Twenty-four novel compounds bearing tetrahydroacridine and N-propargyl moieties have been designed, synthesised, and evaluated in vitro for their anti-cholinesterase and anti-monoamine oxidase activities. Propargyltacrine 23 (IC50 = 21 nM) was the most potent acetylcholinesterase (AChE) inhibitor, compound 20 (IC50 = 78 nM) showed the best inhibitory human butyrylcholinesterase (hBChE) profile, and ligand 21 afforded equipotent and significant values on both ChEs (human AChE [hAChE]: IC50 = 0.095 ± 0.001 μM; hBChE: IC50 = 0.093 ± 0.003 μM). Regarding MAO inhibition, compounds 7, 15, and 25 demonstrated the highest inhibitory potential towards hMAO-B (IC50 = 163, 40, and 170 nM, respectively). In all, compounds 7, 15, 20, 21, 23, and 25 exhibiting the most balanced pharmacological profile, were submitted to permeability and cell viability tests. As a result, 7-phenoxy-N-(prop-2-yn-1-yl)-1,2,3,4-tetrahydroacridin-9-amine hydrochloride (15) has been identified as a permeable agent that shows a balanced pharmacological profile [IC50 (hAChE) = 1.472 ± 0.024 μM; IC50 (hBChE) = 0.659 ± 0.077 μM; IC50 (hMAO-B) = 40.39 ± 5.98 nM], and consequently, as a new hit-ligand that deserves further investigation, in particular in vivo analyses, as the preliminary cell viability test results reported here suggest that this is a relatively safe therapeutic agent.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- Alzheimerova nemoc * farmakoterapie MeSH
- aminy MeSH
- butyrylcholinesterasa * metabolismus MeSH
- cholinesterasové inhibitory farmakologie terapeutické užití MeSH
- inhibitory MAO farmakologie MeSH
- lidé MeSH
- ligandy MeSH
- monoaminoxidasa MeSH
- oxidoreduktasy MeSH
- racionální návrh léčiv MeSH
- takrin terapeutické užití MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
INTRODUCTION: Enoyl-(acyl-carrier-protein) reductase (ENR) is a limiting step enzyme in the Fatty Acid Synthase II system. In mammals, there is no homologue to ENR, which makes it an optimal candidate target for selective anti-infective drugs. Up-to-date, only two ENR inhibitors are used in clinical practice. AREA COVERED: This review is a survey on important patents on low molecular weight compounds with ENR inhibiting activity published in 2011-2015. Common patent databases (SciFinder, esp@cenet, WIPO) were used to locate patent applications on the proposed topic and in the timespan of 2011-2015. EXPERT OPINION: In 2011-2015, we have observed patents in previously known structural groups of diphenyl ethers and acrylamides as well as new structural classes, often identified by high-throughput screening campaigns. The spectrum of activity of applied derivatives covers significant bacteria, mycobacteria, and apicomplexan parasites (Plasmodia and Toxoplasma). Good news from research of ENR inhibitors: a) four selective anti-staphylococcal compounds applied in 2011-2015 or earlier were pushed to Phase I or Phase II clinical trials and some of them proved safety and tolerability after peroral and/or intravenous administration; b) big pharma companies have renewed their interest in the development of new anti-infective compounds against resistant strains of clinical relevance.
- MeSH
- antibiotická rezistence MeSH
- antiinfekční látky škodlivé účinky farmakologie terapeutické užití MeSH
- enoyl-ACP-reduktasa (NADH) antagonisté a inhibitory metabolismus MeSH
- inhibitory enzymů škodlivé účinky farmakologie terapeutické užití MeSH
- lidé MeSH
- patenty jako téma MeSH
- racionální návrh léčiv MeSH
- rychlé screeningové testy MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
INTRODUCTION: Hippocampal neurogenesis in adults is a new and attractive target for the treatment and prevention of neurodegenerative and neuro-psychiatric diseases. Recently, neurogenesis stimulating activity was observed in some of the commonly used small molecule drugs such as antidepressants and atypical antipsychotics. Stimulation of neurogenesis is attractive mainly due to its wide scope of application, ranging from depressions, schizophrenia, dementia, Parkinson`s and Alzheimer`s Disease to various brain injuries. AREAS COVERED: New compounds based on 7-phenyl or 7-pyridinyl-1H-indole-2-carboxamide showed interesting neural stem cell proliferation inducing activity in vitro and were claimed as potential therapeutics for various neurodegenerative and neuropsychiatric diseases as well as brain injuries. The potential of the presented compounds is evaluated with respect to other small molecule neurogenesis inducers in literature. EXPERT OPINION: Nanomolar in vitro activities of presented compounds and their favorable physico-chemical properties, giving a fair chance of good oral bioavailability and sufficient CNS penetration, make these compounds promising drug candidates. The biggest drawback of the presented application is the absence of pharmacokinetics, toxicity and in vivo activity data. On the other hand, the high number of applications in this area (seven published in last two years) indicates that Hoffmann-La Roche takes it seriously.
- MeSH
- biologická dostupnost MeSH
- dospělí MeSH
- duševní poruchy farmakoterapie patofyziologie prevence a kontrola MeSH
- hipokampus účinky léků patofyziologie MeSH
- indoly chemie farmakokinetika farmakologie MeSH
- lidé MeSH
- nervové kmenové buňky účinky léků metabolismus MeSH
- neurodegenerativní nemoci farmakoterapie patofyziologie prevence a kontrola MeSH
- neurogeneze účinky léků MeSH
- patenty jako téma MeSH
- poranění mozku farmakoterapie patofyziologie MeSH
- proliferace buněk účinky léků MeSH
- systémy cílené aplikace léků MeSH
- zvířata MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Design, results of in vitro antimycobacterial evaluation, and study of structure-activity relationships of various pyrazinecarboxylic acid reversible derivatives are presented. This review deals with some pyrazinamide analogues/prodrugs derived from Nphenylpyrazine- 2-carboxamides (1), arylaminopyrazine-2,5-dicarbonitriles (2), aryl/alkylsulphanylpyrazines (3,4), and aroylpyrazines (5) effecting >50% inhibition in the primary antimycobacterial screen. The promising pyrazine candidates for further antimycobacterial evaluation were discovered. Results give good view onto structure-activity relationships of these analogues and promise even better activity of new compounds prepared after some structure optimization experiments.
- MeSH
- antibakteriální látky škodlivé účinky chemie farmakologie MeSH
- buněčné linie MeSH
- lidé MeSH
- mikrobiální testy citlivosti MeSH
- molekulární struktura MeSH
- Mycobacterium účinky léků růst a vývoj MeSH
- prekurzory léčiv škodlivé účinky chemie farmakologie MeSH
- pyrazinamid škodlivé účinky analogy a deriváty chemie farmakologie MeSH
- racionální návrh léčiv MeSH
- viabilita buněk účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
