Furanyl Moiety Research Articles

Synthesis, Anticancer Activity, and Docking Studies of Novel Hydroquinone-Chalcone-Pyrazoline Hybrid Derivatives.

A novel series of antitumor hybrids was synthesized using 1,4-benzohydroquinone and chalcone, furane, or pyrazoline scaffolds. This were achieved through isosteric substitution of the aryl group of the chalcone β-carbon with the furanyl moiety and structural modification of the α,β-unsaturated carbonyl system. The potential antitumor activity of these hybrids was evaluated in vivo on MCF-7 breast adenocarcinoma and HT-29 colorectal carcinoma cells, demonstrating cytotoxic activity with IC50 values ranging from 28.8 to 124.6 µM. The incorporation of furan and pyrazoline groups significantly enhanced antiproliferative properties compared to their analogues and precursors (VII-X), which were inactive against both neoplastic cell lines. Compounds 4, 5, and 6 exhibited enhanced cytotoxicity against both cell lines, whereas compound 8 showed higher cytotoxic activity against HT-29 cells. Molecular docking studies revealed superior free-energy values (ΔGbin) for carcinogenic pathway-involved kinase proteins, with our in silico data suggesting that these derivatives could be promising chemotherapeutic agents targeting kinase pathways. Among all the synthesized PIBHQ compounds, derivatives 7 and 8 exhibited the best drug-likeness properties, with values of 0.53 and 0.83, respectively. ADME results collectively suggest that most of these compounds hold promise as potential candidates for preclinical assays.

Synthesis of Spiro[furan-2,1'-isoindolin]-3'-ones from 2-(4-Hydroxybut-1-yn-1-yl)benzonitriles and Aryl Aldehydes under the Action of Triflic Acid.

The synthesis of spiro[furan-2,1'-isoindolin]-3'-ones from 2-(4-hydroxybut-1-yn-1-yl)benzonitriles and aryl aldehydes is demonstrated. It involves the initial formation of dihydrofuranylideneisoindolinone via intramolecular sequential Prins and Ritter reactions, followed by the ring opening of the furanyl moiety to generate N-acyliminium ions and alcohols for the final cyclization reaction, and the spiro-cyclic compounds are produced in moderate to good yields. It is a one-pot, three-component reaction in which one new quaternary carbon, two five-membered rings, one C-N bond, two C-O bonds, and one C-C bond are formed. The reaction is carried out with a Brønsted acid from 0 °C to room temperature within a short period of time.

Design and Synthesis of Novel Pyrazolo[3,4-d]Pyrimidines: In Vitro Cytotoxic Evaluation and Free Radical Scavenging Activity Studies

With evident biological importance, a new series of pyrazolo[3,4-d]pyrimidines 3a,3b and 4a,4b were synthesized via the formation of pyrazol-3-one 2a and 2b substrates. All compounds were evaluated for in vitro cytotoxic activity against MCF-7 (breast adenocarcinoma) and A549 (lung cancer) cell lines. The obtained results showed that pyrazolo[3,4-d] pyrimidin-4-ol 3a bearing phenyl group at N-1 and p-C6H4 at C-6, and 4b with dinitrophenyl at N-1 and furanyl moiety at C-6 had better inhibitory activity against MCF-7 with IC50 values in a micromolar range as compared to other substrates. The synthesized compounds can be considered as new candidates for further optimization as anticancer agents.

In vitro and in silico evaluations of diarylpentanoid series as α-glucosidase inhibitor

A series of thirty-four diarylpentanoids derivatives were synthesized and evaluated for their α-glucosidase inhibitory activity. Eleven compounds (19, 20, 21, 24, 27, 28, 29, 31, 32, 33 and 34) were found to significantly inhibit α-glucosidase in which compounds 28, 31 and 32 demonstrated the highest activity with IC50 values ranging from 14.1 to 15.1 µM. Structure-activity comparison shows that multiple hydroxy groups are essential for α-glucosidase inhibitory activity. Meanwhile, 3,4-dihydroxyphenyl and furanyl moieties were found to be crucial in improving α-glucosidase inhibition. Molecular docking analyses further confirmed the critical role of both 3,4-dihydroxyphenyl and furanyl moieties as they bound to α-glucosidase active site in different mode. Overall result suggests that diarylpentanoids with both five membered heterocyclic ring and polyhydroxyphenyl moiety could be a new lead design in the search of novel α-glucosidase inhibitor.

New insights on the molecular features and electrophysiological properties of dinotefuran, imidacloprid and acetamiprid neonicotinoid insecticides

Structural features and hydrogen-bond interactions of dinotefuran (DIN), imidacoloprid (IMI) and acetamiprid (ACE) have been investigated experimentally through analyses of new crystal structures and observations in structural databases, as well as by Density Functional Theory quantum chemical calculations. Several conformations are observed experimentally in the solid state, highlighting the large flexibility of these compounds. This feature is confirmed by the theoretical calculations in the gas phase, the numerous and different energetic minima of the three neonicotinoids being located within a 10kJ/mol range. Comparisons of the observed and simulated data sheds light on the hydrogen-bond (HB) strength of the functional group at the tip of the electronegative fragment of each pharmacophore (NO2 for DIN and IMI and CN for ACE). This effect originates in the ‘push–pull’ nature of these fragments and the related extensive electron delocalization. Molecular electrostatic potential calculations provide a ranking of the two fragments of the three neonicotinoid in terms of HB strength. Thus, the NO2 group of DIN is the strongest HB acceptor of the electronegative fragment, closely followed by the cyano group of ACE. These two groups are significantly more potent than the NO2 group of IMI. With respect to the other fragments of the three neonicotinoids, the nitrogen atom of the pyridine of IMI and ACE are stronger HB acceptors than the oxygen atom of the furanyl moiety of DIN. Finally, compared to electrophysiological studies obtained from cockroach synaptic and extrasynaptic receptors, DIN appears more effective than IMI and ACE because it strongly increases dose-dependently the ganglionic depolarisation and the currents amplitudes. These data suggest that DIN, IMI and ACE belong to two subgroups which act differently as agonists of insect nicotinic receptors.

Synthesis and SAR of Thiazolylmethylphenyl Glucoside as Novel C-Aryl Glucoside SGLT2 Inhibitors.

Novel C-aryl glucoside SGLT2 inhibitors containing the thiazole motif were designed and synthesized for biological evaluation. Among the compounds assayed, thiazole containing furanyl moiety 14v and thiophenyl moiety 14y demonstrated the best in vitro inhibitory activity against SGLT2 in this series to date (IC50 = 0.720 nM for 14v and IC50 = 0.772 nM for 14y). Both of these compounds have been further evaluated on a urinary glucose excretion test and the urine volumes excreted.

‘Hybrid’ benzofuran–benzopyran congeners as rigid analogs of hallucinogenic phenethylamines

Phenylalkylamines that possess conformationally rigidified furanyl moieties in place of alkoxy arene ring substituents have been shown previously to possess the highest affinities and agonist functional potencies at the serotonin 5-HT 2A receptor among this chemical class. Further, affinity declines when both furanyl rings are expanded to the larger dipyranyl ring system. The present paper reports the synthesis and pharmacological evaluation of a series of ‘hybrid’ benzofuranyl–benzopyranyl phenylalkylamines to probe further the sizes of the binding pockets within the serotonin 5-HT 2A agonist binding site. Thus, 4( a– b), 5( a– b), and 6 were prepared as homologs of the parent compound, 8-bromo-1-(2,3,6,7-tetrahydrobenzo[1,2- b:4,5- b′]difuran-4-yl)-2-aminopropane 2, and their affinity, functional potency, and intrinsic activity were assessed using cells stably expressing the rat 5-HT 2A receptor. The behavioral pharmacology of these new analogs was also evaluated in the two-lever drug discrimination paradigm. Although all of the hybrid isomers had similar, nanomolar range receptor affinities, those with the smaller furanyl ring at the arene 2-position ( 4a– b) displayed a 4- to 15-fold greater functional potency than those with the larger pyranyl ring at that position ( 5a– b). When the furan ring of the more potent agonist 4b was aromatized to give 6, a receptor affinity similar to the parent difuranyl compound 2 was attained, along with a functional potency equivalent to 2, 4a, and 4b. In drug discrimination experiments using rats trained to discriminate LSD from saline, 4b was more than two times more potent than 5b, with the latter having a potency similar to the classic hallucinogenic amphetamine 1 (DOB).

Construction of Cycloalkane-based Thermomorphic (CBT) Electrolyte Solution Systems and Application for Anodic Conversion of a Furan Derivative

Anodic oxidation of a furan derivative was accomplished in cycloalkane-based thermomorphic (CBT) electrolyte solutions. In the CBT system, hydrophobic phase-tagged substrates were efficiently electrolyzed in the reversibly immixed mono-phasic state followed by on-cooling phase-separation of the tagged product as the cycloalkane solution separated from the polar electrolyte solutions. In the case of anodic oxidation of the phase-tagged furanyl compound, a 3,5-didocosyloxybenzyl tag that possessed higher oxidation potential and high hydrophobicity worked efficiently for achieving the selective anodic oxidation of the furanyl moiety. The electrolytic products were also successfully subjected to catalytic hydrogenation, which is generally difficult for solid-supported substrates. The product was separated from the CBT electrolyte solution simply by on-cooling phase separation.

Design and synthesis of a novel class of furan-based molecules as potential 20S proteasome inhibitors

A novel class of furan-based compounds as potential 20S proteasome inhibitors have been designed and synthesized, among which nine compounds are peptide derivatives and six molecules are statine peptidomimetics. The C-terminal furanyl moiety was introduced to target molecules as furan-based amino acids. All the compounds were obtained steadily with moderate to high yield. Compound 12 was a selective moderate potent proteasome peptidomimetic inhibitor. It inhibited HepG2 and HL-60 proliferation effectively.

Molecular structure of di-aryl-aldimines by multinuclear magnetic resonance and X-ray diffraction

The complete 1H, 13C and 15N NMR analyses for a series of 25 diaryl-aldimines containing phenyl, pyridyl, pyrazolone and furanyl moieties are described herein. Detailed evaluation of substituent chemical shift and coupling constant effects showed that interaction between the lone pair of the pyrazolone carbonyl group or the nitrogen of 2-substitued pyridines with the aldimine hydrogen increases the 1J CH value and shifts the resonance signal for this hydrogen to high frequency, in the 1H NMR spectra. The X-ray crystal structure analysis of pyrazolone substituted aldimines evidenced the planarity of the aryl groups which are conjugated with the CN double bond. In the case of the N-(2-pyridinemethylene)-1,5-dimethyl-2-phenyl-1,2-dihydro-pyrazol-3-one, two rotamers were observed in the same unit cell.

Design, Synthesis, and Biological Evaluation of C9- and C2-Substituted Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines as New A2Aand A3Adenosine Receptors Antagonists

In the past few years, our group has been involved in the development of A(2A) and A(3) adenosine receptor antagonists which led to the synthesis of SCH58261 (5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine, 61), potent and very selective at the A(2A) receptor subtype, and N(8)-substituted-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines-N(5)-urea or amide (MRE series, b), very selective at the human A(3) adenosine receptor subtype. We now describe a large series of C(9)- and C(2)-substituted pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines to represent an extension of structure-activity relationship work on this class of tricyclic compounds. The introduction of a substituent at 9 position of the tricyclic antagonistic structure led to retention of receptor affinity but a loss of selectivity in respect to the lead compounds b, N(8)-substituted-pirazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines-N(5)-urea or -amide. The substitution of the furanyl moiety of compound 61, necessary for receptor binding, with a phenyl or a substituted aromatic ring (compounds 5a-d, 6-8), caused a complete loss of the affinity at all the adenosine receptor subtypes, demonstrating that the furanyl ring is a necessary structural element to guarantee interaction with the adenosine receptor surface. The introduction of an ethoxy group at the ortho position of the aromatic ring to mimic the oxygen of the furan (compound 5c, 5-amino-7-(2-phenylethyl)-2-(2-ethoxyphenyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine) did not enhance affinity. The introduction of the cycloaminomethyl function by Mannich reaction at the 5' position of the furanyl ring of 61 and the C(9)-substituted compound 41 (5-amino-8-methyl-9-methylsulfanyl-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine) resulted in complete water solubility but a loss of receptor affinity. We can conclude that modifications or substitutions at the furanyl ring are not allowed and the introduction of a substituent at the 9-position of the core pyrazolo-triazolo-pyrimidine structure caused a severe loss of selectivity, probably due to an increased steric hindrance of the radical introduced.

Azadirachtol, a tetranortriterpenoid from neem kernels.

The title compound, dimethyl (-)-(2aR,3R,4R,4aS,5R,7aS,8R,10S,10aR)-3,8,10-trihydroxy-4-[(2R,6R)-2-hydroxy-11-methyl-5,7,10-trioxatetracyclo[6.3.1.0(2,6)0(9,11)]dodec-3-en-9-yl]-4-methylperhydroisobenzofurano[5,4,3a-cd]isobenzofuran-5,10a-diacetate, C(28)H(36)O(13), which exhibits higher antifeedant activity than azadirachtin-A, a known potent antifeedant, was isolated from neem kernels. The asymmetric unit of the structure contains two independent molecules, which differ in the conformations of their functional groups and also in the conformations of some of the rings. The relative orientation between the decalin and furanyl moieties is similar to that observed in the majority of azadirachtin structures, but is different from that in azadirachtin-A. The two symmetry-independent molecules are linked into dimeric units by intermolecular O-H.O hydrogen bonds.

Synthesis and characterisation of platinum(II) complexes with the antiviral agents Ftorafur and Furavir

Novel hybrid drugs, [Pt(NH 3) 2(Ftorafur–H) 2] ( 1) and [Pt(NH 3) 2(Furavir) 2](NO 3) 2 ( 2), have been prepared by reaction of Ftorafur (Ft) and Furavir (Fr) with cisplatin. Ftorafur, a prodrug of 5-fluorouracil containing a 2-tetrahydrofuranyl radical linked to N(1), is stable when coordinated to platinum through N(3) but the N(1)furanyl bond is hydrolysed by platinum substrates (such as [Pt(NH 3) 2(H 2O) 2] 2+ and [Pt(dien)(H 2O)] 2+) in the free state. In contrast, Furavir, a derivative of N(2)-acetyl-acyclovir carrying a 2-tetrahydrofuranyl radical linked to the terminal part of the (2-oxy)-ethoxymethyl chain bound to N(9), when coordinated to platinum through N(7), readily undergoes hydrolysis of the Ofuranyl bond releasing 2-hydroxytetrahydrofuran and leaving N(2)-acetyl-acyclovir coordinated to platinum. It is suggested that the hydrolysis of the Xfuranyl bond (X=N or O for Ftorafur and Furavir, respectively), which is catalysed by Lewis acids, is favoured in the latter case by the long and flexible (2-oxy)-ethoxymethyl chain which allows the metal centre to reach over the furanyl moiety. This is not possible in the case of the Ftorafur derivative. This investigation has demonstrated the possibility of controlling the hydrolysis of a coordinated substrate in a multifunctional platinum drug by a suitable choice of the position of the breakable bond with respect to the metal centre.

Studies on the synthesis of highly substituted furans: The synthesis of calicogorgins A and C

A short and highly efficient synthesis of calicogorgin A and C has been accomplished. The key features include a rapid assembly of the furanyl moieties, a sulfonyl anion alkylation to join the two halves and a bis-reductive desulfurization.

Binuclear Transition Metal Complexes of Schiff Base Macrocycles Containing the Furanyl Moiety

Abstract Binucleating macrocycles L comprised of two molecules of 2,5-diformylfuran and two molecules of 1,3-diaminopropane have been synthesized as cobalt(II), nickel(II) and copper(II) complexes by template reactions. On the basis of various spectroscopic studies the 20-membered macrocyclic complexes can be described as having six-coordinate octahedral structures where L is bonding through the nitrogens of 1,3-diaminopropane and the oxygens of the furanyl moiety. The elemental analyses and molecular ion peak from the mass spectra confirm their proposed 2:1 metal ligand stoichiometry. The overall geometries have been proposed on the basis of elemental analysis, i.r., 1H nmr, mass, reflectance spectra and magnetic susceptibility measurements.