Zorbaz_2018_J.Med.Chem_61_10753

Reference

Title : Pyridinium Oximes with Ortho-Positioned Chlorine Moiety Exhibit Improved Physicochemical Properties and Efficient Reactivation of Human Acetylcholinesterase Inhibited by Several Nerve Agents - Zorbaz_2018_J.Med.Chem_61_10753
Author(s) : Zorbaz T , Malinak D , Marakovic N , Macek Hrvat N , Zandona A , Novotny M , Skarka A , Andrys R , Benkova M , Soukup O , Katalinic M , Kuca K , Kovarik Z , Musilek K
Ref : Journal of Medicinal Chemistry , 61 :10753 , 2018
Abstract :

Six chlorinated bispyridinium mono-oximes, analogous to potent charged reactivators K027, K048, and K203, were synthesized with the aim of improving lipophilicity and reducing the p Ka value of the oxime group, thus resulting in a higher oximate concentration at pH 7.4 compared to nonchlorinated analogues. The nucleophilicity was examined and the p Ka was found to be lower than that of analogous nonchlorinated oximes. All the new compounds efficiently reactivated human AChE inhibited by nerve agents cyclosarin, sarin, and VX. The most potent was the dichlorinated analogue of oxime K027 with significantly improved ability to reactivate the conjugated enzyme due to improved binding affinity and molecular recognition. Its overall reactivation of sarin-, VX-, and cyclosarin-inhibited AChE was, respectively, 3-, 7-, and 8-fold higher than by K027. Its universality, PAMPA permeability, favorable acid dissociation constant coupled with its negligible cytotoxic effect, and successful ex vivo scavenging of nerve agents in whole human blood warrant further analysis of this compound as an antidote for organophosphorus poisoning.

PubMedSearch : Zorbaz_2018_J.Med.Chem_61_10753
PubMedID: 30383374

Related information

Reactivator K027-Cl2    K027    K048    K203    PAM

Citations formats

Zorbaz T, Malinak D, Marakovic N, Macek Hrvat N, Zandona A, Novotny M, Skarka A, Andrys R, Benkova M, Soukup O, Katalinic M, Kuca K, Kovarik Z, Musilek K (2018)
Pyridinium Oximes with Ortho-Positioned Chlorine Moiety Exhibit Improved Physicochemical Properties and Efficient Reactivation of Human Acetylcholinesterase Inhibited by Several Nerve Agents
Journal of Medicinal Chemistry 61 :10753

Zorbaz T, Malinak D, Marakovic N, Macek Hrvat N, Zandona A, Novotny M, Skarka A, Andrys R, Benkova M, Soukup O, Katalinic M, Kuca K, Kovarik Z, Musilek K (2018)
Journal of Medicinal Chemistry 61 :10753