Novel pyridinium oximes: synthesis, molecular docking and in vitro reactivation studies

Pooja, Pooja; Aggarwal, Swati; Tiwari, Anjani K.; Kumar, Vikas; Pratap, Ramendra; Singh, Gurmeet; Mishra, Anil K.

doi:10.1039/c4ra14696d

Cited by 4 publications

(3 citation statements)

References 29 publications

(35 reference statements)

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“…The analytical data corresponded to the literature. [47][48][49][50] (E)-N-(Phenylmethylidene)hydroxylamine ( 23…”

Section: General Procedures For the Synthesis Of Oximes 23-27mentioning

confidence: 99%

Spirooxadiazoline‐oxindoles derived from imatinib show antimyeloproliferative potential in K562 cells

de Azevedo,

Leite,

de Oliveira

et al. 2024

Archiv der Pharmazie

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Imatinib mesylate was the first representative BCR‐ABL1 tyrosine kinase inhibitor (TKI) class for the treatment of chronic myeloid leukemia. Despite the revolution promoted by TKIs in the treatment of this pathology, a resistance mechanism occurs against all BCR‐ABL1 inhibitors, necessitating a constant search for new therapeutic options. To develop new antimyeloproliferative substances, we applied a medicinal chemistry tool known as molecular hybridization to design 25 new substances. These compounds were synthesized and biologically evaluated against K562 cells, which express BCR‐ABL1, a constitutively active tyrosine kinase enzyme, as well as in WSS‐1 cells (healthy cells). The new compounds are conjugated hybrids that contain phenylamino‐pyrimidine‐pyridine (PAPP) and an isatin backbone, which are the main pharmacophoric fragments of imatinib and sunitinib, respectively. A spiro‐oxindole nucleus was used as a linker because it occurs in many compounds with antimyeloproliferative activity. Compounds 2a, 2b, 3c, 4c, and 4e showed promise, as they inhibited cell viability by between 45% and 61% at a concentration of 10 µM. The CC50 of the most active substances was determined to be within 0.8–9.8 µM.

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“…The analytical data corresponded to the literature. [47][48][49][50] (E)-N-(Phenylmethylidene)hydroxylamine ( 23…”

Section: General Procedures For the Synthesis Of Oximes 23-27mentioning

confidence: 99%

Spirooxadiazoline‐oxindoles derived from imatinib show antimyeloproliferative potential in K562 cells

de Azevedo,

Leite,

de Oliveira

et al. 2024

Archiv der Pharmazie

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show abstract

“…In addition, so-called direct pharmacological effects such as direct reaction with organophosphorus nerve poisons, anticholinergic effect and properties that decrease the amount of liberated AcCh + into synaptic cleft are also known [1]. The in vitro AcChE binding and reactivation capability of novel lipophilic pyridinium oxime derivatives and their structural analogues are still extensively studied in a search for universal antidote capable to cross the blood-brain barrier [12,13]. However, these pharmacological compounds possess multiple modes of action and alternative bioactivities are an active research topic.…”

Section: Introductionmentioning

confidence: 99%

Novel Insights into the Thioesterolytic Activity of N-Substituted Pyridinium-4-oximes

et al. 2020

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The pyridinium oximes are known esterolytic agents, usually classified in the literature as catalysts, which mimic the catalytic mode of hydrolases. Herein, we combined kinetic and computational studies of the pyridinium-4-oxime-mediated acetylthiocholine (AcSCh+) hydrolysis to provide novel insights into their potential catalytic activity. The N-methyl- and N-benzylpyridinium-4-oximes have been tested as oximolytic agents toward the AcSCh+, while the newly synthesized O-acetyl-N-methylpyridinium-4-oxime iodide was employed for studying the consecutive hydrolytic reaction. The relevance of the AcSCh+ hydrolysis as a competitive reaction to AcSCh+ oximolysis was also investigated. The reactions were independently studied spectrophotometrically and rate constants, koxime, kw and kOH, were evaluated over a convenient pH-range at I = 0.1 M and 25 °C. The catalytic action of pyridinium-4-oximes comprises two successive stages, acetylation (oximolysis) and deacetylation stage (pyridinium-4-oxime-ester hydrolysis), the latter being crucial for understanding the whole catalytic cycle. The complete mechanism is presented by the free energy reaction profiles obtained with (CPCM)/M06–2X/6–311++G(2df,2pd)//(CPCM)/M06–2X/6–31+G(d) computational model. The comparison of the observed rates of AcSCh+ oximolytic cleavage and both competitive AcSCh+ and consecutive pyridinium-4-oxime-ester hydrolytic cleavage revealed that the pyridinium-4-oximes cannot be classified as non-enzyme catalyst of the AcSCh+ hydrolysis but as the very effective esterolytic agents.

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“…With respect to 2-pralidoxime (2-PAM) efficacy, the majority of previously conducted synthetic studies have focused either on developing bis-pyridinium oximes (via alteration of the N -alkyl group) or on modifying the electrostatic character of the core pyridinium. − However, these modifications appear to have been driven by synthetic accessibility rather than establishing systematic and rational structure–activity relationships (SAR) and, therefore, fail to clearly delineate optimal substitution patterns for AChE active site complementarity. To our knowledge, no studies to date have systematically explored SAR for alkyl group substitution on the pyridinium ring of 2-PAM, i.e ., with the position of the alkyl group being the only variable.…”

mentioning

confidence: 99%

Methyl Scanning and Revised Binding Mode of 2-Pralidoxime, an Antidote for Nerve Agent Poisoning

Gambino

Burnett

Koide

2020

ACS Med. Chem. Lett.

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Organophosphorus nerve agents (OPNAs) inhibit acetylcholinesterase (AChE) and, despite the Chemical Weapons Convention arms control treaty, continue to represent a threat to both military personnel and civilians. 2-Pralidoxime (2-PAM) is currently the only therapeutic countermeasure approved by the United States Food and Drug Administration for treating OPNA poisoning. However, 2-PAM is not centrally active due to its hydrophilicity and resulting poor blood−brain barrier permeability; hence, these deficiencies warrant the development of more hydrophobic analogs. Specifically, gaps exist in previously published structure activity relationship (SAR) studies for 2-PAM, thereby making it difficult to rationally design novel analogs that are concomitantly more permeable and more efficacious. In this study, we methodically performed a methyl scan on the core pyridinium of 2-PAM to identify ring positions that could tolerate both additional steric bulk and hydrophobicity. Subsequently, SAR-guided molecular docking was used to rationalize hydropathically feasible binding modes for 2-PAM and the reported derivatives. Overall, the data presented herein provide new insights that may facilitate the rational design of more efficacious 2-PAM analogs.

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Novel pyridinium oximes: synthesis, molecular docking and in vitro reactivation studies

Abstract: A computational approach has been attempted for the screening of 4-pyridoxinium (4P) ring based reactivators for paraoxon inhibited AChE.

Cited by 4 publications

References 29 publications

Spirooxadiazoline‐oxindoles derived from imatinib show antimyeloproliferative potential in K562 cells

Spirooxadiazoline‐oxindoles derived from imatinib show antimyeloproliferative potential in K562 cells

Novel Insights into the Thioesterolytic Activity of N-Substituted Pyridinium-4-oximes

Methyl Scanning and Revised Binding Mode of 2-Pralidoxime, an Antidote for Nerve Agent Poisoning

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