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Chemistry & Biodiversity Jul 2021In search of novel natural product-based bioactive molecules, twenty (ten pairs) novel (Z)-/(E)-anisaldehyde-based oxime ester compounds were designed and synthesized by...
In search of novel natural product-based bioactive molecules, twenty (ten pairs) novel (Z)-/(E)-anisaldehyde-based oxime ester compounds were designed and synthesized by using anisaldehyde as starting material. Structural characterization of the target compounds was carried out by NMR, FT-IR, ESI-MS, and elemental analysis. Their herbicidal and antifungal activities were preliminarily tested. As a result, at 50 μg/mL, compound (E)-5b exhibited excellent to good inhibition rates of 92.3 %, 79.2 %, and 73.9 %, against Rhizoctonia solani, Fusarium oxysporum f. sp. cucumerinum, and Bipolaris maydis, respectively, better than or comparable to that of the positive control chlorothalonil. In addition, at 100 μg/mL, compounds (E)-5b, (E)-5f, (Z)-5f and (E)-5d exhibited excellent to good inhibition rates of 85.8 %, 82.9 %, 78.6 % and 64.2 %, respectively, against the root-growth of rape (B. campestris), much better than that of the positive control flumioxazin. The bioassay result also showed that the synthesized compounds had obvious differences in antifungal and herbicidal activities between (Z)- and (E)-isomers. Preliminary structure-activity relationship was also discussed by theoretical calculation.
Topics: Antifungal Agents; Benzaldehydes; Bipolaris; Esters; Fusarium; Herbicides; Microbial Sensitivity Tests; Molecular Structure; Oximes; Rhizoctonia; Structure-Activity Relationship
PubMed: 34047003
DOI: 10.1002/cbdv.202100235 -
Bioorganic & Medicinal Chemistry Letters Apr 2015Indirubin is a potent inhibitor of cell cycle-related protein kinases by binding to the ATP-binding site and thus is a promising compound for development as an antitumor...
Indirubin is a potent inhibitor of cell cycle-related protein kinases by binding to the ATP-binding site and thus is a promising compound for development as an antitumor drug. We prepared indirubin 3'-(O-oxiran-2-ylmethyl)oxime (Epox/Ind), in which the ATP-binding site orientated part was attached by non-specific alkylating group. The IC50 value of Epox/Ind at 1.7 μM in HepG2 cells is comparable to that of cisplatin (4.0 μM). Furthermore, Epox/Ind was shown to be metabolized by a HepG2 cell lysate into indirubin 3'-(O-2,3-dihydroxypropyl)oxime (E804), the sole extractable metabolite. The lower toxicity of this metabolite may explain the lack of cytotoxicity of 1 μM Epox/Ind observed in HepG2 cells beyond an initial loss of viability in the first 24h of treatment.
Topics: Antineoplastic Agents; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Hep G2 Cells; Humans; Indoles; Molecular Structure; Oximes; Structure-Activity Relationship
PubMed: 25765906
DOI: 10.1016/j.bmcl.2015.02.053 -
Bioorganic & Medicinal Chemistry Jun 2019Herpes simplex virus (HSV) infection has been recognized as the most common mucosal disease in humans, manifesting as a life-threatening infection especially for...
Herpes simplex virus (HSV) infection has been recognized as the most common mucosal disease in humans, manifesting as a life-threatening infection especially for patients with compromised immunity. When combined with the emergence of resistance due to the long-term use of classical antiviral agents, these threats make novel therapeutics for HSV a clinically necessity. We therefore designed and synthesized a series of Janus-type nucleosides by combining the natural genetic alphabets into a singular nucleoside structural unit. We also synthesized a series of new compounds and systematically evaluated their antiviral activity and structure-antiviral activity relationship. The results indicated that both nucleosides and their related intermediates exhibited high anti-HSV-1 activity. Compounds HY17 and HY19, in particular, possessed excellent anti-HSV-1 activity with IC values of 0.05 and 0.04 µg/mL, respectively. They also showed broad-spectrum antiviral activity against a multitude of diverse viruses, such as HSV-2, influenza virus A (H3N2), CVB3, HBV, HCV, and HPV. These results suggest that once their mechanisms are fully elucidated, these compounds will prove to be promising candidates as antiviral agents.
Topics: Animals; Antiviral Agents; Chlorocebus aethiops; Herpesvirus 1, Human; Microbial Sensitivity Tests; Molecular Structure; Nucleotides; Oximes; Structure-Activity Relationship; Vero Cells
PubMed: 30578076
DOI: 10.1016/j.bmc.2018.12.014 -
Expert Opinion on Drug Metabolism &... Jul 2016The absorption, distribution, metabolism, excretion and toxicity (ADME(T)) of oxime reactivators have been assessed with respect to their polarity, a fundamental... (Review)
Review
INTRODUCTION
The absorption, distribution, metabolism, excretion and toxicity (ADME(T)) of oxime reactivators have been assessed with respect to their polarity, a fundamental requirement for their specific mechanism of action in the intoxication with organophosphorous compounds. The limitations of the therapeutic outcome have been associated not only with the severity of intoxication and to particularities of the toxicants, but also to the reduced lipophilicity and consequent restricted permeability across biological barriers.
AREAS COVERED
This article inventories the plethora of mnemotic rules developed throughout the years for defining chemical spaces where drugs share one or more structural and ADME(T) characteristics. Their applicability to oxime is analyzed, especially in relation to intestinal absorption and brain distribution. Other aspects of oximes for antidotal outcome are also reviewed.
EXPERT OPINION
The drugability rules are not applicable to oxime reactivators, because the increase in lipophicity and consequent improved permeability across biological barrier comes together with amplified (neuro)toxicity and reduced reactivating capacity. The available data suggest a high solubility and reduced metabolism, assigning the quaternary oximes to the fourth class of Biopharmaceutical Classification Systems. Reliance upon oral absorption data for designing safe centrally acting oximes can be of potential value, with adequate characterization of uptake-influx transporters interplay.
Topics: Animals; Antidotes; Brain; Cholinesterase Reactivators; Drug Design; Humans; Organophosphate Poisoning; Oximes; Permeability; Solubility; Tissue Distribution
PubMed: 27144662
DOI: 10.1080/17425255.2016.1179282 -
The Journal of Organic Chemistry Jun 2023A 2'-deoxycytidin-4-yl radical (dC·), a strong oxidant that also abstracts hydrogen atoms from carbon-hydrogen bonds, is produced in a variety of DNA damaging...
A 2'-deoxycytidin-4-yl radical (dC·), a strong oxidant that also abstracts hydrogen atoms from carbon-hydrogen bonds, is produced in a variety of DNA damaging processes. We describe here the independent generation of dC· from oxime esters under UV-irradiation or single electron transfer conditions. Support for this σ-type iminyl radical generation is provided by product studies carried out under aerobic and anaerobic conditions, as well as electron spin resonance (ESR) characterization of dC· in a homogeneous glassy solution at low temperature. Density functional theory (DFT) calculations also support fragmentation of the corresponding radical anions of oxime esters and to dC· and subsequent hydrogen atom abstraction from organic solvents. The corresponding 2'-deoxynucleotide triphosphate (dNTP) of isopropyl oxime ester () is incorporated opposite 2'-deoxyadenosine and 2'-deoxyguanosine by a DNA polymerase with approximately equal efficiency. Photolysis experiments of DNA containing support dC· generation and indicate that the radical produces tandem lesions when flanked on the 5'-side by 5'-d(GGT). These experiments suggest that oxime esters are reliable sources of nitrogen radicals in nucleic acids that will be useful mechanistic tools and possibly radiosensitizing agents when incorporated in DNA.
Topics: Free Radicals; Oximes; Esters; Electrons; DNA; Hydrogen
PubMed: 37220149
DOI: 10.1021/acs.joc.3c00646 -
Journal of the American Chemical Society Sep 2017Covalent cross-links are crucial for the folding and stability of triple-helical collagen, the most abundant protein in nature. Cross-linking is also an attractive...
Covalent cross-links are crucial for the folding and stability of triple-helical collagen, the most abundant protein in nature. Cross-linking is also an attractive strategy for the development of synthetic collagen-based biocompatible materials. Nature uses interchain disulfide bridges to stabilize collagen trimers. However, their implementation into synthetic collagen is difficult and requires the replacement of the canonical amino acids (4R)-hydroxyproline and proline by cysteine or homocysteine, which reduces the preorganization and thereby stability of collagen triple helices. We therefore explored alternative covalent cross-links that allow for connecting triple-helical collagen via proline residues. Here, we present collagen model peptides that are cross-linked by oxime bonds between 4-aminooxyproline (Aop) and 4-oxoacetamidoproline placed in coplanar Xaa and Yaa positions of neighboring strands. The covalently connected strands folded into hyperstable collagen triple helices (T ≈ 80 °C). The design of the cross-links was guided by an analysis of the conformational properties of Aop, studies on the stability and functionalization of Aop-containing collagen triple helices, and molecular dynamics simulations. The studies also show that the aminooxy group exerts a stereoelectronic effect comparable to fluorine and introduce oxime ligation as a tool for the functionalization of synthetic collagen.
Topics: Collagen; Oximes; Protein Stability
PubMed: 28872857
DOI: 10.1021/jacs.7b07498 -
Bioorganic & Medicinal Chemistry Apr 2019Generation and screening of oxime libraries by competitive MS Binding Assays represents a powerful tool for the identification of new compounds, with affinity to mGAT1,...
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 pK 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 (pK = 8.55 ± 0.04) was found.
Topics: Binding Sites; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Enzyme Inhibitors; HEK293 Cells; Humans; Mass Spectrometry; Molecular Structure; N-Acetylglucosaminyltransferases; Oximes; Small Molecule Libraries; Structure-Activity Relationship
PubMed: 30777661
DOI: 10.1016/j.bmc.2019.02.015 -
Bioorganic & Medicinal Chemistry Letters Nov 2023This study aimed to explore non-pyridinium oxime acetylcholinesterase (AChE) reactivators that could hold the potential to overcome the limitations of the currently...
This study aimed to explore non-pyridinium oxime acetylcholinesterase (AChE) reactivators that could hold the potential to overcome the limitations of the currently available compounds used in the clinic to treat the neurologic manifestations induced by intoxication with organophosphorus agents. Fifteen compounds with various non-pyridinium oxime moieties were evaluated for AChE activity at different concentrations, including aldoximes, ketoximes, and α-ketoaldoximes. The therapeutic potential of the oxime compounds was evaluated by assessing their ability to reactivate AChE inhibited by paraoxon. Among the tested compounds, α-Ketoaldoxime derivative 13 showed the highest reactivation (%) reaching 67 % and 60 % AChE reactivation when evaluated against OP-inhibited electric eel AChE at concentrations of 1,000 and 100 μM, respectively. Compound 13 showed a comparable reactivation ability of AChE (60 %) compared to that of pralidoxime (56 %) at concentrations of 100 μM. Molecular docking simulation of the most active compounds 12 and 13 was conducted to predict the binding mode of the reactivation of electric eel AChE. As a result, a non-pyridinium oxime moiety 13, is a potential reactivator of OP-inhibited AChE and is taken as a lead compound for the development of novel AChE reactivators with enhanced capacity to freely cross the blood-brain barrier.
Topics: Oximes; Paraoxon; Acetylcholinesterase; Cholinesterase Reactivators; Cholinesterase Inhibitors; Molecular Docking Simulation; Pyridinium Compounds; Acetamides; Organophosphorus Compounds
PubMed: 37838342
DOI: 10.1016/j.bmcl.2023.129504 -
Toxicology and Applied Pharmacology Mar 2007The availability of highly toxic organophosphorus (OP) warfare agents (nerve agents) underlines the necessity for an effective medical treatment. Acute OP toxicity is... (Review)
Review
The availability of highly toxic organophosphorus (OP) warfare agents (nerve agents) underlines the necessity for an effective medical treatment. Acute OP toxicity is primarily caused by inhibition of acetylcholinesterase (AChE). Reactivators (oximes) of inhibited AChE are a mainstay of treatment, however, the commercially available compounds, obidoxime and pralidoxime, are considered to be rather ineffective against various nerve agents, e.g. soman and cyclosarin. This led to the synthesis and investigation of numerous oximes in the past decades. Reactivation of OP-inhibited AChE is considered to be the most important reaction of oximes. Clinical data from studies with pesticide-poisoned patients support the assumption that the various reactions between AChE, OP and oxime, i.e. inhibition, reactivation and aging, can be investigated in vitro with human AChE. In contrast to animal experiments such in vitro studies with human tissue enable the evaluation of oxime efficacy without being affected by species differences. In the past few years numerous in vitro studies were performed by different groups with a large number of oximes and methods were developed for extrapolating in vitro data to different scenarios of human nerve agent poisoning. The present status in the evaluation of new oximes as antidotes against nerve agent poisoning will be discussed.
Topics: Animals; Chemical Warfare Agents; Cholinesterase Inhibitors; Cholinesterase Reactivators; Humans; In Vitro Techniques; Molecular Structure; Organophosphate Poisoning; Organophosphorus Compounds; Oximes; Poisoning; Species Specificity
PubMed: 17112559
DOI: 10.1016/j.taap.2006.10.001 -
Bioorganic & Medicinal Chemistry Letters Mar 2002Oxime derivatives of the sordarin aglycone have been identified as potent antifungal agents. The in vitro spectrum of activity includes coverage against Candida albicans...
Oxime derivatives of the sordarin aglycone have been identified as potent antifungal agents. The in vitro spectrum of activity includes coverage against Candida albicans and Candida glabrata with MICs as low as 0.06 microg/mL. The antifungal activity was established to be exquisitely sensitive to the spatial orientation of the lipophilic side chains.
Topics: Antifungal Agents; Candida; Diterpenes; Hydrophobic and Hydrophilic Interactions; Microbial Sensitivity Tests; Oximes; Structure-Activity Relationship
PubMed: 11958999
DOI: 10.1016/s0960-894x(02)00054-9