Lukas Gorecki

7-Methoxytacrine-p-Anisidine Hybrids as Novel Dual Binding Site Acetylcholinesterase Inhibitors for Alzheimer’s Disease Treatment

Alzheimer’s disease (AD) is a debilitating progressive neurodegenerative disorder that ultimately leads to the patient’s death. Despite the fact that novel pharmacological approaches endeavoring to block the neurodegenerative process are still emerging, none of them have reached use in clinical practice yet. Thus, palliative treatment represented by acetylcholinesterase inhibitors (AChEIs) and memantine are still the only therapeutics used. Following the multi-target directed ligands (MTDLs) strategy, herein we describe the synthesis, biological evaluation and docking studies for novel 7-methoxytacrine-p-anisidine hybrids designed to purposely target both cholinesterases and the amyloid cascade. Indeed, the novel derivatives proved to be effective non-specific cholinesterase inhibitors showing non-competitive AChE inhibition patterns. This compounds’ behavior was confirmed in the subsequent molecular modeling studies.

Profiling donepezil template into multipotent hybrids with antioxidant properties

Abstract Alzheimer’s disease is debilitating neurodegenerative disorder in the elderly. Current therapy relies on administration of acetylcholinesterase inhibitors (AChEIs) -donepezil, rivastigmine, galantamine, and N-methyl-d-aspartate receptor antagonist memantine. However, their therapeutic effect is only short-term and stabilizes cognitive functions for up to 2 years. Given this drawback together with other pathological hallmarks of the disease taken into consideration, novel approaches have recently emerged to better cope with AD onset or its progression. One such strategy implies broadening the biological profile of AChEIs into so-called multi-target directed ligands (MTDLs). In this review article, we made comprehensive literature survey emphasising on donepezil template which was structurally converted into plethora of MTLDs preserving anti-cholinesterase effect and, at the same time, escalating the anti-oxidant potential, which was reported as a crucial role in the pathogenesis of the Alzheimer’s disease. Graphical Abstract

Progress in acetylcholinesterase reactivators and in the treatment of organophosphorus intoxication: a patent review (2006–2016)

ABSTRACT Introduction: organophosphorus compounds act as irreversible inhibitors of the vital enzyme acetylcholinesterase (AChE). this leads in the accumulation of acetylcholine (ACh) leading to cholinergic crisis and death. The main therapeutic approach is based on immediate administration of an ache reactivator as an antidote enabling recovery of the ache function. Areas covered: This review covers the development of AChE reactivators in order to introduce a new efficient drug that will overcome significant failures of common antidotes. Further options together with methods of detection are also discussed in order to assure a complete insight into the treatment of intoxication. Expert opinion: Since organophosphates belong to the most toxic chemical warfare agents, efficient antidotes are a matter of importance. The solution of how to limit the basic drawbacks of clinically used reactivators remained a spotlight for many researches worldwide. Recent strategies of the treatment of OP exposure bring us new possibilities which may overcome classic antidotes. The importance of detection of OP also has to be taken into consideration. Especially, with the fast spreading toxic effect when death can occur within minutes.

In vitro and in silico Evaluation of Non-Quaternary Reactivators of AChE as Antidotes of Organophosphorus Poisoning - a New Hope or a Blind Alley?

BACKGROUND In the last decade, the concept of uncharged reactivators potentially able to penetrate the CNS has been introduced as an alternative to the classic charged oxime reactivators. However, this concept brings with it several associated drawbacks such as higher lipophilicity, difficulty in administration, lower affinity to cholinesterases, and higher toxicity risk. OBJECTIVE In this study, we compare data obtained for a set of five classic charged reactivators and a set of three recently published uncharged oximes supplemented by two novel ones. METHODS This time, we used only in silico prediction and in vitro approaches. RESULTS Our data showed that tested uncharged oximes have low affinity for cholinesterases, do not possess high reactivation potency, and certainly represent a greater toxicity risk due to higher lipophilicity. We assume that balanced physicochemical properties will be required for the successful treatment of OP poisoning. Nevertheless, the compound meeting such criteria and pinpointed in silico (K1280) failed in this particular case. CONCLUSION From the presented data, it seems that the concept of uncharged reactivators will have to be modified, at least to improve the bioavailability and to satisfy requirements for in vivo administration.

Bis-isoquinolinium and bis-pyridinium acetylcholinesterase inhibitors: in vitro screening of probes for novel selective insecticides

Insects have a huge impact on quality of life around the world. They play roles in transmitting diseases, crop-destruction, and as residential pests. Their increased resistance to the existing pesticides and the toxicity of carbamates (CA) and organophosphates (OP) has led to the development of new environmentally safe insecticides. In our study, thirty different bis-isoquinolinium and bis-pyridinium acetylcholinesterase inhibitors were tested as candidates for potential new selective pesticides. Our compounds were evaluated in vitro on insect acetylcholinesterase (AChE) from Musca domestica and human erythrocyte AChE using the modified Ellmans method. The values of IC50 were compared and expressed via a selectivity index (SI) towards the insect enzyme. K299, K416, and K423 provided a high SI and seem to be suitable as new lead structures of novel selective anticholinesterase insecticides. Docking studies further provided the rational background uncovering the disparities in the ligand–enzyme binding modes for each AChE enzyme. In vitro assessments as well as docking studies highlighted K299 and K416 as suitable candidates for lead structures of novel pesticides. However, further evaluation is needed to confirm this statement.

Tetroxime: reactivation potency – in vitro and in silico study

Acetylcholinesterase (AChE) reactivators (oximes) are generally used as treatment in cases of nerve agent poisoning. There is no single oxime applicable in every case of nerve agent intoxication. Based on this fact, novel candidates with broader efficacy are still being sought. In this study, tetroxime – a bisquaternary compound bearing four oxime groups, was evaluated for its potency to reactivate rat brain AChE inhibited by selected nerve agents (tabun, sarin, cyclosarin and VX agent). Despite the fact that this oxime contains four oxime groups that could be plausibly responsible for reactivation, it did not achieve broader reactivation activity. Satisfactory results were obtained only in the case of VX agent-inhibited AChE. In the cases of sarin- and cyclosarin-inhibited AChE, acceptable results were reached at higher oxime concentration only. Tetroxime was unable to reactivate tabun-inhibited AChE. However, compared with the gold standard pralidoxime, this oxime achieved more promising results.