Design, Synthesis and Cytotoxicity of New Coumarin-1,2,3-triazole Derivatives: Evaluation of Anticancer Activity and Molecular Docking Studies.

A library of new coumarin-1,2,3-triazole hybrids 7a-l were synthesized from 4-(diethylamino)-2-hydroxybenzaldehyde precursor through a series of reactions including Vilsmeier-Haack reaction and condensation reaction to achieve key intermediate oxime and further performed click reaction by using different aromatic azides. We screened all molecules in silico against crystal structure of Serine/threonine-protein kinase 24 (MST3), based on these results all molecules were screened for their cytotoxicity against human breast cancer MCF-7 and lung cancer A-549 cell lines. Compound 7 b (p-bromo) showed best activity against both cell lines MCF-7 and A-549 with IC50 value of 29.32 and 21.03 µM, respectively, in comparison to Doxorubicin corresponding IC50 value of 28.76 and 20.82 µM. Another compound 7 f (o-methoxy) also indicated good activity against both cell lines with IC50 value of 29.26 and 22.41 µM. The toxicity of all compounds tested against normal HEK-293 cell lines have not shown any adverse effects.

Multistep Synthesis and In Vitro Anticancer Evaluation of 2-Pyrazolyl-Estradiol Derivatives, Pyrazolocoumarin-Estradiol Hybrids and Analogous Compounds.

Although the hormone independent cytotoxic activity of several estradiol derivatives endowed with a simple substituent at C-2 has been reported so far, 2-heterocyclic and 2,3-condensed analogs are less investigated from both synthetic and pharmacological points of view. Therefore, novel A-ring-connected 2-pyrazoles of estradiol and, for comparison, their structurally simplified non-steroidal pairs were synthesized from estradiol 3-methyl ether and 6-methoxy-1,2,3,4-tetrahydronaphthalene. Friedel-Crafts acetylation of the protected phenolic compounds and subsequent O-demethylation led to ortho-substituted derivatives regioselectively, which were converted to arylhydrazones with phenylhydrazine, 4-tolylhydrazine and 4-chloro-phenylhydrazine, respectively, under microwave conditions. The hydrazones were subjected to cyclization with the Vilsmeier-Haack reagent immediately after preparation and the ring closure/formylation sequence resulted in steroidal and non-steroidal 4'-formylpyrazoles in moderate to good yields. During reductive transformations, 4-hydroxymethyl-pyrazoles were obtained, while oxidative lactonization of the 4-formylpyrazole moiety with the phenolic OH in the presence of the Jones reagent afforded A-ring-integrated pyrazolocoumarin hybrids and related analogs. Steroidal pyrazoles, which were produced as C-17 acetates due to acetylation of C-17 OH during the primary Friedel-Crafts reaction, underwent deacetylation in alkaline methanol to furnish 2-heterocyclic estradiol derivatives. Pharmacological studies revealed the overall and cancer cell-specific cytotoxicity of the derivatives and the half maximal inhibitory concentrations were obtained for the most promising compounds.

A simple and easy to perform synthetic route to functionalized thienyl bicyclo[3.2.1]octadienes.

In order to prepare novel polycyclic derivatives of bicyclo[3.2.1]octadiene systems fused with a thiophene ring, photochemical cyclization and aldol condensation reactions were carried out. The starting substrates were easily obtained by a Vilsmeier-Haack reaction of bicyclo[3.2.1]octadiene thiophene derivatives with dimethylformamide. From the obtained carbaldehydes, novel methyl, methoxy, and cyano-substituted styryl thienobenzobicyclo[3.2.1]octadiene derivatives were synthesized through Wittig reactions and subjected to photochemical cyclization, in terms of obtaining the new annulated structures. As part of this study, the aldol reaction of the starting 2-substituted carbaldehyde with acetone was also performed, which produced the thieno-fused benzobicyclo[3.2.1]octadiene compound with an extended conjugation.

Synthesis of pyrimido[4,5-b]quinolindiones and formylation: ultrasonically assisted reactions.

Ultrasound-assisted synthesis of pyrimido|quinolindione derivatives via a multicomponent reaction and subsequent formylation with Vilsmeier-Haack reagent were performed. Compounds were prepared by a one-pot method from aminopyrimidinones, dimedone and aromatic aldehydes through a Mannich-type reaction sequence, and then functionalized under ultrasound irradiation and Vilsmeier-Haack conditions to give ß-chlorovinylaldehyde products. Ultrasonically assisted reactions, experimental simplicity, good yields without using metallic catalysts and the control of hazardous material release are features of this simple procedure.

Unexpected discovery: "A new 3,3'-bipyrazolo[3,4-b]pyridine scaffold and its comprehensive analysis".

In this study, a novel 3,3'-bipyrazolo [3,4-b]pyridine-type structure was synthesized from 5-acetylamino-3-methyl-1-phenylpyrazole using the Vilsmeier-Haack reaction as a key step. The spectroscopic properties and structural elucidation of the compound were determined with the use of FT-IR, HRMS, 1H NMR, and 13C NMR. Likewise, the theoretical analysis of the IR and NMR spectra allowed peaks to be assigned and a solid correlation was demonstrated between the experimental and theoretical results. Finally, ab initio calculations based on the density functional theory method at the B3LYP/6-311G (d,p) level of theory were used to determine the conformational energy barrier, facilitating the identification of the most probable conformers of the synthesized compound. Overall, our findings contribute to the understanding of bipyrazolo [3,4-b]pyridine derivatives.

Synthesis, in silico screening, and biological evaluation of novel pyridine congeners as anti-epileptic agents targeting AMPA (α-amino-3-hydroxy-5-methylisoxazole) receptors.

The research involves the synthesis of a series of new pyridine analogs 5(i-x) and their evaluation for anti-epileptic potential using in silico and in vivo models. Synthesis of the compounds was accomplished by using the Vilsmeier-Haack reaction principle. AutoDock 4.2 was used for their in silico screening against AMPA (-amino-3-hydroxy-5-methylisoxazole) receptor (PDB ID:3m3f). For in vivo testing, the maximal electroshock seizure (MES) model was used. The physicochemical, pharmacokinetic, drug-like, and drug-score features of all synthesized compounds were assessed using the online Swiss ADME and Protein Plus software. The in silico results showed that all the synthesized compounds 5(i-x) had 1-3 interactions and affinities ranging from -6.5 to -8.0 kJ/mol with the targeted receptor compared to the binding affinities of the standard drug phenytoin and the original ligand of the target (P99), which were -7.6 and -6.8 kJ/mol, respectively. In vivo study results showed that the compound 5-Carbamoyl-2-formyl-1-[2-(4-nitrophenyl)-2-oxo-ethyl]-pyridinium gave 60% protection against epileptic seizures compared to 59% protection afforded by regular phenytoin. All of them met Lipinski's rule of five and had drug-likeness and drug score values of 0.55 and 0.8, respectively, making them chemically and functionally like phenytoin. According to the findings of the studies, the synthesized derivatives have the potential to be employed as a stepping stone in the development of novel anti-epileptic drugs.

Continuous-/Micro-Flow Reactions Using Highly Electrophilic PCl3 and POCl3.

PCl3 and POCl3 are the most important sources of phosphorus-containing compounds. They are also used for large-scale industrial productions. However, chemical reactions using the highly reactive PCl3 and POCl3 tend to result in overreactions. In addition, the reactions are usually exothermic and therefore their utilization sometimes involves significant risk. That is why some phosphorylating reagents with mild electrophilicity such as phosphoramidites have been developed. Although these mild electrophiles are very useful for the highly selective synthesis of organophosphorus compounds, problems persist: the high cost of the reagents, the generation of large amounts of waste, and the requirement of long reaction times and high temperatures. Continuous-flow technology is one of the most promising solutions for these problems. In particular, precise control of reaction times and temperatures enabled by micro-flow technology suppresses undesired reactions and allows the safe operation of exothermic reactions using highly reactive PCl3 and POCl3 . This Review describes recently reported reactions of PCl3 and POCl3 using continuous- and micro-flow technologies.

Ugi/Robinson-Gabriel reactions directed toward the synthesis of 2,4,5-trisubstituted oxazoles.

This Letter discloses a novel concise synthesis of a series of 2,4,5-trisubstituted oxazoles via a tandem Ugi/Robinson-Gabriel sequence. Herein, 2,4-dimethoxybenzylamine 1 was used as an ammonia equivalent in combination with arylglyoxal 3 and supporting Ugi reagents, an isonitrile and carboxylic acid. As such the product of the acid treated Ugi intermediate is ideally configured to undergo a Robinson-Gabriel cyclodehydration reaction to yield the desired oxazole scaffold 5.

Synthesis of 4-styrylpyrazoles and Evaluation of their Inhibitory Effects on Cyclin-dependent Kinases.

BACKGROUND: Cycle-regulating and transcriptional cyclin-dependent kinases (CDKs) are attractive targets in cancer drug development. Several CDK inhibitors have already been obtained or are close to regulatory approval for clinical applications. OBJECTIVE: Phenylazopyrazole CAN508 has been described as the first selective CDK9 inhibitor with an IC50 of 350 nM. Since the azo-moiety is not a suitable functionality for drugs due to pharmacological reasons, the preparation of carbo-analogues of CAN508 with similar biological activities is desirable. The present work is focused on the synthesis of carbo-analogues similar to CAN508 and their CDK inhibition activity. METHODS: Herein, the synthesis of 21 novel carbo analogues of CAN508 and their intermediates is reported. Subsequently, target compounds 8a - 8u were evaluated for protein kinase inhibition (CDK2/cyclin E, CDK4/cyclin D, CDK9/cyclin T) and antiproliferative activities in cell lines (K562, MCF-7, MV4-11). Moreover, the binding mode of derivative 8s in the active site of CDK9 was modelled. RESULTS: Compounds 8a - 8u were obtained from key intermediate 7, which was prepared by linear synthesis involving Vilsmeier-Haack, Knoevenagel, Hunsdiecker, and Suzuki-Miyaura reactions. Styrylpyrazoles 8t and 8u were the most potent CDK9 inhibitors with IC50 values of approximately 1 µM. Molecular modelling suggested binding in the active site of CDK9. The flow cytometric analysis of MV4-11 cells treated with the most active styrylpyrazoles showed a significant G1-arrest. CONCLUSION: The prepared styrylpyrazoles showed inhibition activity towards CDKs and can provide a novel chemotype of kinase inhibitors.

Hemisyntheses and In-silico Study of New Analogues of Carlina Oxide from Carthamus Caeruleus Roots.

AIM AND OBJECTIVE: Nowadays, developing effective antibiotics for bacterial control has become difficult due to increased resistance to the available medicines in the market. Essential oils possess interesting biological properties as some of their components have very powerful antiviral and antibacterial properties. Carthamus caeruleus is a plant that has antibacterial and antioxidant activity due to the presence of an acetylenic compound, Carlina oxide. The aim of this work was to provide, for the first time, the chemical modifications to the structure of Carlina oxide and the insilico study of these analogues. MATERIALS AND METHODS: The essential oil of Carthamus caeruleus was extracted by steam distillation in a Clevenger-type apparatus. Carlina oxide component was separated by column chromatography. Five new analogues were synthetized and identified by spectroscopic analyses (RMN, IR and SM). Molecular docking simulation study was performed using Molecular Operating Environment software (MOE) on three enzymes of bacterial origin (Streptococcus pyogenesis and Enterococcus faecalis). RESULTS: Five new compounds derived from Carlina oxide were synthesized (IM8-IM12), and their structures were characterized by infrared (IR), 1H and 13C nuclear magnetic resonance (NMR). The new synthesized compounds were evaluated as mSpeB, DHFR from Enterococcus faecalis and DNA gyrase inhibitors by a docking analysis using MOE. These results show interesting ligand interactions with the three enzymes, and the best result was attributed to the complexes formed with IM9, which had the lowest score. CONCLUSION: In fact, these new compounds could lead to powerful approaches for the research and development of new antibiotics.

Synthesis of novel Schiff bases using 2-Amino-5-(3-fluoro-4-methoxyphenyl)thiophene-3-carbonitrile and 1,3-Disubstituted pyrazole-4-carboxaldehydes derivatives and their antimicrobial activity.

2-Amino-5-(3-fluoro-4-methoxyphenyl)thiophene-3-carbonitrile have been synthesized from 1-(3-fluoro-4-methoxyphenyl)ethanone, malononitrile, a mild base and sulfur powder using Gewald synthesis technique and the intermediate was treated with 1,3-disubstituted pyrazole-4-carboxaldehyde to obtain the novel Schiff bases. 1,3-disubstituted pyrazole-4-carboxaldehyde derivatives have been synthesized by Vilsmeier-Haack reaction in the course of a multi-step reaction. The structure of novel compounds were established on the basis of their elemental analyses IR, 1H NMR, 13C NMR, and mass spectral data and then screened for their in vitro antimicrobial activity. Among them 5a, 5c, 5f and 5h showed excellent activity when compared to other derivatives. Remaining derivatives showed moderate activity.

Discovery of Tröger's base analogues as selective inhibitors against human breast cancer cell line: design, synthesis and cytotoxic evaluation.

A library of structurally diverse Tröger's base analogues has been constructed via unusual amination of methylene bridge employing Vilsmeier-Haack conditions as well as by the incorporation of five and six membered heterocycles on the aromatic core of Tröger's base framework. The constructed structurally diverse frameworks were evaluated for their cytotoxic activities against a panel of three human cancer lines A549 (lung adenocarcinoma), MDAMB-231 (breast) and SK-N-SH (neuroblastoma). From the activity profile obtained, a redesign of Tröger's base analogues led to the construction of more potent molecular entities. The study led to development of a series of compounds with MDAMB-231 cell line specific cytotoxicity. Of the 30 compounds synthesized and evaluated, 7 compounds were found to possess cytotoxicity that is equivalent or better than standard drug doxorubicin against MDAMB-231 cell line while only one compound was found to be active against SK-N-SH cell line.