Di Pietro O

References (5)

Title : Multicomponent reaction-based synthesis and biological evaluation of tricyclic heterofused quinolines with multi-trypanosomatid activity - Di Pietro_2015_Eur.J.Med.Chem_105_120
Author(s) : Di Pietro O , Vicente-Garcia E , Taylor MC , Berenguer D , Viayna E , Lanzoni A , Sola I , Sayago H , Riera C , Fisa R , Clos MV , Perez B , Kelly JM , Lavilla R , Munoz-Torrero D
Ref : Eur Journal of Medicinal Chemistry , 105 :120 , 2015
Abstract : Human African trypanosomiasis (HAT), Chagas disease and leishmaniasis, which are caused by the trypanosomatids Trypanosoma brucei, Trypanosoma cruzi and Leishmania species, are among the most deadly neglected tropical diseases. The development of drugs that are active against several trypanosomatids is appealing from a clinical and economic viewpoint, and seems feasible, as these parasites share metabolic pathways and hence might be treatable by common drugs. From benzonapthyridine 1, an inhibitor of acetylcholinesterase (AChE) for which we have found a remarkable trypanocidal activity, we have designed and synthesized novel benzo[h][1,6]naphthyridines, pyrrolo[3,2-c]quinolines, azepino[3,2-c]quinolines, and pyrano[3,2-c]quinolines through 2-4-step sequences featuring an initial multicomponent Povarov reaction as the key step. To assess the therapeutic potential of the novel compounds, we have evaluated their in vitro activity against T. brucei, T. cruzi, and Leishmania infantum, as well as their brain permeability, which is of specific interest for the treatment of late-stage HAT. To assess their potential toxicity, we have determined their cytotoxicity against rat myoblast L6 cells and their AChE inhibitory activity. Several tricyclic heterofused quinoline derivatives were found to display an interesting multi-trypanosomatid profile, with one-digit micromolar potencies against two of these parasites and two-digit micromolar potency against the other. Pyranoquinoline 39, which displays IC50 values of 1.5 muM, 6.1 muM and 29.2 muM against T. brucei, L. infantum and T. cruzi, respectively, brain permeability, better drug-like properties (lower lipophilicity and molecular weight and higher CNS MPO desirability score) than hit 1, and the lowest AChE inhibitory activity of the series (IC50 > 30 muM), emerges as an interesting multi-trypanosomatid lead, amenable to further optimization particularly in terms of its selectivity index over mammalian cells.
ESTHER : Di Pietro_2015_Eur.J.Med.Chem_105_120
PubMedSearch : Di Pietro_2015_Eur.J.Med.Chem_105_120
PubMedID: 26479031

Title : Novel Levetiracetam Derivatives That Are Effective against the Alzheimer-like Phenotype in Mice: Synthesis, in Vitro, ex Vivo, and in Vivo Efficacy Studies - Sola_2015_J.Med.Chem_58_6018
Author(s) : Sola I , Aso E , Frattini D , Lopez-Gonzalez I , Espargaro A , Sabate R , Di Pietro O , Luque FJ , Clos MV , Ferrer I , Munoz-Torrero D
Ref : Journal of Medicinal Chemistry , 58 :6018 , 2015
Abstract : We have synthesized a series of heptamethylene-linked levetiracetam-huprine and levetiracetam-(6-chloro)tacrine hybrids to hit amyloid, tau, and cholinergic pathologies as well as beta-amyloid (Abeta)-induced epileptiform activity, some of the mechanisms that eventually lead to cognitive deficits in Alzheimer's disease patients. These hybrids are potent inhibitors of human acetylcholinesterase and butyrylcholinesterase in vitro and moderately potent Abeta42 and tau antiaggregating agents in a simple E. coli model of amyloid aggregation. Ex vivo determination of the brain acetylcholinesterase inhibitory activity of these compounds after intraperitoneal injection to C57BL6J mice has demonstrated their ability to enter the brain. The levetiracetam-huprine hybrid 10 significantly reduced the incidence of epileptic seizures, cortical amyloid burden, and neuroinflammation in APP/PS1 mice after a 4-week treatment with a 5 mg/kg dose. Moreover, the hybrid 10 rescued transgenic mice from cognitive deficits, thereby emerging as an interesting disease-modifying anti-Alzheimer drug candidate.
ESTHER : Sola_2015_J.Med.Chem_58_6018
PubMedSearch : Sola_2015_J.Med.Chem_58_6018
PubMedID: 26181606

Title : Shogaol-huprine hybrids: Dual antioxidant and anticholinesterase agents with beta-amyloid and tau anti-aggregating properties - Perez-Areales_2014_Bioorg.Med.Chem_22_5298
Author(s) : Perez-Areales FJ , Di Pietro O , Espargaro A , Vallverdu-Queralt A , Galdeano C , Ragusa IM , Viayna E , Guillou C , Clos MV , Perez B , Sabate R , Lamuela-Raventos RM , Luque FJ , Munoz-Torrero D
Ref : Bioorganic & Medicinal Chemistry , 22 :5298 , 2014
Abstract : Multitarget compounds are increasingly being pursued for the effective treatment of complex diseases. Herein, we describe the design and synthesis of a novel class of shogaol-huprine hybrids, purported to hit several key targets involved in Alzheimer's disease. The hybrids have been tested in vitro for their inhibitory activity against human acetylcholinesterase and butyrylcholinesterase and antioxidant activity (ABTS(+), DPPH and Folin-Ciocalteu assays), and in intact Escherichia coli cells for their Abeta42 and tau anti-aggregating activity. Also, their brain penetration has been assessed (PAMPA-BBB assay). Even though the hybrids are not as potent AChE inhibitors or antioxidant agents as the parent huprine Y and [4]-shogaol, respectively, they still exhibit very potent anticholinesterase and antioxidant activities and are much more potent Abeta42 and tau anti-aggregating agents than the parent compounds. Overall, the shogaol-huprine hybrids emerge as interesting brain permeable multitarget anti-Alzheimer leads.
ESTHER : Perez-Areales_2014_Bioorg.Med.Chem_22_5298
PubMedSearch : Perez-Areales_2014_Bioorg.Med.Chem_22_5298
PubMedID: 25156301

Title : Tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrids as a new family of anti-Alzheimer agents targeting beta-amyloid, tau, and cholinesterase pathologies - Di Pietro_2014_Eur.J.Med.Chem_84C_107
Author(s) : Di Pietro O , Perez-Areales FJ , Juarez-Jimenez J , Espargaro A , Clos MV , Perez B , Lavilla R , Sabate R , Luque FJ , Munoz-Torrero D
Ref : Eur Journal of Medicinal Chemistry , 84C :107 , 2014
Abstract : Optimization of an essentially inactive 3,4-dihydro-2H-pyrano[3,2-c]quinoline carboxylic ester derivative as acetylcholinesterase (AChE) peripheral anionic site (PAS)-binding motif by double O --> NH bioisosteric replacement, combined with molecular hybridization with the AChE catalytic anionic site (CAS) inhibitor 6-chlorotacrine and molecular dynamics-driven optimization of the length of the linker has resulted in the development of the trimethylene-linked 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrid 5a as a picomolar inhibitor of human AChE (hAChE). The tetra-, penta-, and octamethylene-linked homologues 5b-d have been also synthesized for comparison purposes, and found to retain the nanomolar hAChE inhibitory potency of the parent 6-chlorotacrine. Further biological profiling of hybrids 5a-d has shown that they are also potent inhibitors of human butyrylcholinesterase and moderately potent Abeta42 and tau anti-aggregating agents, with IC50 values in the submicromolar and low micromolar range, respectively. Also, in vitro studies using an artificial membrane model have predicted a good brain permeability for hybrids 5a-d, and hence, their ability to reach their targets in the central nervous system. The multitarget profile of the novel hybrids makes them promising leads for developing anti-Alzheimer drug candidates with more balanced biological activities.
ESTHER : Di Pietro_2014_Eur.J.Med.Chem_84C_107
PubMedSearch : Di Pietro_2014_Eur.J.Med.Chem_84C_107
PubMedID: 25016233

Title : 1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: Synthesis, pharmacological evaluation and mechanistic studies - Di Pietro_2013_Eur.J.Med.Chem_73C_141
Author(s) : Di Pietro O , Viayna E , Vicente-Garcia E , Bartolini M , Ramon R , Juarez-Jimenez J , Clos MV , Perez B , Andrisano V , Luque FJ , Lavilla R , Munoz-Torrero D
Ref : Eur Journal of Medicinal Chemistry , 73C :141 , 2013
Abstract : A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O --> NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (>11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.
ESTHER : Di Pietro_2013_Eur.J.Med.Chem_73C_141
PubMedSearch : Di Pietro_2013_Eur.J.Med.Chem_73C_141
PubMedID: 24389509