Synthesis and Molecular Properties of Nerve Agent Reactivator HLö-7 Dimethanesulfonate

Hsu, Fu‐Lian; Bae, Su Y.; McGuire, Jack; Anderson, Dana R.; Bester, S.M.; Height, J.J.; Pegan, Scott D.; Walz, Andrew J.

doi:10.1021/acsmedchemlett.9b00021

Cited by 8 publications

(4 citation statements)

References 18 publications

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“…The HI-6 analog HLö 7, bearing two oxime functions in position 2 and 4 at one pyridinium ring, was considered to be a broad spectrum oxime with superior reactivating potency compared to HI-6 and good therapeutic efficacy against different nerve agents including tabun (Eyer et al 1992 ; Lundy et al 1992 ). A higher toxicity compared to HI-6, low stability in aqueous solutions and a challenging synthesis were the most likely reasons for the limited interest into HLö 7 in the recent years and the focus on HI-6 as the prime candidate oxime (Psotka et al 2017 ; Hsu et al 2019 ).…”

Section: The Oxime Conceptmentioning

confidence: 99%

Organophosphorus compounds and oximes: a critical review

Worek¹,

2020

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Organophosphorus (OP) pesticides and nerve agents still pose a threat to the population. Treatment of OP poisoning is an ongoing challenge and burden for medical services. Standard drug treatment consists of atropine and an oxime as reactivator of OP-inhibited acetylcholinesterase and is virtually unchanged since more than six decades. Established oximes, i.e. pralidoxime, obidoxime, TMB-4, HI-6 and MMB-4, are of insufficient effectiveness in some poisonings and often cover only a limited spectrum of the different nerve agents and pesticides. Moreover, the value of oximes in human OP pesticide poisoning is still disputed. Long-lasting research efforts resulted in the preparation of countless experimental oximes, and more recently non-oxime reactivators, intended to replace or supplement the established and licensed oximes. The progress of this development is slow and none of the novel compounds appears to be suitable for transfer into advanced development or into clinical use. This situation calls for a critical analysis of the value of oximes as mainstay of treatment as well as the potential and limitations of established and novel reactivators. Requirements for a straightforward identification of superior reactivators and their development to licensed drugs need to be addressed as well as options for interim solutions as a chance to improve the therapy of OP poisoning in a foreseeable time frame.

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Section: The Oxime Conceptmentioning

confidence: 99%

Organophosphorus compounds and oximes: a critical review

Worek¹,

2020

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“…AMPK, PKC, GLS, ASK1, AChE, CP450, and GST proteins were used in the present study. The starting coordinates for each protein were taken from X-ray crystallographic structures: PDB IDs 6C9G [46] for AMPK, 2I0E [47] for PKC, 3VP1 [48] for GLC, 3VW6 [49] for ASK1, 6NEA [50] for AChE, 3NXU [51] for CP450, and 1AQW [52] for GST. If there were missing amino acids, the following steps were followed to add the missing amino acids and build a new model.…”

Section: Protein Structure Preparationmentioning

confidence: 99%

Demystifying Chronic Kidney Disease of Unknown Etiology (CKDu): Computational Interaction Analysis of Pesticides and Metabolites with Vital Renal Enzymes

2021

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Chronic kidney disease of unknown etiology (CKDu) has been recognized as a global non-communicable health issue. There are many proposed risk factors for CKDu and the exact reason is yet to be discovered. Understanding the inhibition or manipulation of vital renal enzymes by pesticides can play a key role in understanding the link between CKDu and pesticides. Even though it is very important to take metabolites into account when investigating the relationship between CKDu and pesticides, there is a lack of insight regarding the effects of pesticide metabolites towards CKDu. In this study, a computational approach was used to study the effects of pesticide metabolites on CKDu. Further, interactions of selected pesticides and their metabolites with renal enzymes were studied using molecular docking and molecular dynamics simulation studies. It was evident that some pesticides and metabolites have affinity to bind at the active site or at regulatory sites of considered renal enzymes. Another important discovery was the potential of some metabolites to have higher binding interactions with considered renal enzymes compared to the parent pesticides. These findings raise the question of whether pesticide metabolites may be a main risk factor towards CKDu.

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“…4 To combat this, AChE reactivators have been developed to remove the offending AChE inhibitors, restoring acetylcholine levels to normal. 5,6 It is really challenging to design a nanoprobe for monitoring AChE activity in the presence of reversible (carbamate, acridine) and irreversible (organophosphorus) inhibitors. The probe reported thus far can determine the inhibition 7 of AChE, and is limited to monitoring percentage reactivation of organophosphorusinhibited enzyme.…”

Section: Introductionmentioning

confidence: 99%