The First Example of the Friedel-Crafts Cyclization Leading to (10-Hydroxy-9,10-dihydroanthr-9-yl)phosphonium Salts without the Expected Bradsher Dehydration.

The reaction of (ortho-acetalaryl)arylmethanols with various phosphines PR1R2R3 (R1 = R2 = R3 = Ph; R1 = R2 = Ph, R3 = Me and R1 = R2 = Me, R3 = Ph) under acidic conditions (e.g., HCl, HBF4, TsOH) unexpectedly led to the formation of (10-hydroxy-9,10-dihydroanthr-9-yl)phosphonium salts instead of the corresponding anthryl phosphonium salts. The cyclization occurred according to the Friedel-Crafts mechanism but without the usually observed Bradsher dehydration, giving cyclic products in the form of cis/trans isomers and their conformers. In case of electron-rich and less-hindered dimethylphenylphosphine, all four stereoisomers were recorded in 31P{1H} NMR spectra, while for the other phosphines, only the two most stable cis/trans stereoisomers were detected. This study was supported by DFT and NCI calculations in combination with FT-IR analysis.

New Perspectives for Antihypertensive Sartans as Components of Co-crystals and Co-amorphous Solids with Improved Properties and Multipurpose Activity.

Sartans (angiotensin II receptor blockers, ARBs), drugs used in the treatment of hypertension, play a principal role in addressing the global health challenge of hypertension. In the past three years, their potential use has expanded to include the possibility of their application in the treatment of COVID-19 and neurodegenerative diseases (80 clinical studies worldwide). However, their therapeutic efficacy is limited by their poor solubility and bioavailability, prompting the need for innovative approaches to improve their pharmaceutical properties. This review discusses methods of co-crystallization and co-amorphization of sartans with nonpolymeric, low molecular, and stabilizing co-formers, as a promising strategy to synthesize new multipurpose drugs with enhanced pharmaceutical properties. The solid-state forms have demonstrated the potential to address the poor solubility limitations of conventional sartan formulations and offer new opportunities to develop dual-active drugs with broader therapeutic applications. The review includes an in-depth analysis of the co-crystal and co-amorphous forms of sartans, including their properties, possible applications, and the impact of synthetic methods on their pharmacokinetic properties. By shedding light on the solid forms of sartans, this article provides valuable insights into their potential as improved drug formulations. Moreover, this review may serve as a valuable resource for designing similar solid forms of sartans and other drugs, fostering further advances in pharmaceutical research and drug development.

Highly Substituted 10-RO-(hetero)acenes-Electric Properties of Vacuum-Deposited Molecular Films.

The functionalization of the aromatic backbone allows the improvement of the electrical properties of acene molecules in the amorphous layered structures of organic thin films. In the present work, we discuss the electric properties of the stable, amorphous, vacuum-deposited films prepared from five highly substituted 10-RO-acenes of various electronic properties, i.e., two extreme electron-donor (1,3-dioxa-cyclopenta[b]) anthracenes with all RO substituents, two anthracene carbaldehydes and one benzo[b]carbazole carbaldehyde possessing both electron-donor and acceptor substituents. The hole mobility data were obtained using subsequent steady state space charge limited currents (SCLC) and Time of Flight (TOF) measurements, performed on the same sample and these were then compared with the results of theoretical hole mobility calculations obtained using the Density Functional Theory (DFT) quantum-chemical calculations using the Marcus-Hush theory. The study shows a good agreement between the theoretical and experimental values which allows for the quick and quantitative estimation of Einstein's mobility values for highly substituted 10-RO anthracene and benzo[b]carbazole based on chemical calculations. This agreement also proves that the transport of holes follows the hopping mechanism. The theoretical calculations indicate that the reorganization energy plays a decisive role in the transport of holes in the amorphous layers of highly substituted hetero(acenes).

Can Pharmaceutical Excipients Threaten the Aquatic Environment? A Risk Assessment Based on the Microtox® Biotest.

The ecotoxicological impact of pharmaceuticals has received considerable attention, primarily focusing on active pharmaceutical ingredients (APIs) while largely neglecting the potential hazards posed by pharmaceutical excipients. Therefore, we analyzed the ecotoxicity of 16 commonly used pharmaceutical excipients, as well as 26 API-excipient and excipient-excipient mixtures utilizing the Microtox® test. In this way, we assessed the potential risks that pharmaceutical excipients, generally considered safe, might pose to the aquatic environment. We investigated both their individual ecotoxicity and their interactions with tablet ingredients using concentration addition (CA) and independent action (IA) models to shed light on the often-overlooked ecotoxicological consequences of these substances. The CA model gave a more accurate prediction of toxicity and should be recommended for modeling the toxicity of combinations of drugs with different effects. A challenge when studying the ecotoxicological impact of some pharmaceutical excipients is their poor water solubility, which hinders the use of standard aquatic ecotoxicity testing techniques. Therefore, we used a modification of the Microtox® Basic Solid Phase protocol developed for poorly soluble substances. The results obtained suggest the high toxicity of some excipients, i.e., SLS and meglumine, and confirm the occurrence of interactions between APIs and excipients. Through this research, we hope to foster a better understanding of the ecological impact of pharmaceutical excipients, prompting the development of risk assessment strategies within the pharmaceutical industry.

O,S-Acetals in a New Modification of oxo-Friedel-Crafts-Bradsher Cyclization-Synthesis of Fluorescent (Hetero)acenes and Mechanistic Considerations.

This paper presents the use of O,S-acetals in a new modification of the oxo-Friedel-Crafts-Bradsher cyclization. In this reaction, under mild reaction conditions (25 °C), three- and four-ring fused RO-acenes (major) and/or HO(CH2)2S-acenes (minor) are formed, the latter products having never been observed before in this type of cyclization. In this way, two electronically different fluorophores could be obtained in a single cyclization reaction, one of them having strong electron donor properties (+M effect of alkoxy groups) and the other having donor-acceptor properties (+M and -I effects of the HO(CH2)2S-group, Hammett's constants). Further increasing the reaction temperature, HCl concentration or prolonging reaction time, surprisingly, yielded a 2:1 mixture of cis and trans dimeric isomers, as the only products of this cyclization. The DFT calculations confirmed a greater stability of the cis isomer compared to the trans isomer. The formation of unexpected dimeric products and HO(CH2)2S-acenes sheds light on the mechanism of oxo-Friedel-Crafts-Bradsher cyclization, involving competitive O/S atom protonation in strained O,S-acetals and in strain-free side groups of intermediate species.

Comprehensive Review on Synthesis, Properties, and Applications of Phosphorus (PIII, PIV, PV) Substituted Acenes with More Than Two Fused Benzene Rings.

This comprehensive review, covering the years 1968-2022, is not only a retrospective investigation of a certain group of linearly fused aromatics, called acenes, but also a presentation of the current state of the knowledge on the synthesis, reactions, and applications of these compounds. Their characteristic feature is substitution of the aromatic system by one, two, or three organophosphorus groups, which determine their properties and applications. The (PIII, PIV, PV) phosphorus atom in organophosphorus groups is linked to the acene directly by a P-Csp2 bond or indirectly through an oxygen atom by a P-O-Csp2 bond.

Organosulfur Materials with High Photo- and Photo-Oxidation Stability: 10-Anthryl Sulfoxides and Sulfones and Their Photophysical Properties Dependent on the Sulfur Oxidation State.

While few studies show only symmetrical and poorly mono-SOn (n = 0-2) substituted acenes, in this study, we present a synthesis of a new group of unsymmetrical, significantly substituted derivatives, which revealed unique photophysical properties. Both sulfides (S), sulfoxides (SO) and sulfones (SO2) showed very high photochemical stabilities, unusual for these groups, during UV-irradiation at 254/365 nm (air O2 and Ar), which was higher than any found in the literature. For the (S)/(SO) series (254 nm), the stabilities of 80-519 min. (air O2 and Ar) were found. At 365 nm, stabilities of 124-812 min./(air O2) for (S)/(SO) and higher for (SO2) were observed. Photoluminescence lifetimes of (SOn) of the lower anthryl symmetry remained in the following order: (SO2) < (S) < (SO); those with full symmetry were in the following order: (S) < (SO) < (SO2). The enhanced photostability was explained with DFT/MS/Hammett's constants, which showed the leading role of the SOn groups in stabilization of HOMO/LUMO frontier orbitals. The SOn (n = 0-2) substituted acenes turned out to be tunable violet/blue/green emitters by oxidation of S atoms and the introduction of rich substitution.

Role of Hydrogen Bonds in Formation of Co-amorphous Valsartan/Nicotinamide Compositions of High Solubility and Durability with Anti-hypertension and Anti-COVID-19 Potential.

Physicochemical properties, in particular solubility and the associated bioavailability, are key factors in determining efficacy of poorly water-soluble drugs, which constitute 40% of new drugs in the market, and improving them is an important challenge for modern pharmacy. A recent strategy to achieve this goal is formation of stable co-amorphous solid dispersions with co-formers of low molecular weight. Here, the amorphization strategy was applied for low-soluble anti-hypertensive valsartan (VAL), an angiotensin II receptor blocker, and nicotinamide, which exhibits lung- and cardio-protective effects. Through interactions with the renin-angiotensin-aldosteron system, VAL may be used to treat both hypertension and the current pandemic coronavirus SARS-CoV-2 infection. Using mechanochemical and liquid- and solid-state approaches, solvated co-amorphous solid dispersions of VAL with nicotinamide were obtained. They were characterized by spectroscopic, thermal, and X-ray analyses. The density functional theory, quantum theory of atoms in molecules, and non-covalent interaction index calculations revealed the presence of two types of hydrogen bonds between VAL and NIC (i.e., N-H···O and O-H···O). One of them had a partially covalent character, which caused conformational changes in the flexible VAL molecule, restricting contribution of the tetrazolyl N-H donor and thus limiting the possibility of co-crystal formation. The recognized VAL/NIC1- and VAL/NIC2-type heterodimeric interactions were responsible for the excellent durability of the solid compositions and up to 24-fold better solubility than VAL alone. The synthesized dispersions constitute a new class of dually acting drugs, containing an active pharmaceutical ingredient (VAL) and supporting nutraceutical (nicotinamide).

Amygdalin: Toxicity, Anticancer Activity and Analytical Procedures for Its Determination in Plant Seeds.

Amygdalin (d-Mandelonitrile 6-O-ß-d-glucosido-ß-d-glucoside) is a natural cyanogenic glycoside occurring in the seeds of some edible plants, such as bitter almonds and peaches. It is a medically interesting but controversial compound as it has anticancer activity on one hand and can be toxic via enzymatic degradation and production of hydrogen cyanide on the other hand. Despite numerous contributions on cancer cell lines, the clinical evidence for the anticancer activity of amygdalin is not fully confirmed. Moreover, high dose exposures to amygdalin can produce cyanide toxicity. The aim of this review is to present the current state of knowledge on the sources, toxicity and anticancer properties of amygdalin, and analytical methods for its determination in plant seeds.

The hetero-Friedel-Crafts-Bradsher Cyclizations with Formation of Ring Carbon-Heteroatom (P, S) Bonds, Leading to Organic Functional Materials.

The interest in functional materials possessing improved properties led to development of new methods of their synthesis, which allowed to obtain new molecular arrangements with carbon and heteroatom motifs. Two of the classical reactions of versatile use are the Friedel-Crafts and the Bradsher reactions, which in the new heteroatomic versions allow to replace ring carbon atoms by heteroatoms. In the present work, we review methods of synthesis of C-S and C-P bonds utilizing thia- and phospha-Friedel-Crafts-Bradsher cyclizations. Single examples of C-As and lack of C-Se bond formation, involving two of the closest neighbors of P and S in the periodic table, have also been noted. Applications of the obtained π-conjugated molecules, mainly as semiconducting materials, flame retardants, and resins hardeners, designed on the basis of five- and six-membered cyclic molecules containing ring phosphorus and sulfur atoms, are also included. This comprehensive review covers literature up to August 2020.

Modification of the Microtox® Basic Solid Phase Test: A new application for the ecotoxicological studies on poorly soluble antihypertensive drugs.

Increasing consumption of angiotensin II receptor blockers (ARBs: valsartan, losartan potassium, telmisartan) is inevitably associated with their appearance in the environment and impact on aquatic and terrestrial organisms. Since the pharmaceuticals do not occur as pure substances in the environment, but as complex mixtures with other active pharmaceutical ingredients (APIs) and excipients used in pharmaceutical formulations, we compared the ecotoxicity of ARBs in various forms: as pure APIs, in pharmaceutical formulations and in mixtures with hydrochlorothiazide (HCT). Because the studied APIs are poorly water-soluble, the Microtox® Basic Solid Phase Test, utilizing bacteria Aliivibrio fischeri, has been modified by using a neutral matrix. Thus, this test, which is correlated with other tests for higher aquatic organisms, may be applied for the ecotoxicological evaluation of poorly soluble APIs. This is the first study reflecting the real situation in the environment, where non-target species are exposed to the pharmaceuticals, which can be dissolved/suspended in the liquid medium or adsorbed on the solid matrix. The results obtained indicate that the excipients are not inert substances and their presence in the environment may cause an increased risk to non-target organisms. Moreover, antagonistic effects were observed for two-component drug-drug (ARBs-HCT) mixtures.

Ecotoxicity of ammonium chlorophenoxyacetate derivatives towards aquatic organisms: Unexpected enhanced toxicity upon oxygen by sulfur replacement.

Phenoxyacetate herbicides, such as 2,4-D and MCPA, having a high toxicity to non-target organisms are commonly used for controlling broadleaf weeds in agriculture. However, novel and environmentally friendly analogs are constantly sought after. For this purpose, various substituents at the phenyl group have been tested to find the optimal balance between the potent herbicidal activity and safety for non-target species. In this work, we investigated the influence of the oxygen by sulfur replacement in the phenoxy moiety of ammonium chlorophenoxyacetates on the toxicity towards aquatic organisms, such as bacteria (Vibrio fischeri), water flea (Daphnia magna) and freshwater fish (Pimephales promelas) by determining experimental (Microtox® test - V. fischeri) and predicted (ACD Lab Percepta software - D. magna, P. promelas) EC50/LC50 values. The achieved results showed that in contrary to the literature observations, where O-compounds were more toxic than their S-analogs (urea/thiourea), the O/S replacement in chlorophenoxyacetate significantly increased ecotoxicity of the S-analogs (up to 11 times). Moreover, one- and two-substituted phenoxyacetates in the form of ammonium salts were less toxic to V. fischeri than the commercially available phenoxy herbicides in the acid form. The logP/logD values were also calculated to understand hydro/lipophilic nature of the investigated compounds and differences in their toxicity.

Ultrasound-assisted synthesis of RO- and RS-substituted (hetero)acenes via oxo- and thio-Friedel-Crafts/Bradsher reactions.

Two heteroatom-variants of the Friedel-Crafts/Bradsher cyclization of o-acetalaryl(aryl)methyl ethers and o-dithioacetalaryl(aryl)methyl thioethers, have been realized with the ultrasound assistance. The environmentally friendly "oxo-variant" (Oxo-F-C/B), proceeding in a medium containing mineral acid and a large amount of water (HClaq/CH3CN) led to a very efficient formation of RO-substituted (hetero)acenes in less than 5 min. In the "thio-variant" (Thio-F-C/B), o-dithioacetalaryl(aryl)methyl thioethers underwent ultrasound-assisted cyclization in nonaqueous medium (FeCl3/KI/EtOH) in less than 25 min., in lower yields than in the "oxygen variant" to give RS-substituted (hetero)acenes. The RO-(hetero)acenes cyclized at 25-60 °C in aqueous media but did not cyclize in organic solvents while the RS-(hetero)acenes required higher temperatures 55-60 °C and cyclized in organic solvents but did not react in aqueous media. The acceleration of the ultrasound-assisted reactions compared to the reactions carried out under silent conditions exceeded 7500 times in the most effective example of the oxo-variant and on average 2 times for the thio-variant. The plausible reaction mechanisms under ultrasound and silent conditions have been proposed. The ultrasonic mechanism involves disturbing of solvation layers and formation of the reactive ("naked") carbocations upon operation of the shock wave produced by the bubble collapse. The o-acetalaryl(aryl)methyl ethers underwent a selective ultrasound-assisted deacetalization to give o-formylaryl(aryl)methyl ethers, without subsequent cyclization under the acidic reaction conditions.

Mono-Aryl/Alkylthio-Substituted (Hetero)acenes of Exceptional Thermal and Photochemical Stability by the Thio-Friedel-Crafts/Bradsher Cyclization Reaction.

The highly substituted mono-aryl/alkylthio-(hetero)acenes prepared in this study have been found to be thermally more stable (Tdecomp. =331-354 °C) than the known di-aryl/alkylthio-substituted acenes by an average of 25 °C. They are also much more photostable at 254 and 365 nm (in both argon and air) than the parent anthracene and other reported anthracenes. The most photostable aryl/alkylthio-anthracenes at 254 nm were found to be 60-70 (in air) and 130 (in argon) times more stable in solution than the unsubstituted anthracene, and much more stable than known EDG/EWG-substituted anthracenes (EDG=electron-donating group, EWG=electron-withdrawing group) with an extended aromatic core. Furthermore, the acenes showed significantly higher photostability at 365 nm in both air and argon. The anthracenes were obtained by the novel thio-Friedel-Crafts/Bradsher cyclization reaction of hitherto unknown [o-(1,3-dithian-2-yl)aryl](aryl)methyl thioethers. The developed approach provides a general access to mono-aryl/alkylthio-substituted (hetero)acene frameworks containing at least three fused (hetero)aromatic rings. The characteristic feature of this approach, which leads to highly substituted acenes, is that the substituents, unlike in other methods, may be introduced at an early stage of the synthesis. DFT and TD-DFT calculations confirmed the stabilizing role of the aryl/alkylthio substituent in the mono-aryl/alkylthio-substituted anthracenes, which are the most stable anthracenes prepared to date. Their high photostability is mainly due to the quenching of singlet oxygen by the acene and the quenching of the acene S1 state by molecular oxygen.

A selective removal of the secondary hydroxy group from ortho-dithioacetal-substituted diarylmethanols.

We present a successful deoxygenation reaction of ortho-1,3-dithianylaryl(aryl)methanols which enables a selective removal of the secondary hydroxy group in presence of the 1,3-dithianyl moiety under reductive conditions. This reaction proceeds well with ZnI2/Na(CN)BH3 in dichloroethane or benzene for both unsubstituted and substituted aryls (by electron-rich groups). This is leading to formyl-protected diarylmethanes with potential application in the synthesis of new pharmaceuticals and optoelectronic materials. This synthetic approach gives an access to a wide variety of functionalized ortho-1,3-dithianylaryl(aryl)methanes in 26-95% yields and is recommended for the substrates containing sulfur atoms, for which transition metal-induced reactions fail.

Ammonium haloacetates - An alternative to glyphosate?

This study shows the design, synthesis and evaluation of eco(phyto)toxic and herbicidal activities of quaternary ammonium salts (QASs), derived from haloacetic acids, in context of the search for safer alternatives to the commonly used herbicide, N-(phosphonomethyl)glycine (glyphosate). The structure of the investigated QASs refers to the heteroatom sequence in the anion of glyphosate in which the (P-C)-N nitrogen atom was replaced by one or more halogens (F, Cl). The ecotoxicity of the synthesized QASs was tested against luminescent marine bacteria Vibrio fischeri (Microtox® test) and the crustaceans Heterocypris incongruens (Ostracodtoxkit F™). The phytotoxic effect of QASs was also studied with respect to spring barley (Hordeum vulgare) and common radish (Raphanus sativus L. radicula Pers.), whereas herbicidal activity was investigated in relation to popular weeds species gallant soldier (Galinsoga parviflora Cav.) and common sorrel (Rumex acetosa L.). The results showed that toxicity of the synthesized QASs depends on a number of halo-substituents, especially for bioluminescent bacteria Vibrio fischeri for which EC50 values were those varying the most. Phytotoxicity tests proved that the investigated QASs had a similar high, toxic effect both on monocotyledonous and dicotyledonous plants with exception of DIPA - DCA. Moreover, their herbicidal activity against common sorrel was comparable to glyphosate.

Synthesis of 1-indanones with a broad range of biological activity.

This comprehensive review describes methods for the preparation of 1-indanones published in original and patent literature from 1926 to 2017. More than 100 synthetic methods utilizing carboxylic acids, esters, diesters, acid chlorides, ketones, alkynes, alcohols etc. as starting materials, have been performed. This review also covers the most important studies on the biological activity of 1-indanones and their derivatives which are potent antiviral, anti-inflammatory, analgesic, antimalarial, antibacterial and anticancer compounds. Moreover, they can be used in the treatment of neurodegenerative diseases and as effective insecticides, fungicides and herbicides.

Ultrasound assisted Bradsher reaction in aqueous and non-aqueous media: First use of ultrasounds in electrophilic aromatic cyclisation leading to polyacenes.

The present work describes the first use of ultrasounds in the Bradsher cyclisation of activated and non-activated ortho-formyl diarylmethanes. This reaction is also the first example of electrophilic, aromatic cyclisation assisted by ultrasounds which leads to pure polycyclic, fused aromatic hydrocarbons containing 3 and 4 fused rings in excellent yields. The reaction proceeds not only in aqueous but also in non-aqueous media at milder conditions (room temperature) and in much shorter reaction times than in conventional protocols.

New Hopes in Cancer Battle - A Review of New Molecules and Treatment Strategies.

BACKGROUND: Cancer is one of the most serious illnesses of our civilization. Therefore, scientists of different disciplines try to find new treatment strategies and new chemical molecules which might be useful in a cancer treatment. OBJECTIVE: The goal of this work is to perform the most significant achievements in the area of chemotherapeutic treatment, published during the last two years. METHODS: We reviewed almost 80 contributions, searching for new molecules with anticancer activity and treatment strategies. RESULTS: We have presented tens of new anticancer molecules interacting with DNA or affecting cell cycle and new findings in this area. These compounds are chemically synthesized as well as are isolated from natural sources. The discovered molecules may induce cancer cells apoptosis, improve other cancer treatments, such as radiotherapy or reduce side effects of chemotherapy. CONCLUSION: The review shows that the cancer battle is still in progress and the combined studies in different disciplines, devoted to this subject, are a rapidly expanding area.

Total synthesis of (±)-epithuriferic acid methyl ester via Diels-Alder reaction.

In this paper, we have described the first total synthesis of (±)-epithuriferic acid methyl ester from non-natural sources, in four steps (20% overall yield). The key step involves the Diels-Alder reaction of isobenzofuran with methyl 3-(dimethoxyphosphoryl)acrylate which is controlled by "ortho" regio- and endo stereoselectivities due to the COOMe group.