A structural series of 7-MEOTA-adamantylamine thioureas was designed, synthesized and evaluated as inhibitors of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE). The compounds were prepared based on the multi-target-directed ligand strategy with different linker lengths (n = 2-8) joining the well-known NMDA antagonist adamantine and the hAChE inhibitor 7-methoxytacrine (7-MEOTA). Based on in silico studies, these inhibitors proved dual binding site character capable of simultaneous interaction with the peripheral anionic site (PAS) of hAChE and the catalytic active site (CAS). Clearly, these structural derivatives exhibited very good inhibitory activity towards hBChE resulting in more selective inhibitors of this enzyme. The most potent cholinesterase inhibitor was found to be thiourea analogue 14 (with an IC₅₀ value of 0.47 µM for hAChE and an IC₅₀ value of 0.11 µM for hBChE, respectively). Molecule 14 is a suitable novel lead compound for further evaluation proving that the strategy of dual binding site inhibitors might be a promising direction for development of novel AD drugs.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- Alzheimerova nemoc farmakoterapie MeSH
- amantadin chemická syntéza chemie farmakologie terapeutické užití MeSH
- cholinesterasové inhibitory chemická syntéza chemie farmakologie terapeutické užití MeSH
- dimerizace * MeSH
- enzymatické testy MeSH
- inhibiční koncentrace 50 MeSH
- lidé MeSH
- molekulární modely * MeSH
- referenční standardy MeSH
- simulace molekulového dockingu MeSH
- takrin analogy a deriváty chemická syntéza chemie farmakologie terapeutické užití MeSH
- thiomočovina chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Cytotoxicity and mutagenicity of trans,trans,trans-[PtCl2(CH3COO)2(NH3)(1-adamantylamine)] [trans-adamplatin(IV)] and its reduced analog trans-[PtCl2(NH3)(1-adamantylamine)] [trans-adamplatin(II)] were examined. In addition, the several factors underlying biological effects of these trans-platinum compounds using various biochemical methods were investigated. A notable feature of the growth inhibition studies was the remarkable circumvention of both acquired and intrinsic cisplatin resistance by the two lipophilic trans-compounds. Interestingly, trans-adamplatin(IV) was considerably less mutagenic than cisplatin. Consistent with the lipophilic character of trans-adamplatin complexes, their total accumulation in A2780 cells was considerably greater than that of cisplatin. The results also demonstrate that trans-adamplatin(II) exhibits DNA binding mode markedly different from that of ineffective transplatin. In addition, the reduced deactivation of trans-adamplatin(II) by glutathione seems to be an important determinant of the cytotoxic effects of the complexes tested in the present work. The factors associated with cytotoxic and mutagenic effects of trans-adamplatin complexes in tumor cell lines examined in the present work are likely to play a significant role in the overall antitumor activity of these complexes.
- MeSH
- adukty DNA chemie MeSH
- amantadin analogy a deriváty farmakologie chemie metabolismus MeSH
- antitumorózní látky farmakologie chemie metabolismus MeSH
- cirkulární dichroismus MeSH
- DNA chemie MeSH
- financování organizované MeSH
- hypoxanthinfosforibosyltransferasa genetika účinky léků MeSH
- lidé MeSH
- mutageny farmakologie chemie metabolismus MeSH
- nádorové buněčné linie MeSH
- organoplatinové sloučeniny chemie metabolismus farmakologie MeSH
- Check Tag
- lidé MeSH
- MeSH
- amantadin analogy a deriváty chemická syntéza chemie MeSH
- antitumorózní látky farmakologie chemická syntéza chemie MeSH
- buněčné linie MeSH
- chemorezistence MeSH
- cisplatina farmakologie MeSH
- finanční podpora výzkumu jako téma MeSH
- myši MeSH
- organoplatinové sloučeniny farmakologie chemická syntéza MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- MeSH
- adjuvancia imunologická farmakologie MeSH
- amantadin analogy a deriváty farmakologie chemie MeSH
- dipeptidy farmakologie chemie MeSH
- edém chemicky indukované imunologie prevence a kontrola MeSH
- glutamin analogy a deriváty farmakologie MeSH
- myši MeSH
- T-lymfocyty imunologie účinky léků MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
