MDPI - Publisher of Open Access Journals

26 pages, 36015 KiB

Open AccessReview

FDA-Approved Oximes and Their Significance in Medicinal Chemistry

by Jyothi Dhuguru, Eugene Zviagin and Rachid Skouta

Pharmaceuticals 2022, 15(1), 66; https://doi.org/10.3390/ph15010066 - 4 Jan 2022

Cited by 39 | Viewed by 10206

Despite the scientific advancements, organophosphate (OP) poisoning continues to be a major threat to humans, accounting for nearly one million poisoning cases every year leading to at least 20,000 deaths worldwide. Oximes represent the most important class in medicinal chemistry, renowned for their widespread applications as OP antidotes, drugs and intermediates for the synthesis of several pharmacological derivatives. Common oxime based reactivators or nerve antidotes include pralidoxime, obidoxime, HI-6, trimedoxime and methoxime, among which pralidoxime is the only FDA-approved drug. Cephalosporins are β-lactam based antibiotics and serve as widely acclaimed tools in fighting bacterial infections. Oxime based cephalosporins have emerged as an important class of drugs with improved efficacy and a broad spectrum of anti-microbial activity against Gram-positive and Gram-negative pathogens. Among the several oxime based derivatives, cefuroxime, ceftizoxime, cefpodoxime and cefmenoxime are the FDA approved oxime-based antibiotics. Given the pharmacological significance of oximes, in the present paper, we put together all the FDA-approved oximes and discuss their mechanism of action, pharmacokinetics and synthesis. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

► Show Figures

Figure 1

---

Figure 3

---

Figure 4

---

Figure 5

---

Figure 6

---

Figure 7

---

Figure 8

---

Figure 9

---

Figure 10

---

Figure 11

---

Figure 12

---

Scheme 1

---

Scheme 2

---

Scheme 3

---

Scheme 4

---

Scheme 5

---

Scheme 6

13 pages, 1989 KiB

Open AccessArticle

Understanding the Interaction Modes and Reactivity of Trimedoxime toward MmAChE Inhibited by Nerve Agents: Theoretical and Experimental Aspects

by Alexandre A. de Castro, Daniel A. Polisel, Bruna T. L. Pereira, Elaine F. F. da Cunha, Kamil Kuca, Eugenie Nepovimova and Teodorico C. Ramalho

Int. J. Mol. Sci. 2020, 21(18), 6510; https://doi.org/10.3390/ijms21186510 - 5 Sep 2020

Cited by 2 | Viewed by 2029

Abstract

Organophosphorus (OP) compounds are used as both chemical weapons and pesticides. However, these agents are very dangerous and toxic to humans, animals, and the environment. Thus, investigations with reactivators have been deeply developed in order to design new antidotes with better efficiency, as well as a greater spectrum of action in the acetylcholinesterase (AChE) reactivation process. With that in mind, in this work, we investigated the behavior of trimedoxime toward the Mus musculus acetylcholinesterase (MmAChE) inhibited by a range of nerve agents, such as chemical weapons. From experimental assays, reactivation percentages were obtained for the reactivation of different AChE–OP complexes. On the other hand, theoretical calculations were performed to assess the differences in interaction modes and the reactivity of trimedoxime within the AChE active site. Comparing theoretical and experimental data, it is possible to notice that the oxime, in most cases, showed better reactivation percentages at higher concentrations, with the best result for the reactivation of the AChE–VX adduct. From this work, it was revealed that the mechanistic process contributes most to the oxime efficiency than the interaction in the site. In this way, this study is important to better understand the reactivation process through trimedoxime, contributing to the proposal of novel antidotes. Full article

(This article belongs to the Collection Computational Studies of Biomolecules)

► Show Figures

Figure 1

---

Figure 3

---

Figure 4

16 pages, 2336 KiB

Open AccessArticle

Novel Group of AChE Reactivators—Synthesis, In Vitro Reactivation and Molecular Docking Study

by David Malinak, Eugenie Nepovimova, Daniel Jun, Kamil Musilek and Kamil Kuca

Molecules 2018, 23(9), 2291; https://doi.org/10.3390/molecules23092291 - 7 Sep 2018

Cited by 14 | Viewed by 3551

Abstract

The acetylcholinesterase (AChE) reactivators (e.g., obidoxime, asoxime) became an essential part of organophosphorus (OP) poisoning treatment, together with atropine and diazepam. They are referred to as a causal treatment of OP poisoning, because they are able to split the OP moiety from AChE active site and thus renew its function. In this approach, fifteen novel AChE reactivators were determined. Their molecular design originated from former K-oxime compounds K048 and K074 with remaining oxime part of the molecule and modified part with heteroarenium moiety. The novel compounds were prepared, evaluated in vitro on human AChE (HssAChE) inhibited by tabun, paraoxon, methylparaoxon or DFP and compared to commercial HssAChE reactivators (pralidoxime, methoxime, trimedoxime, obidoxime, asoxime) or previously prepared compounds (K048, K074, K075, K203). Some of presented oxime reactivators showed promising ability to reactivate HssAChE comparable or higher than the used standards. The molecular modelling study was performed with one compound that presented the ability to reactivate GA-inhibited HssAChE. The SAR features concerning the heteroarenium part of the reactivator’s molecule are described. Full article

(This article belongs to the Special Issue QSAR and QSPR: Recent Developments and Applications)

► Show Figures

Figure 1

---

Figure 3

---

Figure 4

---

Figure 5

---

Figure 6

---

Scheme 1

381 KiB

Open AccessArticle

The Evaluation of the Reactivating and Neuroprotective Efficacy of Two Newly Prepared Bispyridinium Oximes (K305, K307) in Tabun-Poisoned Rats—A Comparison with Trimedoxime and the Oxime K203

by Jiri Kassa, Jan Misik, Jana Hatlapatkova, Jana Zdarova Karasova, Vendula Sepsova, Filip Caisberger and Jaroslav Pejchal

Molecules 2017, 22(7), 1152; https://doi.org/10.3390/molecules22071152 - 11 Jul 2017

Cited by 8 | Viewed by 3374

Abstract

The ability of two newly developed oximes (K305, K307) to protect tabun-poisoned rats from tabun-induced inhibition of brain acetylcholinesterase, acute neurotoxic signs and symptoms and brain damage was compared with that of the oxime K203 and trimedoxime. The reactivating and neuroprotective effects of the oximes studied combined with atropine on rats poisoned with tabun at a sublethal dose were evaluated. The reactivating efficacy of a newly developed oxime K305 is lower compared to the reactivating efficacy of the oxime K203 and trimedoxime while the ability of the oxime K307 to reactivate tabun-inhibited acetylcholinesterase (AChE) in the brain roughly corresponds to the reactivating efficacy of the oxime K203 and it is slightly lower compared to trimedoxime. In addition, only one newly developed oxime (K307) combined with atropine was able to markedly decrease tabun-induced neurotoxicity although it did not eliminate all tabun-induced acute neurotoxic signs and symptoms. These results correspond to the histopathological evaluation of tabun-induced brain damage. Therefore, the newly developed oximes are not suitable for the replacement of commonly used oximes (especially trimedoxime) in the treatment of acute tabun poisonings. Full article

(This article belongs to the Special Issue The Cholinesterases—Structure, Mechanism, Function and Drug Design: The 25th Anniversary of the Solution of the Crystal Structure of Acetylcholinesterase by Joel L. Sussman and Israel Silman)

► Show Figures

Graphical abstract

297 KiB

Open AccessArticle

Acetylcholinesterase Reactivators (HI-6, Obidoxime, Trimedoxime, K027, K075, K127, K203, K282): Structural Evaluation of Human Serum Albumin Binding and Absorption Kinetics

by Filip Zemek, Jana Karasova Zdarova, Vendula Sepsova and Kamil Kuca

Int. J. Mol. Sci. 2013, 14(8), 16076-16086; https://doi.org/10.3390/ijms140816076 - 2 Aug 2013

Cited by 14 | Viewed by 6995

Abstract

Acetylcholinesterase (AChE) reactivators (oximes) are compounds predominantly targeting the active site of the enzyme. Toxic effects of organophosphates nerve agents (OPNAs) are primarily related to their covalent binding to AChE and butyrylcholinesterase (BChE), critical detoxification enzymes in the blood and in the central nervous system (CNS). After exposure to OPNAs, accumulation of acetylcholine (ACh) overstimulates receptors and blocks neuromuscular junction transmission resulting in CNS toxicity. Current efforts at treatments for OPNA exposure are focused on non-quaternary reactivators, monoisonitrosoacetone oximes (MINA), and diacylmonoxime reactivators (DAM). However, so far only quaternary oximes have been approved for use in cases of OPNA intoxication. Five acetylcholinesterase reactivator candidates (K027, K075, K127, K203, K282) are presented here, together with pharmacokinetic data (plasma concentration, human serum albumin binding potency). Pharmacokinetic curves based on intramuscular application of the tested compounds are given, with binding information and an evaluation of structural relationships. Human Serum Albumin (HSA) binding studies have not yet been performed on any acetylcholinesterase reactivators, and correlations between structure, concentration curves and binding are vital for further development. HSA bindings of the tested compounds were 1% (HI-6), 7% (obidoxime), 6% (trimedoxime), and 5%, 10%, 4%, 15%, and 12% for K027, K075, K127, K203, and K282, respectively. Full article

(This article belongs to the Section Biochemistry)

► Show Figures

---

185 KiB

Open AccessArticle

In Vitro Ability of Currently Available Oximes to Reactivate Organophosphate Pesticide-Inhibited Human Acetylcholinesterase and Butyrylcholinesterase

by Daniel Jun, Lucie Musilova, Kamil Musilek and Kamil Kuca

Int. J. Mol. Sci. 2011, 12(3), 2077-2087; https://doi.org/10.3390/ijms12032077 - 23 Mar 2011

Cited by 24 | Viewed by 8461

Abstract

We have in vitro tested the ability of common, commercially available, cholinesterase reactivators (pralidoxime, obidoxime, methoxime, trimedoxime and HI-6) to reactivate human acetylcholinesterase (AChE), inhibited by five structurally different organophosphate pesticides and inhibitors (paraoxon, dichlorvos, DFP, leptophos-oxon and methamidophos). We also tested reactivation of human butyrylcholinesterase (BChE) with the aim of finding a potent oxime, suitable to serve as a “pseudocatalytic” bioscavenger in combination with this enzyme. Such a combination could allow an increase of prophylactic and therapeutic efficacy of the administered enzyme. According to our results, the best broad-spectrum AChE reactivators were trimedoxime and obidoxime in the case of paraoxon, leptophos-oxon, and methamidophos-inhibited AChE. Methamidophos and leptophos-oxon were quite easily reactivatable by all tested reactivators. In the case of methamidophos-inhibited AChE, the lower oxime concentration (10⁻⁵ M) had higher reactivation ability than the 10⁻⁴ M concentration. Therefore, we evaluated the reactivation ability of obidoxime in a concentration range of 10⁻³–10⁻⁷ M. The reactivation of methamidophos-inhibited AChE with different obidoxime concentrations resulted in a bell shaped curve with maximum reactivation at 10⁻⁵M. In the case of BChE, no reactivator exceeded 15% reactivation ability and therefore none of the oximes can be recommended as a candidate for “pseudocatalytic” bioscavengers with BChE. Full article

(This article belongs to the Section Molecular Toxicology)

► Show Figures

Graphical abstract

---

105 KiB

Open AccessArticle

Reactivation of Human Acetylcholinesterase and Butyrylcholinesterase Inhibited by Leptophos-Oxon with Different Oxime Reactivators in Vitro

by Daniel Jun, Lucie Musilova, Miroslav Pohanka, Young-Sik Jung, Pavel Bostik and Kamil Kuca

Int. J. Mol. Sci. 2010, 11(8), 2856-2863; https://doi.org/10.3390/ijms11082856 - 3 Aug 2010

Cited by 15 | Viewed by 9688

Abstract

We have evaluated in vitro the potency of 23 oximes to reactivate human erythrocyte acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BChE) inhibited by racemic leptophos-oxon (O-[4-bromo-2,5-dichlorophenyl]-O-methyl phenyl-phosphonate), a toxic metabolite of the pesticide leptophos. Compounds were assayed in concentrations of 10 and 100 µM. In case of leptophos-oxon inhibited AChE, the best reactivation potency was achieved with methoxime, trimedoxime, obidoxime and oxime K027. The most potent reactivators of inhibited BChE were K033, obidoxime, K117, bis-3-PA, K075, K074 and K127. The reactivation efficacy of tested oximes was lower in case of leptophos-oxon inhibited BChE. Full article

(This article belongs to the Section Biochemistry)

► Show Figures

199 KiB

Open AccessArticle

Effect of Seven Newly Synthesized and Currently Available Oxime Cholinesterase Reactivators on Cyclosarin-Intoxicated Rats

by Jana Zdarova Karasova, Jiri Kassa, Kamil Musilek, Miroslav Pohanka, Ladislav Novotny and Kamil Kuca

Int. J. Mol. Sci. 2009, 10(7), 3065-3075; https://doi.org/10.3390/ijms10073065 - 7 Jul 2009

Cited by 13 | Viewed by 9807

Abstract

Seven new oxime-based acetylcholinesterase reactivators were compared with three currently available ones (obidoxime, trimedoxime, HI-6) for their ability to lessen cholinesterase inhibition in blood and brain of cyclosarin-treated rats. Oximes were given at doses of 5% their LD₅₀ along with 21 mg/kg atropine five min before the LD₅₀ of cyclosarin (120 ug/kg) was administered. Blood and brain samples were collected 30 minutes later. The greatest difference between acetylcholinesterase inhibition in blood of cyclosarin-treated rats was found after administration of HI-6 (40%), compared to 22% for trimedoxime and 6% for obidoxime. Only two of the seven newly synthesized oximes had any effect (K203 at 7%, K156 at 5%). Effective oximes against cyclosarin-inhibited plasma butyrylcholinesterase were HI-6 (42%), trimedoxime (11%), and K156 (4%). The oximes were less effective in brain than in blood, with reactivation values for HI-6 30% against acetylcholinesterase and 10% against butyrylcholinesterase. Values for newly synthesized oximes were less than 10% for K206, K269 and K203. Full article

(This article belongs to the Section Biochemistry)

► Show Figures

---

65 KiB

Open AccessArticle

Effect of Several New and Currently Available Oxime Cholinesterase Reactivators on Tabun-intoxicated Rats

by Jana Zdarova Karasova, Jiri Kassa, Young-Sik Jung, Kamil Musilek, Miroslav Pohanka and Kamil Kuca

Int. J. Mol. Sci. 2008, 9(11), 2243-2252; https://doi.org/10.3390/ijms9112243 - 14 Nov 2008

Cited by 17 | Viewed by 10425

Abstract

The therapeutical efficacies of eleven oxime-based acetylcholinesterase reactivators were compared in an in vivo (rat model) study of treatment of intoxication caused by tabun. In this group there were some currently available oximes (obidoxime, trimedoxime and HI-6) and the rest were newly synthesized compounds. The best reactivation efficacy for acetylcholinesterase in blood (expressed as percent of reactivation) among the currently available oximes was observed after administration of trimedoxime (16%) and of the newly synthesized K127 (22432) (25%). The reactivation of butyrylcholinesterase in plasma was also studied; the best reactivators were trimedoxime, K117 (22435), and K127 (22432), with overall reactivation efficacies of approximately 30%. Partial protection of brain ChE against tabun inhibition was observed after administration of trimedoxime (acetylcholinesterase 20%; butyrylcholinesterase 30%) and obidoxime (acetylcholinesterase 12%; butyrylcholinesterase 16%). Full article

(This article belongs to the Section Biochemistry)

► Show Figures

---

64 KiB

Open AccessCommunication

Targeted Synthesis of 1-(4-Hydroxyiminomethylpyridinium)-3-pyridiniumpropane Dibromide – A New Nerve Agent Reactivator

by Kamil Kuca, Kamil Musilek, Martin Paar, Daniel Jun, Petr Stodulka, Martina Hrabinova and Jan Marek

Molecules 2007, 12(8), 1964-1972; https://doi.org/10.3390/12081964 - 20 Aug 2007

Cited by 16 | Viewed by 9422

Abstract

Preparation of 1-(4-hydroxy-iminomethylpyridinium)-3-pyridiniumpropane dibromide is described. This compound represents a new acetylcholinesterase (AChE) reactivator, which has no substituents on the second pyridinium ring as found in other commonly used AChE reactivators. The reactivation ability of this reactivator was tested on tabun- and cyclosarin-inhibited AChE. According to the results obtained, the new compound (without substitution and with decreased molecule size) showed increased reactivation potency in case of cyclosarin inhibited AChE. A potent oxime for treatment of tabun and cyclosarin-caused intoxications was thus obtained via slight modification of the reactivator structure (compared to trimedoxime and K027). Full article

► Show Figures

Figure 1

---

Figure 3

---

Figure 4

---

Figure 5

Search Results (10)

Further Information

Guidelines

MDPI Initiatives

Follow MDPI

Saved Queries

Search Filter Reset All

Years

Feature Papers

Subjects

Journals

Article Types

Countries / Regions

Search Results (10)

Further Information

Guidelines

MDPI Initiatives

Follow MDPI