Acylhydrazone Derivatives Research Articles

Synthesis, molecular modeling and evaluation of novel N′-2-(4-benzylpiperidin-/piperazin-1-yl)acylhydrazone derivatives as dual inhibitors for cholinesterases and Aβ aggregation

To develop new drugs for treatment of Alzheimer’s disease, a group of N′-2-(4-Benzylpiperidin-/piperazin-1-yl)acylhydrazones was designed, synthesized and tested for their ability to inhibit acetylcholinesterase, butyrylcholinesterase and aggregation of amyloid beta peptides (1–40, 1–42 and 1–40_1–42). The enzyme inhibition assay results indicated that compounds moderately inhibit both acetylcholinesterase and butyrylcholinesterase. β-Amyloid aggregation results showed that all compounds exhibited remarkable Aβ fibril aggregation inhibition activity with a nearly similar potential as the reference compound rifampicin, which makes them promising anti-Alzheimer drug candidates. Docking experiments were carried out with the aim to understand the interactions of the most active compounds with the active site of the cholinesterase enzymes.

Oral Antithrombotic Effects of Acylhydrazone Derivatives

In the search for new antithrombotic drug candidates, the synthesis and anti-platelet activity of a new series of N-acylhydrazones that were designed as thrombin inhibitors has been previously described. The aim of this work was to further characterize the effects of these compounds on thrombin-induced platelet aggregation and induced thrombosis in vivo. In this work, four compounds were tested, LASSBio-693, 694, 743 and 752, on platelet aggregation induced by thrombin, ADP and TRAP-4A. These compounds were further tested using a mouse pulmonary thromboembolism model induced by collagen (500 µg/kg) and norepinephrine (80 µg/kg) or thrombin (2,000 UI), and a deep venous thrombosis model. At 200 µM, the compounds showed between 36% and 82% inhibition (for L-743 and L-752, respectively) of thrombin-induced platelet aggregation. The receptor agonist of PAR-4, TRAP-4A (250 µM), was used and inhibition between 43% and 77% was observed for each compound (200 µM).Compounds LASSBio-752 and 743 were the most effective in the venous thrombosis model, increasing the survival of the treated animals to 63% and 46%, respectively, in the model of collagen-induced thromboembolism and increasing to 80% (both) in the thrombin-induced model. LASSBio 743 was more effective for deep vein thrombosis, reducing the weight of the thrombus by approximately 70%. All compounds were administered orally and have shown effective antithrombotic action independently of the thrombotic stimulus. These results indicate that compounds LASSBio-743 and 752 are potential candidates for the treatment of cardiovascular diseases.

Acylhydrazones Contribute to Serum Glucose Homeostasis Through Dual Physiological Targets

In this study the in vivo and in vitro antidiabetic effects of four acylhydrazone derivatives were investigated in rats. The secretagogue action, oral glucose tolerance, insulinogenic index and mechanism of action of these acylhydrazones in relation to calcium uptake in pancreatic islets were studied. Also, the insulinomimetic effect on glycemia in diabetic rats was verified. Of the acylhydrazones studied, 1 and 4 were able to increase glucose tolerance in an acute time-course. A powerful secretagogue effect was exhibited by 1 and glibenclamide with an insulinogenic index around 3.9 and 1.3-fold higher than that of the hyperglycemic group, respectively. Moreover, an acute and dose-dependent effect of glibenclamide and 1 on calcium uptake in pancreatic islets was observed. The rapid stimulatory effect of 1 on calcium uptake seems to be mediated, at least in part, by ATP-dependent K+ channels (K+-ATP) since the stimulatory effect of 1 was similar to that observed for glibenclamide but was not potentiated by sulphonylurea. Furthermore, both extracellular and calcium from stocks mediate the signal transduction of stimulatory effect of 1 on calcium uptake which may contribute to insulin secretion. In addition, the insulinomimetic effect of 1 was evidenced through the level of serum glucose lowering in alloxan-induced diabetic rats. Also, 1 induced a significant increase in glycogen content in vivo and glucose uptake in soleus muscle in vitro. The results of this study indicate dual physiological targets for the acylhydrazone 1, i.e., pancreatic islets and skeletal muscle, as a result of insulin secretagogue and insulinomimetic action.

Design, synthesis and antibacterial activities of vanillic acylhydrazone derivatives as potential β-ketoacyl-acyl carrier protein synthase III (FabH) inhibitors

Fatty acid biosynthesis is essential for bacterial survival. FabH, β-ketoacyl-acyl carrier protein (ACP) synthase III, is a particularly attractive target, since it is central to the initiation of fatty acid biosynthesis and is highly conserved among Gram-positive and Gram-negative bacteria. A series of acylhydrazone derivatives were synthesized and developed as potent inhibitors of FabH. This inhibitor class demonstrates strong broad-spectrum antibacterial activity. Compounds with potent antibacterial activities were tested for their Escherichia coli FabH inhibitory activity. Especially, compound E9 showed the most potent antibacterial activity with MIC values of 0.39–1.56 μg/mL against the tested bacterial strains and exhibited the most potent E. coli FabH inhibitory activity with IC50 of 2.5 μM. Docking simulation was performed to position compound E9 into the E. coli FabH active site to determine the probable binding conformation.

Synthesis, Structure Optimization and Antifungal Screening of Novel Tetrazole Ring Bearing Acyl-Hydrazones

Azoles are generally fungistatic, and resistance to fluconazole is emerging in several fungal pathogens. In an attempt to find novel azole antifungal agents with improved activity, a series of tetrazole ring bearing acylhydrazone derivatives were synthesized and screened for their in vitro antifungal activity. The mechanism of their antifungal activity was assessed by studying their effect on the plasma membrane using flow cytometry and determination of the levels of ergosterol, a fungal-specific sterol. Propidium iodide rapidly penetrated a majority of yeast cells when they were treated with the synthesized compounds at concentrations just above MIC, implying that fungicidal activity resulted from extensive lesions of the plasma membrane. Target compounds also caused a considerable reduction in the amount of ergosterol. The results also showed that the presence and position of different substituents on the phenyl ring of the acylhydrazone pendant seem to play a role on the antifungal activity as well as in deciding the fungistatic and fungicidal nature of the compounds.

Synthesis and Fungicidal Activity ofα-Terpinene-maleimide-based acylhydrazone Derivatives

α-Pinene was converted into α-terpinene by Wagner-Meerwein rearrangement under catalysis of protonic acid, followed by Diels-Alder cycloaddtion reaction of α-terpinene with maleic anhydride to obtain α-terpinene-maleic anhydride (3). Then, N-amino-α-terpinene-maleimide (4) was prepared by the reaction of compound 3 with hydrazine hydrate. Seventeen novel α-terpinene-maleimide-based acylhydrazones 5a~5q were synthesized by the reaction of compound 4 with substituted phenyl aldehydes under catalysis of glacial acetic acid. The synthetic conditions were investigated preliminarily. The target compounds were characterized by means of elemental analysis, 1 H NMR, 13 C NMR, LC-MS and FT-IR techniques. The pre- liminary bioassay showed that most of the title compounds exhibited a certain fungicidal activity, in which 4-hydroxyl-3- methoxyphenyl-α-terpinene-maleimide-based acylhydrazone (5n) had inhibition rates of 91%, 83.3% and 76.7% against Phy- salospora piricola, Cercospora rachidicola, and Alternaria solani, respectively, at the concentration of 50 mg/L. Keywords α-pinene; N-amino-α-terpinene-maleimide; α-terpinene-maleimide-based acylhydrazone; synthesis; fungicidal activity

ChemInform Abstract: New Class of Potent Antitumor Acylhydrazone Derivatives Containing Furan.

AbstractA pair of isomeric structures of N‐acylhydrazones is designed and synthesized.

New class of potent antitumor acylhydrazone derivatives containing furan

A pair of chemical isomeric structures of N-acylhydrazone compounds I and II were designed and synthesized. The reaction was carried out with high diastereoselectivity to obtain one configurational isomer in excellent yields. The exact configuration and conformation of IIa and IIe were confirmed by the X-ray single crystal diffraction. The antitumor bioassay revealed that some compounds exhibited excellent activity against the selected cancer cell lines. In particular, IIf (IC 50 = 16.4 μM) was better than doxorubicin (IC 50 = 53.3 μM) against human promyelocytic leukemic cells (HL-60). Their toxicities were predicted in silico. The results showed that compounds II were safe and eligible to be development candidates. IIf showed great promise as a novel lead compound for further anticancer discovery.

2,3‐Dihydro‐1‐Benzofuran Derivatives as a Series of Potent Selective Cannabinoid Receptor 2 Agonists: Design, Synthesis, and Binding Mode Prediction through Ligand‐Steered Modeling

We recently discovered and reported a series of N-alkyl-isatin acylhydrazone derivatives that are potent cannabinoid receptor 2 (CB(2)) agonists. In an effort to improve the druglike properties of these compounds and to better understand and improve the treatment of neuropathic pain, we designed and synthesized a new series of 2,3-dihydro-1-benzofuran derivatives bearing an asymmetric carbon atom that behave as potent selective CB(2) agonists. We used a multidisciplinary medicinal chemistry approach with binding mode prediction through ligand-steered modeling. Enantiomer separation and configuration assignment were carried out for the racemic mixture for the most selective compound, MDA7 (compound 18). It appeared that the S enantiomer, compound MDA104 (compound 33), was the active enantiomer. Compounds MDA42 (compound 19) and MDA39 (compound 30) were the most potent at CB(2). MDA42 was tested in a model of neuropathic pain and exhibited activity in the same range as that of MDA7. Preliminary ADMET studies for MDA7 were performed and did not reveal any problems.

Synthesis and antiviral activities of novel acylhydrazone derivatives targeting HIV-1 capsid protein

HIV-1 capsid protein (CA) plays important roles in the viral replication cycle. A number of acylhydrazone derivatives that act as inhibitors of HIV-1 CA assembly, were designed and synthesized. The synthesized compounds were tested for their antiviral activities and cytotoxicities using CEM cells. Some derivatives also were assayed for their ability to inhibit HIV-1 CA assembly in vitro. Among them, compounds 14f and 14i display the most promising potency with EC 50 values of 0.21 and 0.17 μΜ, respectively.

6-Methoxy-N-alkyl Isatin Acylhydrazone Derivatives as a Novel Series of Potent Selective Cannabinoid Receptor 2 Inverse Agonists: Design, Synthesis, and Binding Mode Prediction

Recently, we discovered and reported a series of N-alkyl isatin acylhydrazone derivatives that are potent CB2 agonists. Here, we describe a novel series of selective CB2 inverse agonists resulting from introduction of a methoxy moiety in position 6 of the isatin scaffold. These novel 6-methoxy-N-alkyl isatin acylhydrazone derivatives exhibited high CB2 functional activity and selectivity at human CB2. Compound 16 (MDA77) had high activity (EC(50) = 5.82 nM) at CB2 and no activity at CB1. Compound 15 (MDA55) (K(i) = 89.9 nM, EC(50) = 88.2 nM at CB2) inhibited the effect of compound 1 (MDA7), a selective CB2 agonist, in an animal model of neuropathic pain. The molecular modeling study presented here represents a first study of CB2 based on the structure of beta(2)-adrenergic receptor. A ligand-based homology model of the CB2 binding site was developed, and on the basis of our results, we propose a general binding mode for this class of inverse agonists with CB2.

Design and Synthesis of a Novel Series of N-Alkyl Isatin Acylhydrazone Derivatives that Act as Selective Cannabinoid Receptor 2 Agonists for the Treatment of Neuropathic Pain

There is growing interest in using cannabinoid receptor 2 (CB2) agonists for the treatment of neuropathic pain. We have synthesized a novel series of N-alkyl isatin acylhydrazone derivatives and have identified and characterized several of them as novel analogues with high functional activity and selectivity at human CB2 receptors using [(35)S]GTP-gamma-S assays. Binding affinities at human CB2 and CB1 were determined for compounds 28, 33, 40, 48, and 58. Structure-activity relationship studies of this novel series led to optimization of our lead compound, compound 33 (MDA19). Compound 33 possessed potent antiallodynic effects in a rat model of neuropathic pain but did not affect rat locomotor activity. More potent and more CB2-receptor-selective compounds, including compounds 37, 40, and 48, were also discovered.

ChemInform Abstract: Synthesis and Antiplatelet Activity of Novel Arylsulfonate—Acylhydrazone Derivatives, Designed as Antithrombotic Candidates.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis and anti-platelet activity of novel arylsulfonate–acylhydrazone derivatives, designed as antithrombotic candidates

In this work, we describe a new class of promising anti-platelet drug candidates with significant antithrombotic activity in vivo. This new series of compounds was structurally planned by modification of known thrombin inhibitors based on the use of acylhydrazone subunit, as a nonpeptide scaffold, and variations at P1 moiety. Three different families of arylsulfonate–acylhydrazone derivatives were designed. The bioassays indicated the first class of derivatives represented by 4f (LASSBio-693) and 4j (LASSBio-743), which were active in inhibiting the platelet aggregation induced by thrombin. The second class represented by compounds 4e (LASSBio-774) and 4h (LASSBio-480) that selectively inhibit the platelet aggregation involving TXA 2 formation. Finally, the third class of derivatives was identified acting as a novel symbiotic agent able to inhibit the platelet aggregation induced by collagen or AA and by thrombin, represented by compounds 4b (LASSBio-694) and 4g (LASSBio-770).

Gelation-driven component selection in the generation of constitutional dynamic hydrogels based on guanine-quartet formation

The guanosine hydrazide 1 yields a stable supramolecular hydrogel based on the formation of a guanine quartet (G-quartet) in presence of metal cations. The effect of various parameters (concentration, nature of metal ion, and temperature) on the properties of this gel has been studied. Proton NMR spectroscopy is shown to allow a molecular characterization of the gelation process. Hydrazide 1 and its assemblies can be reversibly decorated by acylhydrazone formation with various aldehydes, resulting in formation of highly viscous dynamic hydrogels. When a mixture of aldehydes is used, the dynamic system selects the aldehyde that leads to the most stable gel. Mixing hydrazides 1, 9 and aldehydes 6, 8 in 1:1:1:1 ratio generated a constitutional dynamic library containing the four acylhydrazone derivatives A, B, C, and D. The library constitution displayed preferential formation of the acylhydrazone B that yields the strongest gel. Thus, gelation redirects the acylhydrazone distribution in the dynamic library as guanosine hydrazide 1 scavenges preferentially aldehyde 8, under the pressure of gelation because of the collective interactions in the assemblies of G-quartets B, despite the strong preference of the competing hydrazide 9 for 8. Gel formation and component selection are thermoreversible. The process amounts to gelation-driven self-organization with component selection and amplification in constitutional dynamic hydrogels based on G-quartet formation and reversible covalent connections. The observed self-organization and component selection occur by means of a multilevel self-assembly involving three dynamic processes, two of supramolecular and one of reversible covalent nature. They extend constitutional dynamic chemistry to phase-organization and phase-transition events.

New class of potent antinociceptive and antiplatelet 10H-phenothiazine-1-acylhydrazone derivatives

The synthesis and pharmacological evaluation of new 10 H -phenothiazine-1-acylhydrazone derivatives ( 6 ) is reported. In this work, we reported the synthesis and evaluation of the analgesic, antiinflammatory, and antiplatelet properties of new phenothiazine-attached acylhydrazone derivatives ( 6 ), designed exploring the molecular hybridization approach between antipsychotic chlorpromazine ( 4 ) and other heterocyclic derivatives ( 3 ) and ( 5 ) developed at LASSBio. Target compounds were synthesized in very good yields exploiting diphenylamine ( 7 ) as starting material, through regioselective functionalization of the C-1 position of 10 H -phenothiazine ring. The evaluation of platelet antiaggregating profile lead us to identify a new potent prototype of antiplatelet derivative, that is ( 6a ) (IC 50 =2.3 μM), which acts in arachidonic acid pathway probably by inhibition of platelet COX-1 enzyme. Additionally, the change of para -substituent group of acylhydrazone framework permitted us to identify hydrophilic carboxylate derivative ( 6g ) and hydrophobic bromo derivative ( 6b ) as two new leads of analgesics more active than dipyrone used as standard and with selective peripheral or central mechanism of action.

New class of potent antinociceptive and antiplatelet 10 H-phenothiazine-1-acylhydrazone derivatives

In this work, we reported the synthesis and evaluation of the analgesic, antiinflammatory, and antiplatelet properties of new phenothiazine-attached acylhydrazone derivatives ( 6), designed exploring the molecular hybridization approach between antipsychotic chlorpromazine ( 4) and other heterocyclic derivatives ( 3) and ( 5) developed at LASSBio. Target compounds were synthesized in very good yields exploiting diphenylamine ( 7) as starting material, through regioselective functionalization of the C-1 position of 10 H-phenothiazine ring. The evaluation of platelet antiaggregating profile lead us to identify a new potent prototype of antiplatelet derivative, that is ( 6a) (IC 50=2.3 μM), which acts in arachidonic acid pathway probably by inhibition of platelet COX-1 enzyme. Additionally, the change of para-substituent group of acylhydrazone framework permitted us to identify hydrophilic carboxylate derivative ( 6g) and hydrophobic bromo derivative ( 6b) as two new leads of analgesics more active than dipyrone used as standard and with selective peripheral or central mechanism of action.

New Phenothiazine Derivatives with Potential Pharmacological Properties and Chelating Activity

AbstractFor Abstract see ChemInform Abstract in Full Text.

THERMAL ANALYSIS IN STRUCTURAL CHARACTERIZATION OF HYDRAZONE LIGANDS AND THEIR COMPLEXES

Results of our research on synthesis and characterization of complexes with acylhydrazone derivatives are described in this review paper. Structural characterization of newly synthesized complexes by thermal analysis (TG, DTA, DSC) is particularly emphasized in this paper. Thermal analysis enabled us to study not only structural changes of substances during thermal treatment, but also the mode of coordination and degree of deprotonation of acylhydrazones, as well as geometry of the coordination sphere of complexes, the structure of which had not been determined by X-ray analysis. Topics in this paper are as follows: complexes of dioxomolybdenum(VI) with tridentate hydrazones, usnic acid derivatives and their Cu(II) complexes, as well as transition metal complexes with 2,6-diacetylpyridine bis(hydrazones).

Synthesis and pharmacological evaluation of novel heterotricyclic acylhydrazone derivatives, designed as PAF antagonists

This paper describes the synthesis and the antiplatelet properties of new heterotricyclic N-acylhydrazone derivatives (7a–e), structurally analogous to known hetrazepinic PAF antagonists, exploring molecular hybridization as a tool for molecular designing. The synthetic route employed to access compounds (7a–e) used, as starting material, the previously described methyl 3-hydroxy-8-methyl-6-phenyl-6 H-pyrazolo[3,4- b]thieno[2,3- d]pyridine-2-carboxylate derivative. The results from inhibitory effects of these novel acylhydrazone derivatives (7a–e) upon PAF-induced platelet aggregation, indicated that all compounds present a significant antithrombotic profile.