Pharmacophoric Groups Research Articles

Computer-Aided Design of Self-Assembled Nanoparticles to Enhance Cancer Chemoimmunotherapy via Dual-Modulation Strategy.

The rational design of self-assembled compounds is crucial for the highly efficient development of carrier-free nanomedicines. Herein, based on computer-aided strategies, important physicochemical properties are identified to guide the rational design of self-assembled compounds. Then, the pharmacophore hybridization strategy is used to design self-assemble nanoparticles by preparing new chemical structures by combining pharmacophore groups of different bioactive compounds. Hydroxychloroquine is grafted with the lipophilic vitamin E succinate and then co-assembled with bortezomib to fabricate the nanoparticle. The nanoparticle can reduce M2-type tumor-associated macrophages (TAMs) through lysosomal alkalization and induce immunogenic cell death (ICD) and nuclear factor-κB (NF-κB) inhibition in tumor cells. In mouse models, the nanoparticles induce decreased levels of M2-type TAMs, regulatory T cells, and transforming growth factor-β (TGF-β), and increase the proportion of cytotoxicity T lymphocytes. Additionally, the nanoparticles reduce the secretion of Interleukin-6 (IL-6) by inhibiting NF-κB and enhance the programmed death ligand-1 (PD-L1) checkpoint blockade therapy. The pharmacophore hybridization-derived nanoparticle provides a dual-modulation strategy to reprogram the tumor microenvironment, which will efficiently enhance the chemoimmunotherapy against triple-negative breast cancer.

2-Aminothiophene Derivatives-New Drug Candidates Against Leishmaniasis: Drug Design, Synthesis, Pharmacomodulation, and Antileishmanial Activity.

Background/Objectives: Leishmaniasis is one of the 20 Neglected Tropical Diseases according to the WHO, affecting approximately 12 million people in four continents, generating serious public health problems. The lack of therapeutic options, associated with toxicity and the emergence of resistance to the few available drugs, makes it urgent to develop new drug options. In this context, the aims of this work are to expand the knowledge about the pharmacophore group responsible for the antileishmanial potential of 2-aminothiophene derivatives. Thus, new compounds were synthesized containing chemical modifications at the C-3, C-4, and C-5 positions of the 2-aminothiophene ring, in addition to the S-Se bioisosterism. Methods: Dozens of 2-AT and 2-aminoselenophen (2-AS) derivatives were sequentially synthesized through applications of the Gewald reaction and were then evaluated in vitro for their activities against L. amazonensis and for cytotoxicity against macrophages. Results: Several series of compounds were synthesized, and it was possible to identify some substitution patterns favorable to the activity generating compounds with IC50 values below 10 µM, such as the non-essentiality of the presence of a carbonitrile group at C-3; the importance of the presence and size of cycloalkyl/piperidinyl chains at C-4 and C-5 in modulating the activity; and the increase in activity without affecting the safety of the S/Se bioisosteric substitution. Conclusions: Taken together, these findings reaffirm the great potential of 2-aminothiophenes to generate antileishmanial drug candidates and offers contributions to the drug design of compounds with an even more promising profile for the problem of leishmaniasis.

VIRTUAL SCREENING AND PREDICTION OF ADME PERAMETERS OF A SERIES OF 5-ARYLIDENE SUBSTITUTED DERIVATIVES OF RHODANINE WITH BENZOTHIAZOLE MOIETY IN THE MOLECULES

The knowledge of the ADME profile of the active substance’s molecules is important in the development of new drugs. Before starting the synthesis, it is advisable to determine the value of the compounds for medicinal chemistry and to predict their bio- and synthetic availability. For the assessment of the drug-like properties of the molecules, it is necessary to determine their physicochemical and pharmacokinetic properties. The 2-thioxothiazolidin-4-one (rhodanine) derivatives are interesting in pharmacological terms, as their diverse activity is influenced by the 5-arylidene moiety. It is known that they have antiviral, antidiabetic, anticonvulsant and other types of biological activity. In order to find effective ligands that have affinity for several biotargets, it is advisable to combine the so-called privileged structures in one molecule. One of such molecules with a wide range of biological effects (antitumor, antiviral, antituberculosis and other) is benzothiazole. A considerable number of possible ways for the structure modification of these heterocycles prompted us to study them in depth. The preliminary studies allow us to state that the combination of 5-arylidene-substituted 4-thiazolidine scaffold with a benzothiazole moiety is a viable approach to create drug-like molecules. In continuation of our previous studies, we decided to use an open access in silico tool to calculate the molecular descriptors of the studied compounds in order to predict their behaviour inside the human body, and to thoroughly study the most promising ones in vitro and in vivo in the future. The aim of the research. On the basis of the molecular structure of differently substituted 5-arylidene thiazolidine derivatives with a benzothiazole moiety at the 3-position of the basic heterocycle, perform in silico prediction of their ADME parameters. Materials and methods. On the basis of the pharmacological potential of the lead compound (N-(4-oxo-2-thioxothiazolidin-3-yl)-2-(2-oxobenzo[d]thiazol-3(2H)-yl)acetamide), 17 differently substituted 5-arylidene derivatives were selected for virtual screening. To determine the physicochemical and pharmacokinetic parameters of the molecules, their drug-like properties and suitability for medicinal chemistry, we used the SwissADME web service, which is in open access. Research results. We have studied the effect of aryl substituents at position 5 of the rhodanine cycle on the peroral availability of molecules, predicted the absorption, distribution, metabolism and excretion of compounds. The obtained prognosis data indicate the viability of the search for promising compounds with optimal physicochemical and pharmacokinetic parameters for medicinal chemistry among rhodanine derivatives with a benzothiazole moiety in the molecules. All the investigated derivatives are characterised by sufficient drug-like properties with moderate bioavailability and easy synthesis, and compound 8 is predicted to have the best ADME profile. Conclusions. The in silico prediction results outline a plan of further actions for the targeted synthesis of compounds and experimental confirmation of the data obtained. To optimise the ADME profile, we plan to carry out structural modification of the compounds. A promising direction we consider is the modification of the 5-arylidene moiety by introducing potential pharmacophore groups. The search for pharmacologically active compounds among rhodanine derivatives with a benzothiazole moiety is ongoing.

Synthesis of Oxazoles Containing CF3-Substituted Alcohol Unit via Tandem Cycloisomerization/Hydroxyalkylation from N-Propargylamides with Trifluoropyruvates.

Oxazoles are important five-membered heterocycles that contain both nitrogen and oxygen atoms. Due to their wide range of biological activities, many oxazoles demonstrate potential for extensive application in various fields, including medicinal chemistry. Trifluoromethyl carbinol, an important pharmacophore, contains both trifluoromethyl and hydroxyl groups and is common in molecules with important biological activities. Constructing oxazoles that contain a trifluoromethyl carbinol unit is undoubtedly important and valuable for expanding the chemical space in drug discovery. In this study, a simple and efficient method was developed for the synthesis of oxazoles containing a CF3-substituted alcohol unit via the tandem cycloisomerization/hydroxyalkylation of N-propargylamides with trifluoropyruvates through a rational Lewis acid catalytic mechanism. This Zn(OTf)2-catalyzed synthetic protocol is operationally simple and provides a series of oxazoles in moderate to good yields. The protocol demonstrates broad substrate scope, high functional group tolerance, and high atom economy and can achieve gram-level reactions, indicating the strong possibility of its practical application.

Natriuretic effect of 4′,5-dihydroxy-6,7-methylenedioxyflavonol-3-O-α-L-rhamnopyranosyl-(1→2)-β-D-xylopyranoside from Boldoa purpurascens: in silico and in vivo studies

Aqueous leaf extracts of Boldoa purpurascens are widely used because of their diuretic, natriuretic, antiurolithiatic, anti-inflammatory and antihypertensive properties. The major component of the extract is the flavonoid 4′,5-dihydroxy-6,7-methylenedioxyflavonol-3-O-α-L-rhamnopyranosyl-(1→2)-β-D–xylopyranoside, but it is not known if this compound is responsible for the biological activity. The objective of this work is to develop effective in silico tools that allow predicting the possible activity of the flavonoid aglycone as an inhibitor of metalloproteases that regulate renal fluid excretion. First, a mathematical ligand-based classification model was developed, using an artificial intelligence and machine learning technique of support vector machines to find the relationship between chemical structure and biological activity. This showed good fit of the statistical parameters with an accuracy greater than 90%, offering a priori information of the flavonoid activity. Subsequently, the flavonoid aglycone was docked to the active site of the enzymes thermolysin (PDB: 6YMS), angiotensin-converting enzyme (PDB: 6TT4) and neprilysin (PDB: 6SUK) using the Extra Precision glide method (Glide-XP), showing conformations with binding energies lower than −5 Kcal/mol. In this study, possible interactions were determined at the catalytic site, where the coordination of negatively charged pharmacophoric groups with the zinc atom of these enzymes is observed. Finally, a preliminary in vivo evaluation was carried out using a diuresis-natriuresis model with sodium quantification in urine which revealed good activity profiles. These results are in correspondence with the ethnopharmacological use of the plant as a diuretic-natriuretic and for the treatment of hypertension.

SYNTHESIS, INTRAMOLECULAR CYCLIZATION AND ANTINOCICEPTIVE ACTIVITY OF 4-(HET)ARYL-2-{[3-(ETHOXYCARBONYL)-4-(4-R-PHENYL)THIOPHEN-2-YL]AMINO}- 4-OXOBUT-2-ENOIC ACIDS

In this work, new substituted 4-(het)aryl-4-oxo-2-{[4-(4-R-phenyl)-3-(ethoxycarbonyl)thiophen-2-yl]amino}but-2-enoic acids were studied. It was found that the intramolecular cyclisation of these acids under the action of a dehydrating agent leads to the formation of the corresponding substituted 3-(thiophen-2-yl)imino-3H-furan-2-ones, which are of great interest for further study. A content of several reaction centers in its structure allows to obtain products of heterocyclic and acyclic structure, which, at the same time, retain such important pharmacophore groups as the 2-aminothiophene fragment and 2,4-dioxobutanoic acid fragment. The studied 4-(het)aryl-4-oxo-2-{[4-(4-R-phenyl)-3-(ethoxycarbonyl)thiophen-2-yl]amino}but-2-enoic acids were obtained by a one-step method, providing high yields and involving the interaction of substituted 4-(het)aryl-2-hydroxy-4-oxobut-2-enoic acids with substituted ethyl 2-amino-4-(4-R-phenyl)thiophen-3-carboxylates. The structure of the isolated final compounds was confirmed by 1H and 13C NMR spectroscopy and elemental analysis. Substituted 4-(het)aryl-4-oxo-2-thienylaminobut-2-enoic acids were then screened in vivo to detect and evaluate their biological activity and acute toxicity. The antinociceptive activity was studied in white mice of both sexes by hot plate thermal irritation intraperitonally. Acute toxicity was studied according to Pershin's method, based on observation of mice condition during 10 days after intraperitoneal injection of tested compounds. According to the results obtained, the tested compounds have a pronounced antinociceptive activity, and the acute toxicity assessment indicates that they belong to the V class of practically non-toxic drugs. High values of antinociceptive activity in combination with low toxicity makes the considered 4-(het)aryl-4-oxo-2-{[4-(4-R-phenyl)-3-(ethoxycarbonyl)thiophen-2-yl]amino}but-2-enoic acids a highly promising class for further study in order to search and develop new biologically active compounds with analgesic action and low toxicity. For citation: Nikonov I.P., Sharavyeva Yu.O., Makhmudov R.R., Shipilovskikh D.A., Gorbunova I.A. Synthesis, intramolecular cyclization and antinociceptive activity of 4-(het)aryl-2-{[3-(ethoxycarbonyl)-4-(4-R-phenyl)thiophen-2-yl]amino}-4-oxobut-2-enoic acids. ChemChemTech [Izv. Vyssh. Uchebn. Zaved. Khim. Khim. Tekhnol.]. 2024. V. 67. N 11. P. 22-32. DOI: 10.6060/ivkkt.20246711.7055.

Synthesis and Antitumour Activity of Hybrid Compounds Based on 4-Aminophenylarsonic Acid and Spatially Hindered Phenols.

One of the main modern approaches to the creation of effective drugs is the design of new biologically active substances containing two or more pharmacophore groups in their structure. In recent years, there have been many publications on the synthesis and study of biological activity, including antitumour activity, of new organo-arsenic compounds. It is known that spatially hindered phenols can also have antitumor activity, so the synthesis and study of hybrid compounds based on organo-arsenic compounds and spatially hindered phenols is a relevant area of research. In this work, the modification of 4-aminophenylarsonic acid with 3,5-di-tert-butyl-4-hydroxybenzylacetate was carried out. In contrast to a similar transformation of 2-aminophenylarsonic acid, in this case it was possible to obtain both mono- and di-benzyl derivatives of the acid. Using the Zandmeyer method, the oxime isatin containing an arsonic acid fragment in the fifth position of the heterocycle was synthesised. Azo derivatives containing fragments of para-aminophenylarsonic acid and sterically hindered phenols were obtained. 4-((3,5-Di-tert-butyl-2-hydroxyphenyl)diazenyl)phenylarsonic acid was isolated in pure form. At the same time, it was found that the reaction of the diazonium azo salt of 4-aminophenylarsonic acid with 2-hydroxymethyl-4-tert-butylphenol proceeds in two directions. In addition to the classical diazotisation reaction at the 6-position of 2-hydroxymethyl-4-tert-butylphenol, a diazotisation accompanied by a dehydroxymethylation process occurs. The obtained compounds showed cytotoxic activity against human tumor cell lines M-HeLa (cervical epithelioid carcinoma) and HuTu 80 (duodenal adenocarcinoma cells). The most promising is the sodium salt of 4-((3,5-di-tert-butyl-2-hydroxyphenyl)diazenyl)phenylarsonic acid, which is superior to Tamoxifen and 5-fluorouracil in terms of selectivity index towards M-HeLa and HuTu 80 cells.

Turn-Adopting Peptidomimetic as a Formyl Peptide Receptor-1 Antagonist.

The design, synthesis, and characterization of a new peptidomimetic acting as a formyl peptide receptor (FPR1) antagonist (N-19004) are herein reported. The molecule has been identified with docking studies of the highly potent FPR1 antagonist UPARANT on human receptor. N-19004 recapitulates all pharmacophoric groups necessary for recognition into a minimal structure, with a crucial role of the 2,6-diamino-thiophenyl scaffold mimicking the positions of Cα atoms of Arg residues in the turned Arg-Aib-Arg segment of UPARANT. N-19004 demonstrated to interfere with the biological properties of FPR1 both in vitro and in vivo. In a mouse model of choroidal neovascularization, N-19004 markedly reduced the size of laser-induced choroidal lesions, with reabsorption of the edema regions by a systemic administration route.

New quinoxaline-oxadiazole hybrids as tubulin inhibitors: Synthesis, cytotoxicity, and molecular dynamics simulations

This study describes the synthesis and biological evaluation of a series of novel quinoxaline-oxadiazole hybrid compounds. These compounds were designed to enhance anticancer activity through the incorporation of specific pharmacophoric groups. Structural characterization using NMR and HRMS spectroscopy confirmed the successful synthesis of the hybrids. Cytotoxicity assays revealed that several compounds exhibited significant activity against various cancer cell lines. Compounds 8a and 8f demonstrated potent activity against A549 cells, while 8a, 8b, and 8c were effective against HaCaT cells. Additionally, compounds 8i and 8a showed activity against HepG2 cells. Molecular docking and dynamics simulations suggested that compounds 8c and 8d bind strongly to the tubulin protein, a target for anticancer drugs. These compounds exhibited binding affinities comparable to known anticancer compounds. The results of this study highlight the potential of quinoxaline-oxadiazole hybrids, especially those with halogen substitutions, as promising candidates for the development of novel anticancer therapeutics.

Methyl 6,7-Difluoro-2-[(4-fluorobenzyl)sulfanyl]-4-hydroxyquinoline-3-carboxylate

A convenient synthesis of a novel fluoroquinolone precursor, methyl 6,7-difluoro-2-[(4-fluorobenzyl)sulfanyl]-4-hydroxyquinoline-3-carboxylate, at a 78% yield starting from 3,4-difluorophenyl isothiocyanate was developed. The structure of the product was established by 1H, 13C, and 19F NMR spectroscopy, mass spectrometry, IR spectroscopy and confirmed by elemental analysis. The title compound, containing the pharmacophoric 4-fluorobenzyl group, will be used in the synthesis of novel fluoroquinolone derivatives.

Identification of the cytochrome P450s responsible for the biosynthesis of two types of aporphine alkaloids and their de novo biosynthesis in yeast.

Aporphine alkaloids have diverse pharmacological activities; however, our understanding of their biosynthesis is relatively limited. Previous studies have classified aporphine alkaloids into two categories based on the configuration and number of substituents of the D-ring and have proposed preliminary biosynthetic pathways for each category. In this study, we identified two specific cytochrome P450 enzymes (CYP80G6 and CYP80Q5) with distinct activities toward (S)-configured and (R)-configured substrates from the herbaceous perennial vine Stephania tetrandra, shedding light on the biosynthetic mechanisms and stereochemical features of these two aporphine alkaloid categories. Additionally, we characterized two CYP719C enzymes (CYP719C3 and CYP719C4) that catalyzed the formation of the methylenedioxy bridge, an essential pharmacophoric group, on the A- and D-rings, respectively, of aporphine alkaloids. Leveraging the functional characterization of these crucial cytochrome P450 enzymes, we reconstructed the biosynthetic pathways for the two types of aporphine alkaloids in budding yeast (Saccharomyces cerevisiae) for the de novo production of compounds such as (R)-glaziovine, (S)-glaziovine, and magnoflorine. This study provides key insight into the biosynthesis of aporphine alkaloids and lays a foundation for producing these valuable compounds through synthetic biology.

Structure-activity relationship of pharmacophores and toxicophores: the need for clinical strategy.

Sometimes clinical efficacy and potential risk of therapeutic and toxic agents are difficult to predict over a long period of time. Hence there is need for literature search with a view to assessing cause of toxicity and less efficacy of drugs used in clinical practice. Hence literatures were searched for physicochemical properties, chemical formulas, molecular masses, pH values, ionization, receptor type, agonist and antagonist, therapeutic, toxic and structure-activity relationship of chemical compounds with pharmacophore and toxicophore, with a view to identifying high efficacious and relative low toxic agents. Inclusion criteria were manuscripts published on PubMed, Scopus, Web of Science, PubMed Central, Google Scholar among others, between 1960 and 2023. Keywords such as pharmacophore, toxicophore, structure-activity-relationship and disease where also searched. The exclusion criteria were the chemicals that lack pharmacophore, toxicophore and manuscripts published before 1960. Findings have shown that pharmacophore and toxicophore functional groups determine clinical efficacy and safety of therapeutics, but if they overlap therapeutic and toxicity effects go concurrently. Hence the functional groups, dose, co-administration and concentration of drugs at receptor, drug-receptor binding and duration of receptor binding are the determining factors of pharmacophore and toxicophore activity. Molecular mass, chemical configuration, pH value, receptor affinity and binding capacity, multiple pharmacophores, hydrophilic/lipophilic nature of the chemical contribute greatly to functionality of pharmacophore and toxicophore. Daily single therapy, avoidance of reversible pharmacology, drugs with covalent adduct, maintenance of therapeutic dose, and the use of multiple pharmacophores for terminal diseases will minimize toxicity and improve efficacy.

Synthesis and Psychotropic Properties of Novel Condensed Triazines for Drug Discovery.

The exploration of heterocyclic compounds and their fused analogs, featuring key pharmacophore fragments like pyridine, thiophene, pyrimidine, and triazine rings, is pivotal in medicinal chemistry. These compounds possess a wide array of biological activities, making them an intriguing area of study. The quest for new neurotropic drugs among derivatives of these heterocycles with pharmacophore groups remains a significant research challenge. The aim of this research work was to develop a synthesis method for new heterocyclic compounds, evaluate their neurotropic and neuroprotective activities, study histological changes, and perform docking analysis. Classical organic synthesis methods were used in the creation of novel heterocyclic systems containing pharmacophore rings. To evaluate the neurotropic activity of these synthesized compounds, a range of biological assays were employed. Docking analysis was conducted using various software packages and methodologies. The neuroprotective activity of compound 13 was tested in seizures with and without pentylenetetrazole (PTZ) administration. Histopathological examinations were performed in different experimental groups in the hippocampus and the entorhinal cortex. As a result of chemical reactions, 16 new, tetra- and pentacyclic heterocyclic compounds were obtained. The biologically studied compounds exhibited protection against PTZ seizures as well as some psychotropic effects. The biological assays evidenced that 13 of the 16 studied compounds showed a high anticonvulsant activity by antagonism with PTZ. The toxicity of the compounds was low. According to the results of the study of psychotropic activity, it was found that the selected compounds have a sedative effect, except compound 13, which exhibited activating behavior and antianxiety effects (especially compound 13). The studied compounds exhibited antidepressant effects, especially compound 13, which is similar to diazepam. Histopathological examination showed that compound 13 produced moderate changes in the brain and exhibited neuroprotective effects in the entorhinal cortex against PTZ-induced damage, reducing gliosis and neuronal loss. Docking studies revealed that out of 16 compounds, 3 compounds bound to the γ-aminobutyric acid type A (GABAA) receptor. Thus, the selected compounds demonstrated anticonvulsant, sedative, and activating behavior, and at the same time exhibited antianxiety and antidepressant effects. Compound 13 bound to the GABAA receptor and exhibited antianxiety, antidepressant, and neuroprotective effects in the entorhinal cortex against PTZ-induced changes.

Thiazole, Isatin and Phthalimide Derivatives Tested in vivo against Cancer Models: A Literature Review of the Last Six Years.

Cancer is a disease characterized by the abnormal multiplication of cells and is the second leading cause of death in the world. The search for new effective and safe anticancer compounds is ongoing due to factors such as low selectivity, high toxicity, and multidrug resistance. Thus, heterocyclic compounds derived from isatin, thiazole and phthalimide that have achieved promising in vitro anticancer activity have been tested in vivo and in clinical trials. This review focused on the compilation of promising data from thiazole, isatin, and phthalimide derivatives, reported in the literature between 2015 and 2022, with in vivo anticancer activity and clinical trials. A bibliographic search was carried out in the PUBMED, MEDLINE, ELSEVIER, and CAPES PERIODIC databases, selecting relevant works for each pharmacophoric group with in vivo antitumor activity in the last 6 years. In our study, 68 articles that fit the scope were selected and critically analyzed. These articles were organized considering the type of antitumor activity and their year of publication. Some compounds reported here demonstrated potent antitumor activity against several tumor types. This review allowed us to highlight works that reported promising structures for the treatment of various cancer types and also demonstrated that the privileged structures thiazole, isatin and phthalimide are important in the design of new syntheses and molecular optimization of compounds with antitumor activity.

SYNTHESIS AND STUDY OF ANTINOCICEPTIVE ACTIVITY OF SUBSTITUTED 2-(3-CYANO-4,5,6,7-TETRAHYDROBENZO[B]THIOPHEN-2-YLAMINO)-4-OXOBUT-2-ENOATES

In the current work, we present results the study of synthetic transformations of substituted 3-thienylimino-3H-furan-2-one derivatives containing a nitrile substituent in the third position of the thiophene ring under the action of nucleophilic reagents. This class of compounds is of great for study due to the presence of several reaction centers in its structure, which makes it possible to obtain products of various structures, while retaining important pharmacophore groups - fragments of 2-aminothiophene and a fragment of 2,4-dioxobutanoic acid. We have synthesized and studied for biological activity substituted 2-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylamino)-4-oxobut-2-enoates, which were obtained by a multistep synthesis method. The proposed method provides high yields of target compounds and includes the reaction of 4-aryl-2-hydroxy-4-oxobutanoic acids with 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile, followed by intramolecular cyclization of the resulting products under the action of propionic anhydride, as well as decyclization of the resulting substituted 3-thienylimino-3H-furan-2-ones under the action of primary alcohols. The structure of the finally isolated compounds was confirmed by 1H and 13C NMR spectroscopy and the elemental analysis. The resulting compounds were screened in vivo to detect and evaluate their biological activity and acute toxicity. Antinociceptive activity was studied in white outbred mice of both sexes by the hot plate test with intraperitoneal injection. Acute toxicity was studied according to the Pershin method, based on monitoring the condition of mice for 10 days after intraperitoneal injection of the test compounds. According to the results obtained, the tested compounds have a pronounced antinociceptive activity, and the assessment of acute toxicity indicates that they belong to the V class of practically non-toxic drugs. The high values of antinociceptive activity in combination with low toxicity make the considered substituted 2-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylamino)-4-oxobut-2-enoates a highly promising class for further study in order to search for and develop new biologically active compounds with analgesic effect. For citation: Sharavyeva Yu.O., Makhmudov R.R., Shipilovskikh D.A., Silaichev P.S., Gorbunova I.A. Synthesis and study of antinociceptive activity of substituted 2-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-ylamino)-4-oxobut-2-enoates. ChemChemTech [Izv. Vyssh. Uchebn. Zaved. Khim. Khim. Tekhnol.]. 2024. V. 67. N 7. P. 19-27. DOI: 10.6060/ivkkt.20246707.7029.

Ultrasound-Assisted, BF3·OEt2-Promoted, Multicomponent Synthesis of Chromene-Based Podophyllotoxin Analogues

AbstractA novel method was developed to synthesise chromene-lactone analogues of podophyllotoxin using an ultrasound-assisted multicomponent reaction (MCR). The MCR involved tetronic acid, phenols, and aromatic aldehydes and was promoted by BF3·OEt2, resulting in the production of ten derivatives with different substituents on the aromatic rings in yields ranging from 32% to 93%. These compounds are of interest due to their reported activity against tumour cells. Their ease of synthesis through the MCR may allow for more in-depth studies on anticancer activity, as well as investigations of other biological targets. The synthesised derivatives contain important pharmacophoric groups for potential applications in medicinal chemistry.

Synthesis And Anticancer Activity Of New Hybrid 3-Methylidene-2,3-Dihydro-1,8-Naphthyridinones.

Synthesis of molecular hybrids, obtained by combination of two or more pharmacophoric groups of different bioactive substances in order to produce more efficient drugs, is now a frequently used approach in medicinal chemistry. Following this strategy, we synthetized a library of 3-methylidene-1-tosyl-2,3-dihydro-1,8-naphthyridin-4(1H)-ones, combining a 1,8-naphthyridin-4-one motif with an exo-methylidene bond conjugated with a carbonyl group, pharmacophoric units that are present in many natural, biologically active compounds with anticancer potential. We reasoned that such bifunctional conjugates may have enhanced cytotoxic activity. The title compounds were synthesized in a four step reaction sequence. β-Ketophosphonate, obtained from methyl N-tosylnicotinate and diethyl methylphosphonate, was reacted with various aldehydes giving 3-diethoxyphosphoryl-2,3-dihydro-1,8-naphthyridin-4(1H)-ones as keto-enol tautomers. Later, these compounds were transformed into 3-methylidene-1-tosyl-2,3-dihydro-1,8-naphthyridin-4(1H)-ones applying the Horner-Wadsworth-Emmons methodology. Then, the cytotoxicity of the new compounds was assessed on two cancer cell lines, promyelocytic leukemia HL-60 and breast cancer adenocarcinoma MCF-7, and for comparison, on human umbilical vein endothelial cells HUVEC. The most active and selective analog, 2-ethyl-3-methylidene-1-tosyl-2,3-dihydro-1,8-naphthyridin-4(1H)-one 4 a was chosen for more detailed studies on HL-60 cell line, to determine molecular mechanisms of its anticancer activity. It was shown that 4 a strongly inhibited proliferation and induced apoptosis which could be attributed to its ability to cause DNA damage.

Varpha-K Prototype, the Evolution of Anticoagulant Treatment with More Safety and Efficiency: Will this be the End of Bleeding?

Pharmaceutical chemistry seeks to discover and develop new chemical molecules that can be useful as medicines, in addition to the possibility of improvement in some molecular physicochemical aspect. These modifications cannot alter the pharmacophoric group, which is the chemical functional group responsible for the therapeutic effects (KOROLKOVAS 1982). Thus, our objective was to present the physicochemical aspects related to the association of vitamin K with warfarin molecule (VAR), in order to develop the Varfa-K Prototype, a new drug that has fewer toxic effects, mainly reducing bleeding events caused by VAR. Therefore, we used the methodology of molecular association and insertion of bulky groups. By adding a molecule (vitamin K) to the parent drug and its own antidote against bleeding.

Organocatalytic Synthesis and DNA Interactive Studies of New 1,2,3-triazolyl-thiazolidines Hybrids.

An organocatalytic [3+2] cycloaddition reaction between thiazolidine-containing β-ketoester 1 and aryl azides 2 was employed to synthesize new 1,2,3-triazolyl-thiazolidine hybrids 3. In this metal-free approach, twelve compounds were isolated in yields ranging from 23 % to 96 % by using diethylamine (10 mol%) and DMSO at 75 °C for 24 hours. DNA-binding assays were conducted through absorption, emission spectroscopy and viscosimetry analysis, to evaluate the interaction capacity of the studied derivatives with nucleic acids. All the synthesized compounds were evaluated for their interactions with a specific group of compounds containing the pharmacophoric groups triazole and thiazolidine through a molecular docking speculative study, aimed at identifying the interaction profile of these compounds with DNA. The obtained results suggest that 1,2,3-triazolyl-thiazolidine hybrids could be a promising approach in the development of novel therapeutic agents targeting DNA-related processes.

Clustering of atoms relative to vector space in the Z-matrix coordinate system and ‘graphical fingerprint’ analysis of 3D pharmacophore structure

The behavior of a molecule within its environment is governed by chemical fields present in 3D space. However, beyond local descriptors in 3D, the conformations a molecule assumes, and the resulting clusters also play a role in influencing structure–activity models. This study focuses on the clustering of atoms according to the vector space of four atoms aligned in the Z-Matrix Reference system for molecular similarity. Using 3D-QSAR analysis, it was aimed to determine the pharmacophore groups as interaction points in the binding region of the β2-adrenoceptor target of fenoterol stereoisomers. Different types of local reactive descriptors of ligands have been used to elucidate points of interaction with the target. Activity values for ligand-receptor interaction energy were determined using the Levenberg–Marquardt algorithm. Using the Molecular Comparative Electron Topology method, the 3D pharmacophore model (3D-PhaM) was obtained after aligning and superimposing the molecules and was further validated by the molecular docking method. Best guesses were calculated with a non-output validation (LOO-CV) method. Finally, the data were calculated using the ‘graphic fingerprint’ technique. Based on the eLKlopman (Electrostatic LUMO Klopman) descriptor, the Q2 value of this derivative set was calculated as 0.981 and the R2ext value is calculated as 0.998.