Imidazolylacetophenone oxime-based multifunctional neuroprotective agents: Discovery and structure-activity relationships.

Alzheimer's disease (AD) possesses a complex pathogenetic mechanism. Nowadays, multitarget agents are considered to have potential in effectively treating AD via triggering molecules in functionally complementary pathways at the same time. Here, based on the screening (∼1400 compounds) against neuroinflammation, an imidazolylacetophenone oxime ether (IOE) was discovered as a novel hit. In order to obtain SARs, a series of imidazolylacetophenone oxime derivatives were constructed, and their C=N bonds were confirmed as the Z configuration by single crystals. These derivatives exhibited potential multifunctional neuroprotective effects including anti-neuroinflammatory, antioxidative damage, metal-chelating, inhibition of acetylcholinesterase (AChE) properties. Among these derivatives, compound 12i displayed the most potent inhibitory activity against nitric oxide (NO) production with EC50 value of 0.57 µM 12i can dose-dependently suppress the expression of iNOS and COX-2 but not change the expression of HO-1 protein. Moreover, 12i exhibited evidently neuroprotective effects on H2O2-induced PC12 cells damage and ferroptosis without cytotoxicity at 10 µM, as well as selectively metal chelating properties via chelating Cu2+. In addition, 12i showed a mixed-type inhibitory effect on AChE in vitro. The structure-activity relationships (SARs) analysis indicated that dioxolane groups on benzene ring and rigid oxime ester can improve the activity. Parallel artificial membrane permeation assay (PAMPA) also verified that 12i can overcome the blood-brain barrier (BBB). Overall, this is the first report on imidazolylacetophenone oxime-based multifunctional neuroprotective effects, suggesting that this type of compounds might be novel multifunctional agents against AD.

Screening oxime libraries by means of mass spectrometry (MS) binding assays: Identification of new highly potent inhibitors to optimized inhibitors γ-aminobutyric acid transporter 1.

Generation and screening of oxime libraries by competitive MS Binding Assays represents a powerful tool for the identification of new compounds, with affinity to mGAT1, the most abundant plasma membrane bound GABA transporter in the CNS. By screening a guvacine derived oxime library, new potent inhibitors of mGAT1 had been revealed. In the present study, oxime libraries generated by reaction of a large excess of a rac-nipecotic acid derivative displaying a hydroxylamine functionality in which various aldehydes under suitable conditions, were examined for new potent inhibitors of mGAT1. The pKi values obtained of the best hits were compared with those of related compounds displaying a guvacine instead of a nipecotic acid subunit as hydrophilic moiety. Amongst the new compounds one of the most affine ligands of mGAT1 known so far (pKi = 8.55 ±â€¯0.04) was found.

Synthesis of novel isoindoline-1,3-dione-based oximes and benzenesulfonamide hydrazones as selective inhibitors of the tumor-associated carbonic anhydrase IX.

The synthesis, characterization and biological evaluation of a library of isoindoline-1,3-dione-based oximes and benzenesulfonamide hydrazones is disclosed. The set of hydroxyiminoethyl aromatic derivatives 10-18 was designed to assess the potentiality as zinc-binder for a feebly studied functional group in the field of carbonic anhydrase (CA, EC 4.2.1.1) inhibition. Analogue phenylphthalimmides were linked to benzenesulfonamide scaffold by hydrazone spacers in the second subset of derivatives 20-28 to further investigate the application of the "tail approach" as tool to afford CA selective inhibition profiles. The compounds were assayed for the inhibition of physiologically relevant isoforms of human carbonic anhydrases (hCA, EC 4.2.1.1), the cytosolic CA I and II, and the membrane-bound CA IV and tumor-associated CA IX. The new zinc-binders, both of the oxime and sulfonamide types, showed a striking selective activity against the target hCA IX over ubiquitous hCA I and II, with diverse inhibitory ranges and ratio differing the two subsets. With CA IX being a strongly current antitumor/antimetastatic drug target, these series of compounds may be of interest for the development of new, both conventional and unconventional anticancer drugs targeting hypoxia-induced CA isoforms such as CA IX with minimum ubiquitous CAs-related side effects.

Development of benzoxazole deoxybenzoin oxime and acyloxylamine derivatives targeting innate immune sensors and xanthine oxidase for treatment of gout.

Both the inhibition of inflammatory flares and the treatment of hyperuricemia itself are included in the management of gout. Extending our efforts to development of gout therapy, two series of benzoxazole deoxybenzoin oxime derivatives as inhibitors of innate immune sensors and xanthine oxidase (XOD) were discovered in improving hyperuricemia and acute gouty arthritis. In vitro studies revealed that most compounds not only suppressed XOD activity, but blocked activations of NOD-like receptor (NLRP3) inflammasome and Toll-like receptor 4 (TLR4) signaling pathway. More importantly, (E)-1-(6-methoxybenzo[d]oxazol-2-yl)-2-(4-methoxyphenyl)ethanone oxime (5d) exhibited anti-hyperuricemic and anti-acute gouty arthritis activities through regulating XOD, NLRP3 and TLR4. Compound 5d may serve as a tool compound for further design of anti-gout drugs targeting both innate immune sensors and XOD.

A novel 3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime compound is a potent Transient Receptor Potential Ankyrin 1 and Vanilloid 1 (TRPA1 and V1) receptor antagonist.

Transient Receptor Potential Ankyrin 1 and Vanilloid 1 (TRPA1, TRPV1) ion channels expressed on nociceptive primary sensory neurons are important regulators of pain and inflammation. TRPA1 is activated by several inflammatory mediators including formaldehyde and methylglyoxal that are products of the semicarbazide-sensitive amine-oxidase enzyme (SSAO). SZV-1287 is a new 3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime SSAO inhibitor, its chemical structure is similar to other oxime derivatives described as TRPA1 antagonists. Therefore, we investigated its effects on TRPA1 and TRPV1 receptor activation on the cell bodies and peripheral terminals of primary sensory neurons and TRPA1 or TRPV1 receptor-expressing cell lines. Calcium influx in response to the TRPA1 agonist allyl-isothiocyanate (AITC) (200 µM) and the TRPV1 stimulator capsaicin (330 nM) in rat trigeminal neurons or TRPA1 and TRPV1 receptor-expressing cell lines was measured by microfluorimetry or radioactive (45)Ca(2+) uptake experiments. Calcitonin gene-related peptide (CGRP) release as the indicator of 100 µM AITC - or 100 nM capsaicin-induced peripheral sensory nerve terminal activation was measured by radioimmunoassay. SZV-1287 (100, 500 and 1000 nM) exerted a concentration-dependent significant inhibition on both AITC- and capsaicin-evoked calcium influx in trigeminal neurons and TRPA1 or TRPV1 receptor-expressing cell lines. It also significantly inhibited the TRPA1, but not the TRPV1 activation-induced CGRP release from the peripheral sensory nerve endings in a concentration-dependent manner. In contrast, the reference SSAO inhibitor LJP 1207 with a different structure had no effect on TRPA1 or TRPV1 activation in either model system. This is the first evidence that our novel oxime compound SZV-1287 originally developed as a SSAO inhibitor has a potent dual antagonistic action on TRPA1 and TRPV1 ion channels on primary sensory neurons.

Preclinical evaluation and test-retest studies of [(18)F]PSS232, a novel radioligand for targeting metabotropic glutamate receptor 5 (mGlu5).

PURPOSE: A novel, (18)F-labelled metabotropic glutamate receptor subtype 5 (mGlu5) derivative of [(11)C]ABP688 ([(11)C]1), [(18)F]PSS232 ([(18)F] ]5), was evaluated in vitro and in vivo for its potential as a PET agent and was used in test-retest reliability studies METHODS: The radiosynthesis of [(18)F]5 was accomplished via a one-step reaction using a mesylate precursor. In vitro stability was determined in PBS and plasma, and with liver microsomal enzymes. Metabolite studies were performed using rat brain extracts, blood and urine. In vitro autoradiography was performed on horizontal slices of rat brain using 1 and 8, antagonists for mGlu5 and mGlu1, respectively. Small-animal PET, biodistribution, and test-retest studies were performed in Wistar rats. In vivo, dose-dependent displacement studies were performed using 6 and blocking studies with 7. RESULTS: [(18)F]5 was obtained in decay-corrected maximal radiochemical yield of 37 % with a specific activity of 80 - 400 GBq/µmol. Treatment with rat and human microsomal enzymes in vitro for 60 min resulted in 20 % and 4 % of hydrophilic radiometabolites, respectively. No hydrophilic decomposition products or radiometabolites were found in PBS or plasma. In vitro autoradiography on rat brain slices showed a heterogeneous distribution consistent with the known distribution of mGlu5 with high binding to hippocampal and cortical regions, and negligible radioactivity in the cerebellum. Similar distribution of radioactivity was found in PET images. Under displacement conditions with 6, reduced [(18)F]5 binding was found in all brain regions except the cerebellum. 7 reduced binding in the striatum by 84 % on average. Test-retest studies were reproducible with a variability ranging from 6.8 % to 8.2 %. An extended single-dose toxicity study in Wistar rats showed no compound-related adverse effects. CONCLUSION: The new mGlu5 radiotracer, [(18)F]5, showed specific and selective in vitro and in vivo properties and is a promising radioligand for PET imaging of mGlu5 in humans.

Novel pyrazoline amidoxime and their 1,2,4-oxadiazole analogues: synthesis and pharmacological screening.

A novel series of pyrazoline amidoxime (2a-d) and pyrazoly-1,2,4-oxadiazole (3a-p) and (4) of pharmacological significance have been synthesised. Structures of newly synthesised compounds were characterized by spectral studies. New compounds were screened for their in vitro antioxidant, antimicrobial and antiinflammatory activities. Among the synthesized compounds, compound 2a, 3l and 3o were found to be active antimicrobial agents in addition to having potent antioxidant activity, while the compound 3f showed promising antiinflammatory activity in comparison with standard drug.

Syntheses and evaluation of macrocyclic engelhardione analogs as antitubercular and antibacterial agents.

The natural product engelhardione is an underexplored chemotype for developing novel treatments for bacterial infections; we therefore explored this natural product scaffold for chemical diversification and structure-activity relationship studies. Macrocyclic engelhardione and structural regioisomers were synthesized using a series of aldol condensations and selective hydrogenations to generate the 1,7-diarylheptan-3-one derivatives, followed by microwave-assisted intramolecular Ullmann coupling to afford a series of macrocyclic diaryl ether analogs. An extended macrocyclic chemical library was then produced by oxime formation, reductive amination and O-alkylation. Antibacterial evaluation revealed that the reductive amination derivatives 7b and 7d showed moderate activities (minimum inhibitory concentrations: 12.5-25 µg ml(-1)) against Mycobacterium tuberculosis and Gram-positive pathogens, as well as anti-Gram-negative activity against an efflux impaired Escherichia coli strain. These results provide validated leads for further optimization and development.

Syntheses and in vitro evaluations of uncharged reactivators for human acetylcholinesterase inhibited by organophosphorus nerve agents.

Organophosphorus nerve agents (OPNAs) are highly toxic compounds that represent a threat to both military and civilian populations. They cause an irreversible inhibition of acetylcholinesterase (AChE), by the formation of a covalent P-O bond with the catalytic serine. Among the present treatment of nerve agents poisoning, pyridinium and bis-pyridinium aldoximes are used to reactivate this inhibited enzyme but these compounds do not readily cross the blood brain barrier (BBB) due to their permanent cationic charge and thus cannot efficiently reactivate cholinesterases in the central nervous system (CNS). In this study, a series of seven new uncharged oximes reactivators have been synthesized and their in vitro ability to reactivate VX and tabun-inhibited human acetylcholinesterase (hAChE) has been evaluated. The dissociation constant K(D) of inhibited enzyme-oxime complex, the reactivity rate constant kr and the second order reactivation rate constant k(r2) have been determined and have been compared to reference oximes HI-6, Obidoxime and 2-Pralidoxime (2-PAM). Regarding the reactivation of VX-inhibited hAChE, all compounds show a better reactivation potency than those of 2-PAM, nevertheless they are less efficient than obidoxime and HI-6. Moreover, one of seven described compounds presents an ability to reactivate tabun-inhibited hAChE equivalent to those of 2-PAM.

Synthesis and screening of aromatase inhibitory activity of substituted C19 steroidal 17-oxime analogs.

The synthesis and aromatase inhibitory activity of androst-4-en-, androst-5-en-, 1ß,2ß-epoxy- and/or androsta-4,6-dien-, 4ß,5ß-epoxyandrostane-, and 4-substituted androst-4-en-17-oxime derivatives are described. Inhibition activity of synthesized compounds was assessed using aromatase enzyme and [1ß-3H]androstenedione as substrate. Most of the compounds displayed similar to or more aromatase inhibitory activity than formestane (74.2%). 4-Chloro-3ß-hydroxy-4-androsten-17-one oxime (14, 93.8%) showed the highest activity, while 4-azido-3ß-hydroxy-4-androsten-17-one oxime (17, 32.8%) showed the lowest inhibitory activity for aromatase.

The discovery of furo[2,3-c]pyridine-based indanone oximes as potent and selective B-Raf inhibitors.

Virtual and high-throughput screening identified imidazo[1,2-a]pyrazines as inhibitors of B-Raf. We describe the rationale, SAR, and evolution of the initial hits to a series of furo[2,3-c]pyridine indanone oximes as highly potent and selective inhibitors of B-Raf.

Synthesis and evaluation of novel bis-pyridinium oximes as reactivators of DFP-inhibited acetylcholinesterase.

A series of novel bis-pyridinium oximes connected by bis-methoxymethyl benzene, 1,4-bis-methoxymethyl (cis)-but-2-ene and 1,4-bis-methoxymethyl but-2-yne linkers were synthesized and their in vitro reactivation efficacy was evaluated against diisopropyl phosphorofluoridate (DFP) inhibited acetylcholinesterase (AChE) and compared with the established antidote 2-PAM and obidoxime. However, the best reactivation was observed with the standard oxime 2-PAM. The reactivation efficacy of 1,3-dimethoxymethyl benzene bis-[4,4'-(hydroxyiminomethyl) pyridinium] dichloride (3d) and 1,4-dimethoxy but-2-ene bis-[4,4'-(hydroxyiminomethyl) pyridinium] dichloride (3g) was comparable with that of obidoxime, another standard antidote.

New oxime reactivators connected with CH2O(CH2)nOCH2 linker and their reactivation potency for organophosphorus agents-inhibited acetylcholinesterase.

New bis-pyridinium oxime reactivators 6 with CH(2)O(CH(2))(2)OCH(2) and CH(2)O(CH(2))(4)OCH(2) linkers between the two pyridinium rings were designed and synthesized. In the in vitro test of their potency to reactivate AChE inhibited by organophosphorus agents at 5 x 10(-3)M concentration, the reactivation ability of 1,2-dimethoxy-ethylene-bis-N,N'-4-pyridiumaldoxime dichloride (6a) was 63% for housefly (HF) AChE inhibited by diisopropyl fluorophosphates (DFP), 51% for bovine red blood cell (RBC) AChE inhibited by DFP, 67% for HF-AChE inhibited by paraoxon, and 81% for RBC-AChE inhibited by paraoxon. Except in the case of DFP-inhibited HF AChE test of 2-PAM, the activities of 6a are much higher than the activities of 2-PAM and HI-6 which are AChE reactivators currently in use.

1-aryl-3-(4-pyridine-2-ylpiperazin-1-yl)propan-1-one oximes as potent dopamine D4 receptor agonists for the treatment of erectile dysfunction.

A new series of dopamine D4 receptor agonists, 1-aryl-3-(4-pyridinepiperazin-1-yl)propanone oximes, was designed through the modification of known dopamine D4 receptor agonist PD 168077. Replacement of the amide group with a methylene-oxime moiety produced compounds with improved stability and efficacy. Structure-activity relationsips (SAR) of the aromatic ring linked to the N-4-piperazine ring confirmed the superiority of 2-pyridine as a core for D4 agonist activity. A two-methylene linker between the oxime group and the N-1-piperazine ring displayed the best profile. New dopamine D4 receptor agonists, exemplified by (E)-1-(4-chlorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-methyloxime (59a) and (E)-1-(3-chloro-4-fluorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-methyloxime (64a), exhibited favorable pharmacokinetic profiles and showed oral bioavailability in rat and dog. Subsequent evaluation of 59a in the rat penile erection model revealed in vivo activity, comparable in efficacy to apomorphine. Our results suggest that the oximes provide a novel structural linker for 4-arylpiperazine-based D4 agonists, possessing leadlike quality and with potential to develop a new class of potent and selective dopamine D4 receptor agonists.

Synthesis of some oxime ether derivatives of 1-(2-naphthyl)-2-(1,2,4-triazol-1-yl)ethanone and their anticonvulsant and antimicrobial activities.

In this study, oxime and oxime ether derivatives of [1-(2-naphthyl)-2-(1,2,4-triazol-1-yl)ethanone] were prepared as potential anticonvulsant and antimicrobial compounds. The oxime was synthesized by the reaction of ketone and hydroxylamine hydrochloride. O-Alkylation of the oxime by various alkyl halides gave the oxime ether derivatives. Anticonvulsant activity of the compounds was determined by maximal electroshock and subcutaneous metrazole tests in mice and rats according to procedures of the Anticonvulsant Screening Program of National Institutes of Health. Neurotoxicity was determined by the rotorod test in mice and the positional sense test, gait and stance test in rats. In addition to anticonvulsant tests, all compounds were also evaluated against the following microorganisms: S. aureus, E. coli, P. aeruginosa, E. faecalis, C. albicans, C. parapsilosis, and C. krusei using microdilution broth method for possible antibacterial and antifungal activities. Although most of the O-alkyl substituted oxime ethers exhibited both anticonvulsant and antimicrobial activities, the O-arylalkyl substituted compounds were found to be inactive in both screening paradigms.

Piperazinyl oxime ethers as NK-1 receptor antagonists.

The synthesis and structure-activity relations for a new class of centrally active NK-1 receptor antagonists are described. The new compounds are based on piperazine 2 and contain an oxime ether functionality. Several new compounds have high affinity for the NK-1 receptor and show good antagonistic activity in the gerbil foot-tapping assay.

Synthesis and antiamoebic activity of new oxime ether derivatives containing 2-acetylpyridine/2-acetylfuran.

Various oxime ether derivatives of 2-acetylpyridine and 2-acetylfuran series have been synthesised. O-Alkylation of the oximes by various alkylaminoethyl halides gave the corresponding oxime ether derivatives. The structures of these compounds were elucidated by UV, IR, 1H NMR, 13C NMR spectroscopic methods and elemental analyses. All the compounds were screened in vitro against the HM1:IMSS strain of Entamoeba histolytica. Based on the 50% inhibitory concentration (IC50) data of the 12 compounds evaluated, two of the 2-acetylpyridine series and two in the 2-acetylfuran series showed better IC50 values in vitro when compared with the standard amoebicidal drug, metronidazole. Moreover, one compound showed the most promising antiamoebic activity (IC50=0.5 microM vs IC50=1.9 microM of metronidazole).

Synthesis and DNA binding properties of dioxime-peptide nucleic acids.

Peptide nucleic acids (PNAs) C- or N-modified with dioxime ligands were prepared by solid-phase synthesis using iron(II)-clathrochelates as protected dioxime building blocks. These PNA bind complementary DNA sequence specifically, though with much reduced affinity in comparison with nonmodified PNA. The dioxime-PNA conjugates bind Cu2+ and Ni2+ at microM concentration.

[Synthesis and antiviral activity of hydrazides and substituted benzalhydrazides of betulinic acid and its derivatives]. / Sintez i protivovirusnaia aktivnost' gidrazidov i zameshchennykh benzal'gidrazidov betulinovoi kisloty i ee proizvodnykh.

New nitrogen-containing derivatives of betulinic and betulonic acids, hydrazides and N'-benzalhydrazides, were synthesized. Their antiviral activities toward of influenza A virus, herpes simplex type I virus, enterovirus ECHO6, and HIV-1 were studied in vitro. Betulinic acid 3-oxime was found to have the highest activity against the influenza virus. Betulonic acid, betulinic acid 4-chlorobenzalhydrazide, betulonic acid 3-oxime benzalhydrazide, and betulinic acid hydrazide inhibited the replication of herpes simplex type I virus. Betulinic acid hydrazide also showed antiviral activity toward HIV-1. All the derivatives of betulinic acid under study displayed a low antiviral activity toward enterovirus ECHO6.