Abstract
A set of 25 novel, silicon-based carbamate derivatives as potential acetyl- and butyrylcholinesterase (AChE/BChE) inhibitors was synthesized and characterized by their in vitro inhibition profiles and the selectivity indexes (SIs). The prepared compounds were also tested for their inhibition potential on photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. In fact, some of the newly prepared molecules revealed comparable or even better inhibitory activities compared to the marketed drugs (rivastigmine or galanthamine) and commercially applied pesticide Diuron®, respectively. Generally, most compounds exhibited better inhibition potency towards AChE; however, a wider activity span was observed for BChE. Notably, benzyl N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(2-hydroxyphenyl)carbamoyl]ethyl]-carbamate (2) and benzyl N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(3-hydroxyphenyl)carbamoyl]ethyl]-carbamate (3) were characterized by fairly high selective indexes. Specifically, compound 2 was prescribed with the lowest IC50 value that corresponds quite well with galanthamine inhibition activity, while the inhibitory profiles of molecules 3 and benzyl-N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(4-hydroxyphenyl)carbamoyl]ethyl]carbamate (4) are in line with rivastigmine activity. Moreover, a structure–activity relationship (SAR)-driven similarity evaluation of the physicochemical properties for the carbamates examined appeared to have foreseen the activity cliffs using a similarity–activity landscape index for BChE inhibitory response values. The ‘indirect’ ligand-based and ‘direct’ protein-mediated in silico approaches were applied to specify electronic/steric/lipophilic factors that are potentially valid for quantitative (Q)SAR modeling of the carbamate analogues. The stochastic model validation was used to generate an ‘average’ 3D-QSAR pharmacophore pattern. Finally, the target-oriented molecular docking was employed to (re)arrange the spatial distribution of the ligand property space for BChE and photosystem II (PSII).
Highlights
Finding critical in vitro and/or in silico parameters of the hit→lead→seed→drug route is still a long-term aspiration and monumental challenge in drug discovery projects, mainly due to the intrinsic multidimensionality of the problem [1]
Over 50% of commercially available herbicides that belong to different chemical chemotypes act by reversible binding to the reaction center (RC) of the photosystem II (PSII) complex in order to compete with the native plastoquinone (PQ) molecules QA and QB
The solvent was evaporated under reduced pressure and the residue was triturated with EtOAc/petroleum ether to give white crystals of (2S)-2-{[(benzyloxy)carbonyl]amino}-3-[(tert-butyldimethylsilyl)oxy]propanoic acid
Summary
Finding critical in vitro and/or in silico parameters (descriptors or properties) of the hit→lead→seed→drug route is still a long-term aspiration and monumental challenge in drug discovery projects, mainly due to the intrinsic multidimensionality of the problem [1]. In other words, finding the optimal balance between ADMET-related properties and desired drug potency (‘sweet spot’) can be rationalized graphically by extension of the 2D similarity-based projection with activity data in the form of a ‘biological response surface’ or SAR landscapes [11]. The synthesis and SAR-driven similarity evaluation of physicochemical properties for a novel series of 25 silicon-based carbamates as potential AChE/BChE/PET inhibitors is reported. A SAR-driven similarity evaluation of physicochemical properties for the carbamates examined is reported to foresee the activity cliffs using a similarity–activity landscape index for BChE inhibitory response values. For all effective BChE and AChE inhibitors (compounds 2–4, 25, 7 and 6), permeation via the BBB using ACD/Percepta 14.0.0 was predicted and compared to clinically-used drug profiles (see Tables S1–S10) and for all newly designed molecules, brain penetration sufficient for CNS activity was predicted as well
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