Bergamini C

References (8)

Title : Quinolinetrione-tacrine hybrids as multi-target-directed ligands against Alzheimer's disease - Uliassi_2023_Bioorg.Med.Chem_91_117419
Author(s) : Uliassi E , Bergamini C , Rizzardi N , Naldi M , Cores A , Bartolini M , Carlos Menendez J , Bolognesi ML
Ref : Bioorganic & Medicinal Chemistry , 91 :117419 , 2023
Abstract : Multi-target drug discovery is one of the most active fields in the search for new drugs against Alzheimer's disease (AD). This is because the complexity of AD pathological network might be adequately tackled by multi-target-directed ligands (MTDLs) aimed at modulating simultaneously multiple targets of such a network. In a continuation of our efforts to develop MTDLs for AD, we have been focusing on the molecular hybridization of the acetylcholinesterase inhibitor tacrine with the aim of expanding its anti-AD profile. Herein, we manipulated the structure of a previously developed tacrine-quinone hybrid (1). We designed and synthesized a novel set of MTDLs (2-6) by replacing the naphthoquinone scaffold of 1 with that of 2,5,8-quinolinetrione. The most interesting hybrid 3 inhibited cholinesterase enzymes at nanomolar concentrations. In addition, 3 exerted antioxidant effects in menadione-induced oxidative stress of SH-SY5Y cells. Importantly, 3 also showed low hepatotoxicity and good anti-amyloid aggregation properties. Remarkably, we uncovered the potential of the quinolinetrione scaffold, as a novel anti-amyloid aggregation and antioxidant motif to be used in further anti-AD MTDL drug discovery endeavors.
ESTHER : Uliassi_2023_Bioorg.Med.Chem_91_117419
PubMedSearch : Uliassi_2023_Bioorg.Med.Chem_91_117419
PubMedID: 37487339

Title : Sustainable Drug Discovery of Multi-Target-Directed Ligands for Alzheimer's Disease - Rossi_2021_J.Med.Chem_64_4972
Author(s) : Rossi M , Freschi M , de Camargo Nascente L , Salerno A , de Melo Viana Teixeira S , Nachon F , Chantegreil F , Soukup O , Prchal L , Malaguti M , Bergamini C , Bartolini M , Angeloni C , Hrelia S , Soares Romeiro LA , Bolognesi ML
Ref : Journal of Medicinal Chemistry , 64 :4972 , 2021
Abstract : The multifactorial nature of Alzheimer's disease (AD) is a reason for the lack of effective drugs as well as a basis for the development of "multi-target-directed ligands" (MTDLs). As cases increase in developing countries, there is a need of new drugs that are not only effective but also accessible. With this motivation, we report the first sustainable MTDLs, derived from cashew nutshell liquid (CNSL), an inexpensive food waste with anti-inflammatory properties. We applied a framework combination of functionalized CNSL components and well-established acetylcholinesterase (AChE)/butyrylcholinesterase (BChE) tacrine templates. MTDLs were selected based on hepatic, neuronal, and microglial cell toxicity. Enzymatic studies disclosed potent and selective AChE/BChE inhibitors (5, 6, and 12), with subnanomolar activities. The X-ray crystal structure of 5 complexed with BChE allowed rationalizing the observed activity (0.0352 nM). Investigation in BV-2 microglial cells revealed antineuroinflammatory and neuroprotective activities for 5 and 6 (already at 0.01 microM), confirming the design rationale.
ESTHER : Rossi_2021_J.Med.Chem_64_4972
PubMedSearch : Rossi_2021_J.Med.Chem_64_4972
PubMedID: 33829779
Gene_locus related to this paper: human-BCHE

Title : Discovery of sustainable drugs for Alzheimer's disease: cardanol-derived cholinesterase inhibitors with antioxidant and anti-amyloid properties - de Andrade Ramos_2021_RSC.Med.Chem_12_1154
Author(s) : de Andrade Ramos G , Souza de Oliveira A , Bartolini M , Naldi M , Liparulo I , Bergamini C , Uliassi E , Wu L , Fraser PE , Abreu M , Kiametis AS , Gargano R , Silveira ER , Brand GD , Prchal L , Soukup O , Korabecny J , Bolognesi ML , Soares Romeiro LA
Ref : RSC Med Chem , 12 :1154 , 2021
Abstract : As part of our efforts to develop sustainable drugs for Alzheimer's disease (AD), we have been focusing on the inexpensive and largely available cashew nut shell liquid (CNSL) as a starting material for the identification of new acetylcholinesterase (AChE) inhibitors. Herein, we decided to investigate whether cardanol, a phenolic CNSL component, could serve as a scaffold for improved compounds with concomitant anti-amyloid and antioxidant activities. Ten new derivatives, carrying the intact phenolic function and an aminomethyl functionality, were synthesized and first tested for their inhibitory potencies towards AChE and butyrylcholinesterase (BChE). 5 and 11 were found to inhibit human BChE at a single-digit micromolar concentration. Transmission electron microscopy revealed the potential of five derivatives to modulate Abeta aggregation, including 5 and 11. In HORAC assays, 5 and 11 performed similarly to standard antioxidant ferulic acid as hydroxyl scavenging agents. Furthermore, in in vitro studies in neuronal cell cultures, 5 and 11 were found to effectively inhibit reactive oxygen species production at a 10 microM concentration. They also showed a favorable initial ADME/Tox profile. Overall, these results suggest that CNSL is a promising raw material for the development of potential disease-modifying treatments for AD.
ESTHER : de Andrade Ramos_2021_RSC.Med.Chem_12_1154
PubMedSearch : de Andrade Ramos_2021_RSC.Med.Chem_12_1154
PubMedID: 34355181

Title : Multitarget drug design strategy in Alzheimer's disease: focus on cholinergic transmission and amyloid-beta aggregation - Simoni_2017_Future.Med.Chem_9_953
Author(s) : Simoni E , Bartolini M , Abu IF , Blockley A , Gotti C , Bottegoni G , Caporaso R , Bergamini C , Andrisano V , Cavalli A , Mellor IR , Minarini A , Rosini M
Ref : Future Med Chem , 9 :953 , 2017
Abstract : AIM: Alzheimer pathogenesis has been associated with a network of processes working simultaneously and synergistically. Over time, much interest has been focused on cholinergic transmission and its mutual interconnections with other active players of the disease. Besides the cholinesterase mainstay, the multifaceted interplay between nicotinic receptors and amyloid is actually considered to have a central role in neuroprotection. Thus, the multitarget drug-design strategy has emerged as a chance to face the disease network.
METHODS: By exploiting the multitarget approach, hybrid compounds have been synthesized and studied in vitro and in silico toward selected targets of the cholinergic and amyloidogenic pathways.
RESULTS: The new molecules were able to target the cholinergic system, by joining direct nicotinic receptor stimulation to acetylcholinesterase inhibition, and to inhibit amyloid-beta aggregation. CONCLUSION: The compounds emerged as a suitable starting point for a further optimization process.
ESTHER : Simoni_2017_Future.Med.Chem_9_953
PubMedSearch : Simoni_2017_Future.Med.Chem_9_953
PubMedID: 28632446

Title : New pyridine derivatives as inhibitors of acetylcholinesterase and amyloid aggregation - Pandolfi_2017_Eur.J.Med.Chem_141_197
Author(s) : Pandolfi F , De Vita D , Bortolami M , Coluccia A , Di Santo R , Costi R , Andrisano V , Alabiso F , Bergamini C , Fato R , Bartolini M , Scipione L
Ref : Eur Journal of Medicinal Chemistry , 141 :197 , 2017
Abstract : A new series of pyridine derivatives with carbamic or amidic function has been designed and synthesized to act as cholinesterase inhibitors. The synthesized compounds were tested toward EeAChE and hAChE and toward eqBChE and hBChE. The carbamate 8 was the most potent hAChE inhibitor (IC50 = 0.153 +/- 0.016 muM) while the carbamate 11 was the most potent inhibitor of hBChE (IC50 = 0.828 +/- 0.067 muM). A molecular docking study indicated that the carbamate 8 was able to bind AChE by interacting with both CAS and PAS, in agreement with the mixed inhibition mechanism. Furthermore, the carbamates 8, 9 and 11 were able to inhibit Abeta42 self-aggregation and possessed quite low toxicity against human astrocytoma T67 and HeLa cell lines, being the carbamate 8 the less toxic compound on both cell lines.
ESTHER : Pandolfi_2017_Eur.J.Med.Chem_141_197
PubMedSearch : Pandolfi_2017_Eur.J.Med.Chem_141_197
PubMedID: 29031067

Title : Novel 8-Hydroxyquinoline Derivatives as Multitarget Compounds for the Treatment of Alzheimer's Disease - Prati_2016_ChemMedChem_11_1284
Author(s) : Prati F , Bergamini C , Fato R , Soukup O , Korabecny J , Andrisano V , Bartolini M , Bolognesi ML
Ref : ChemMedChem , 11 :1284 , 2016
Abstract : We discovered a small series of hit compounds that show multitargeting activities against key targets in Alzheimer's disease (AD). The compounds were designed by combining the structural features of the anti-AD drug donepezil with clioquinol, which is able to chelate redox-active metals, thus decreasing metal-driven oxidative phenomena and beta-amyloid (Abeta)-mediated neurotoxicity. The majority of the new hybrid compounds selectively target human butyrylcholinesterase at micromolar concentrations and effectively inhibit Abeta self-aggregation. In addition, compounds 5-chloro-7-((4-(2-methoxybenzyl)piperazin-1-yl)methyl)-8-hydroxyquinoline (1 b), 7-((4-(2-methoxybenzyl)piperazin-1-yl)methyl)-8-hydroxyquinoline (2 b), and 7-(((1-benzylpiperidin-4-yl)amino)methyl)-5-chloro-8-hydroxyquinoline (3 a) are able to chelate copper(II) and zinc(II) and exert antioxidant activity in vitro. Importantly, in the case of 2 b, the multitarget profile is accompanied by high predicted blood-brain barrier permeability, low cytotoxicity in T67 cells, and acceptable toxicity in HUVEC primary cells.
ESTHER : Prati_2016_ChemMedChem_11_1284
PubMedSearch : Prati_2016_ChemMedChem_11_1284
PubMedID: 26880501

Title : Multitarget Drug Design Strategy: Quinone-Tacrine Hybrids Designed To Block Amyloid-beta Aggregation and To Exert Anticholinesterase and Antioxidant Effects - Nepovimova_2014_J.Med.Chem_57_8576
Author(s) : Nepovimova E , Uliassi E , Korabecny J , Pena-Altamira LE , Samez S , Pesaresi A , Garcia GE , Bartolini M , Andrisano V , Bergamini C , Fato R , Lamba D , Roberti M , Kuca K , Monti B , Bolognesi ML
Ref : Journal of Medicinal Chemistry , 57 :8576 , 2014
Abstract : We report the identification of multitarget anti-Alzheimer compounds designed by combining a naphthoquinone function and a tacrine fragment. In vitro, 15 compounds displayed excellent acetylcholinesterase (AChE) inhibitory potencies and interesting capabilities to block amyloid-beta (Abeta) aggregation. The X-ray analysis of one of those compounds in complex with AChE allowed rationalizing the outstanding activity data (IC50 = 0.72 nM). Two of the compounds showed negligible toxicity in immortalized mouse cortical neurons Neuro2A and primary rat cerebellar granule neurons. However, only one of them was less hepatotoxic than tacrine in HepG2 cells. In T67 cells, both compounds showed antioxidant activity, following NQO1 induction. Furthermore, in Neuro2A, they were able to completely revert the decrease in viability induced by Abeta. Importantly, they crossed the blood-brain barrier, as demonstrated in ex vivo experiments with rats. When ex vivo results were combined with in vitro studies, these two compounds emerged to be promising multitarget lead candidates worthy of further pursuit.
ESTHER : Nepovimova_2014_J.Med.Chem_57_8576
PubMedSearch : Nepovimova_2014_J.Med.Chem_57_8576
PubMedID: 25259726
Gene_locus related to this paper: torca-ACHE

Title : Toward a rational design of multitarget-directed antioxidants: merging memoquin and lipoic acid molecular frameworks - Bolognesi_2009_J.Med.Chem_52_7883
Author(s) : Bolognesi ML , Cavalli A , Bergamini C , Fato R , Lenaz G , Rosini M , Bartolini M , Andrisano V , Melchiorre C
Ref : Journal of Medicinal Chemistry , 52 :7883 , 2009
Abstract : Novel multitargeted antioxidants 3-6 were designed by combining the antioxidant features, namely, a benzoquinone fragment and a lipoyl function, of two multifunctional lead candidates. They were then evaluated to determine their profile against Alzheimer's disease. They showed antioxidant activity, improved following enzymatic reduction, in mitochondria and T67 cell line. They also displayed a balanced inhibitory profile against amyloid-beta aggregation and acetylcholinesterase, emerging as promising molecules for neuroprotectant lead discovery.
ESTHER : Bolognesi_2009_J.Med.Chem_52_7883
PubMedSearch : Bolognesi_2009_J.Med.Chem_52_7883
PubMedID: 19813747