Tryprostatin B Using Prenyltransferase CdpNPT

Tryprostatin A and B are prenylated, tryptophan-containing, diketopiperazine natural products, displaying cytotoxic activity through different mechanisms of action. The presence of the 6-methoxy substituent on the indole moiety of tryprostatin A was shown to be essential for the dual inhibition of topoisomerase II and tubulin polymerization. However, the inability to perform late-stage modification of the indole ring has limited the structure–activity relationship studies of this class of natural products. Herein, we describe an efficient chemoenzymatic approach for the late-stage modification of tryprostatin B using a cyclic dipeptide N-prenyltransferase (CdpNPT) from Aspergillus fumigatus, which generates novel analogs functionalized with allylic, benzylic, heterocyclic, and diene moieties. Notably, this biocatalytic functionalizational study revealed high selectivity for the indole C6 position. Seven of the 11 structurally characterized analogs were exclusively C6-alkylated, and the remaining four contained predominant C6-regioisomers. Of the 24 accepted substrates, 10 provided >50% conversion and eight provided 20–50% conversion, with the remaining six giving <20% conversion under standard conditions. This study demonstrates that prenyltransferase-based late-stage diversification enables direct access to previously inaccessible natural product analogs.

Effect of the position of a methoxy substituent on the antimicrobial activity and crystal structures of 4-methyl-1,6-diphenylpyrimidine-2(1H)-selenone derivatives

Derivatives of pyrimidine-2(1H)-selenone are a group of compounds with very strong antimicrobial activity. In order to study the effect of the position of the methoxy substituent on biological activity, molecular geometry and intermolecular interactions in the crystal, three derivatives were prepared and evaluated with respect to their antimicrobial activities, and their crystal structures were determined by X-ray diffraction. The investigated compounds, namely, 1-(X-methoxyphenyl)-4-methyl-6-phenylpyrimidine-2(1H)-selenones (X = 2, 3 and 4 for 1, 2 and 3, respectively), C18H16N2OSe, showed very strong activity against selected strains of Gram-positive bacteria and fungi. Two compounds, 1 and 2, crystallize in the monoclinic space group P21/c, while 3 crystallizes in the space group P21/n; 1 has two molecules in the asymmetric unit and the other two (2 and 3) have one molecule. The geometries of the investigated compounds differ slightly in the mutual orientations of the aromatic and pyrimidineselenone rings. The O atom in 1 stabilizes the conformation of the molecules via intramolecular C—H...O hydrogen bonding. The packing of molecules is determined by weak C—H...N and C—H...Se intermolecular interactions and additionally in 1 and 2 by C—H...O intermolecular interactions. The introduction of the methoxy substituent results in greater selectivity of the investigated compounds.

The effect of methyl and methoxy substituents on dianilines for a thermosetting polyimide system

4,4′-Methylenedianiline (MDA) is widely used in high-temperature polyimide resins, including polymerization of monomer reactants-15. The toxicity of MDA significantly limits the manufacturability using this resin. Modifying the substitution and electronics of MDA could allow for the reduction of toxicity while maintaining the high-performing properties of the materials derived from the modified MDA. The addition of a single methyl substituent, methoxy substituent, location of these substituents, and location of the amine relative to the phenolic bridge were modified as were other non-aniline diamines. Various anilines were condensed with paraformaldehyde under acidic conditions to yield dianilines. These dianilines and diamines were reacted with nadic anhydride and 3,3′,4,4′-benzophenonetetracarboxylic dianhydride in methanol to form the polyamic acid oligomers and heated at elevated temperature to form polyimide oligomers. It was found that the molecular weight of the oligomers derived from MDA alternatives was generally lower than that of MDA oligomers resulting in lower glass transition temperatures ( T gs) and degradation temperatures. Additionally, methoxy substituents further reduce the T g of the polymers versus methyl substituents and reduce the thermal stability of the resin. Methyl-substituted alternatives produced polyimides with similar T gs and degradation temperatures. The toxicity of the MDA alternatives was examined. Although a few were identified with reduced toxicities, the alternatives with properties similar to that of MDA also had high toxicities.

Novel Synthesis of Substituted 2-Trifluoromethyl and 2-Perfluoroalkyl N-Arylpyridinium Compounds—Mechanistic Insights

We report a new one-pot synthesis of 2-trifluoromethylated/2-perfluoroalkylated N-aryl-substituted pyridiniums, 5,6,7,8-tetrahydroquinoliniums and 6,7,8,9-tetrahydro-5H-cyclohepta[b]-pyridinium compounds starting from an activated β-dicarbonyl analogue (here a perfluoro-alkylated gem-iodoacetoxy derivative), an aromatic amine and a (cyclic or acyclic) ketone. The key step of this multicomponent reaction, involves the formation of a 3-perfluoroalkyl-N,N’-diaryl-1,5-diazapentadiene intermediate, various examples of which were isolated and characterized for the first time, together with investigation of their reactivity. We propose a mechanism involving a concurrent inverse electron demand Diels-Alder or Aza-Robinson cascade cyclisation, followed by a bis-de-anilino-elimination. Noteworthy, a meta-methoxy substituent on the aniline directs the reaction towards a 2-perfluoroalkyl-7-methoxyquinoline, resulting from the direct cyclization of the diazapentadiene intermediate, instead of pyridinium formation. This is the first evidence of synthesis of pyridinium derivatives from activated β-dicarbonyls, ketones, and an aromatic amine, the structures of which (both reactants and products) being analogous to species involved in biological systems, especially upon neurodegenerative diseases such as Parkinson’s. Beyond suggesting chemical/biochemical analogies, we thus hope to outline new research directions for understanding the mechanism of in vivo formation of pyridiniums, hence possible pharmaceutical strategies to better monitor, control or prevent it.

Comparison of the behavioral effects of mescaline analogs using the head twitch response in mice

Background: In recent years, there has been increasing scientific interest in the effects and pharmacology of serotonergic hallucinogens. While a large amount of experimental work has been conducted to characterize the behavioral response to hallucinogens in rodents, there has been little systematic investigation of mescaline and its analogs. The hallucinogenic potency of mescaline is increased by α-methylation and by homologation of the 4-methoxy group but it not clear whether these structural modifications have similar effects on the activity of mescaline in rodent models. Methods: In the present study, the head twitch response (HTR), a 5-HT2A receptor-mediated behavior induced by serotonergic hallucinogens, was used to assess the effects of mescaline and several analogs in C57BL/6J mice. HTR experiments were conducted with mescaline, escaline (4-ethoxy-3,5-dimethoxyphenylethylamine) and proscaline (3,5-dimethoxy-4-propoxyphenylethylamine), their α-methyl homologs TMA (3,4,5-trimethoxyamphetamine), 3C-E (4-ethoxy-3,5-dimethoxyamphetamine) and 3C-P (3,5-dimethoxy-4-propoxyamphetamine), and the 2,4,5-substituted regioisomers TMA-2 (2,4,5-trimethoxyamphetamine), MEM (4-ethoxy-2,5-dimethoxyamphetamine) and MPM (2,5-dimethoxy-4-propoxyamphetamine). Results: TMA induced the HTR and was twice as potent as mescaline. For both mescaline and TMA, replacing the 4-methoxy substituent with an ethoxy or propoxy group increased potency in the HTR assay. By contrast, although TMA-2 also induced the HTR with twice the potency of mescaline, potency was not altered by homologation of the 4-alkoxy group in TMA-2. Conclusions: The potency relationships for these compounds in mice closely parallel the human hallucinogenic data. These findings are consistent with evidence that 2,4,5- and 3,4,5-substituted phenylalkylamine hallucinogens exhibit distinct structure-activity relationships. These results provide additional evidence that the HTR assay can be used to investigate the structure-activity relationships of serotonergic hallucinogens.