This review is devoted to the development in Povarov reaction and focuses on new efficient approaches based on this reaction to construct simple substituted (tetrahydro)quinolines and diverse
...N-polyheterocycles, including some alkaloids, which contain pyrroloquinoline or cyclopentaquinoline ring systems.
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Each metabolite, regardless of its molecular simplicity or complexity, has a mission or function in the organism biosynthesizing it. In this review, the biological, allelochemical, and chemical ...properties of acetophenone, as a metabolite involved in multiple interactions with various (mi-cro)organisms, are discussed. Further, the details of its biogenesis and chemical synthesis are provided, and the possibility of its application in different areas of life sciences, i.e., the status quo of acetophenone and its simple substituted analogs, is examined. In particular, natural and synthetic simple acetophenone derivatives are analyzed as promising agrochemicals and useful scaffolds for drug research and development.
The human immune system is compromised in microgravity (MG) conditions during an orbital flight and upon return to Earth. T cells are critical for the immune response and execute their functions via ...actin-mediated immune cell-cell interactions that could be disturbed by MG conditions. In our study, we have applied two conventional platforms to simulate MG conditions: fast rotating clinostat (CL) and random positioning machine (RPM), followed by global T cell transcriptome analysis using RNA sequencing. Noteworthily, both selected rotational simulated MG platforms employ forced cell movement in cultural medium and expose cells to shear forces, therefore inducing certain cell response to hydrodynamic stress. We demonstrate that the T cell transcriptome profile in response to simulated MG treatment was clearly distinguishable from the T cell transcriptome response to hydrodynamic stress (HS). Gene expression profiling of genes related to or involved in actin cytoskeleton networks using RT-qPCR confirmed two sets of differentially regulated genes in the T cell response to MG or to HS. Several key genes potentially involved in T cell gravisensing (Fam163b, Dnph1, Trim34, Upk-1b) were identified. A number of candidate biomarker genes of the response to MG (VAV1, VAV2, VAV3, and NFATC2) and of the response to HS (ITGAL, ITGB1, ITGB2, RAC1, and RAC2) could be used to distinguish between these processes on the gene transcription level. Together, MG induces changes in the overall transcriptome of T cells, leading to specific shifts in the expression of cytoskeletal network genes.
The new virus of the of β-Coronaviruses genus, SARS-CoV-2, is the causative agent of coronavirus disease-2019 (COVID-19) and is winning a proverbial chess match against all players simultaneous, ...including physicians, clinicians, pathologists, doctors, scientists, economists, athletes and politicians. The COVID-19 outbreak has seriously threatened public health, killing the most vulnerable persons and causing general panic. To stop this disease, effective remedies (i.e., drugs, vaccines, personal protection elements, etc.) are urgently required. Unfortunately, no registered specific therapies (including antiviral therapies, immune-modulating agents and vaccines) are currently available to treat coronavirus infections, highlighting an urgent need for therapeutics targeting SARS-CoV-2. In this work, fourteen existing small molecule drugs or/and experimental drugs selected by experts and examined from the point of view of bioavailability via the Lipinski-Veber rules and assessment of their physicochemical descriptors. The aim of this study is to discover selected pattern similarities and peculiar characteristics that could be useful for antiviral drug optimization, drug combination or new antiviral agent design.
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•The current investigation of small molecule drugs as promising medicine for COVID-19 is discussed.•Examination and comparative analysis of the physicochemical descriptors of approved and experimental drugs selected for COVID-19 treatment could be useful for antiviral drug optimization, drug combination tactic.•Among 14 selected potential drugs based on small heterocyclic molecules, no molecule is “ideal” according to the Lipinski-Veber rules and bioactivity scores.•Drug combination based on a hybridization concept could be a useful and efficient approach in the creation of an antiviral molecule hybrid drug against SARS-CoV-2.
This critical review highlights the advances in developing new molecules for treating pain syndrome, an important issue for human health. Acetaminophen (APAP, known as paracetamol) and nonsteroidal ...anti-inflammatory drugs (NSAIDs) are commonly used in clinical practice despite their adverse effects. Research is being conducted to develop innovative drugs with improved pharmaceutical properties to mitigate these effects. A more practical way to achieve that is to study well-known and time-tested drugs in their molecular combinations. Accordingly, the present work explores APAP and their combined chemical entities,
i.e.
, prodrugs (soft drugs), codrugs (mutual prodrugs), and hybrids. Due to their molecular structure, APAP prodrugs or codrugs could be considered merged or conjugated hybrids; all these names are very fluid terms. This article proposed a structural classification of these entities to better analyze their advances. So, the following: carrier-linked O-modified APAP, -linked N-modified APAP derivatives (prodrugs), and direct- and spacer-N,O-linked APAP hybrids (codrugs) are the central parts of this review and are examined, especially ester and amide NSAID-APAP molecules. The C-linked APAP and nitric oxide (NO)-releasing APAP hybrids were also briefly discussed. Prime examples of APAP-based drugs such as propacetamol, benorylate, acetaminosalol, nitroparacetamol, and agent JNJ-10450232 weave well into this classification. The proposed classification is the first and original, giving a better understanding of the SAR studies for new pain relievers research and the design development for the analgesic APAP-(or NSAID)-based compounds.
The new classification of APAP combinations (prodrugs, codrugs, and hybrids) was proposed. It makes a better understanding of the SAR studies for new pain relievers research and the design development for the analgesic APAP-based compounds.
Leishmaniasis, Chagas disease and African sleeping sickness have been considered some of the most important tropical protozoan afflictions. As the number of drugs currently available to treat these ...human illnesses is severely limited and the majority has poor safety profiles and complicated administration schedules, actually there is an urgent need to develop new effective, safe and cost-effective drugs. Because quinoline alkaloids with antiprotozoal activity (quinine, chimanine, cryptolepine or huperzine groups) were historically and are still essential models for drug research to combat these parasitic infections, synthetic or semi-synthetic quinoline-based molecules are important for anti-kinetoplastid drug design approaches and synthetic methods of their preparation become a key task that is the central subject of this review. Its goal is to highlight the advances in the conventional and current syntheses of new 2-(3,4)-alkenyl (aryl) quinoline derivatives, which kill the most important kinetoplastid protozoa, -
Leishmania
and
Trypanosoma
and could be useful models for antileishmanial and antitrypanosomal research. An attempt has been made to present and discuss the more recent contributions in this field over the period 2015-2019, paying special attention to molecular design, synthetic efforts to new green reaction conditions for classical methods such as Skraup synthesis, Friedländer synthesis, Conrad-Limpach, Doebner-Miller, as well as contemporary methods like Gould-Jacobs, Meth-Cohn and Povarov reactions. This review includes brief general information on these neglected tropical diseases, their current chemotherapies, and primary natural models (quinoline alkaloids), suitable for development of anti-kinetoplastid quinoline-based agents. The main part of the review comprises critical discussion on the synthesis and chemistry of new quinolines diversely substituted by alkyl (alkenyl, aryl) fragments on the pyridine part of the quinoline skeleton, which could be considered interesting analogues of chimanine alkaloids. The methods described in this review were developed with the aim of overcoming the drawbacks of the traditional protocols using revolutionary precursors and strategies.
Leishmaniasis, Chagas disease and African sleeping sickness have been considered some of the most important tropical protozoan afflictions.
A rapid, efficient, and original synthesis of novel pyrido3,2,1-
phenanthridin-6-ones is reported. First, the key cinnamamide intermediates
-
were easily prepared from commercial substituted ...anilines, cinnamic acid, and 2-bromobenzylbromide in a tandem amidation and
-alkylation protocol. Then, these
-aryl-
-(2-bromobenzyl) cinnamamides
-
were subjected to a TFA-mediated intramolecular Friedel-Crafts alkylation followed by a Pd-catalyzed direct C-H arylation to obtain a series of potentially bioactive 4-phenyl-4,5-dihydro-6
,8
-pyrido3,2,1-
phenanthridin-6-one derivatives
-
in good yields. Finally, the toxicological profile of the prepared final compounds, including their corresponding intermediates, was explored through in silico computational methods, while the acute toxicity toward zebrafish embryos (96 hpf-LC
, 50% lethal concentration) was also determined in the present study.
An efficient approach to the synthesis of olefin metathesis HG-type catalysts containing an N→Ru bond in a six-membered chelate ring was proposed. For the most part, these ruthenium chelates can be ...prepared easily and in high yields based on the interaction between 2-vinylbenzylamines and
(the common precursor for Ru-complex synthesis). It was demonstrated that the increase of the steric volume of substituents attached to the nitrogen atom and in the α-position of the benzylidene fragment leads to a dramatic decrease in the stability of the target ruthenium complexes. The bulkiest
Pr substituent bonded to the nitrogen atom or to the α-position does not allow the closing of the chelate cycle. N,N-Diethyl-1-(2-vinylphenyl)propan-1-amine is a limiting case; its interaction with
makes it possible to isolate the corresponding ruthenium chelate in a low yield (5%). Catalytic activity of the synthesized complexes was tested in RCM reactions and compared with α-unsubstituted catalysts obtained previously. The structural peculiarities of the final ruthenium complexes were thoroughly investigated using XRD and NMR analysis, which allowed making a reliable correlation between the structure of the complexes and their catalytic properties.
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•New N-biphenylcinnamamides/3-arylpropanamides.•Microwave-assisted Suzuki coupling.•Simple synthetic procedures.•High yielding.•Short time set up.
We hereby report an efficient method ...for the preparation of a series of new N-biphenyl-cinnamamides/3-arylpropanamides through a three–step, clean, good–yielding, environment–friendly microwave-assisted procedure for the Suzuki–Miyaura coupling/basic hydrolysis/N-amidation from 2-bromoacetanilides and arylboronic acids as available starting reagents. The N-biphenyl-3-arylpropanamides obtained were converted into new 6-phenethylphenanthridine derivatives carrying out a subsequent cyclization reaction by means of a Pictet–Hubert microwave–assisted process. The structures of the compounds were fully characterized by FT-IR, 1H, and 13C NMR and are reported for the first time.
The quinoline derivative, N-(7-chloro-4-morpholinoquinolin-2-yl)benzamide, was synthesized in a conventional three-step procedure from 4,7-dichloroquinoline using a N-oxidation reaction/C2-amide ...formation reaction/C4 SNAr reaction sequence. The structure of the compound was fully characterized by FT-IR, 1H-, 13C-NMR, DEPT-135°, and ESI-MS techniques. Its physicochemical parameters (Lipinski’s descriptors) were also calculated using the online SwissADME database. Such derivatives are relevant therapeutic agents exhibiting potent anticancer, antibacterial, antifungal, and antiparasitic properties.
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