Valenti P

References (10)

Title : Design, synthesis, and evaluation of benzophenone derivatives as novel acetylcholinesterase inhibitors - Belluti_2009_Eur.J.Med.Chem_44_1341
Author(s) : Belluti F , Piazzi L , Bisi A , Gobbi S , Bartolini M , Cavalli A , Valenti P , Rampa A
Ref : Eur Journal of Medicinal Chemistry , 44 :1341 , 2009
Abstract : Starting from a structure-based drug design, new acetylcholinesterase inhibitors were designed and synthesized as analogues of donepezil. The compounds were composed by an aromatic function and a tertiary amino moiety connected by a suitable spacer. In particular, the benzophenone nucleus and the N,N-benzylmethylamine function were selected. The easily accessible three-step synthesis of these compounds resulted to be significantly less difficult and expensive than that of donepezil. Several compounds possess anti-cholinesterase activity in the order of micro and sub-micromolar. Particularly, compounds 1 and 10 were the most potent inhibitors of the series.
ESTHER : Belluti_2009_Eur.J.Med.Chem_44_1341
PubMedSearch : Belluti_2009_Eur.J.Med.Chem_44_1341
PubMedID: 18396354

Title : Genome plasticity of BCG and impact on vaccine efficacy - Brosch_2007_Proc.Natl.Acad.Sci.U.S.A_104_5596
Author(s) : Brosch R , Gordon SV , Garnier T , Eiglmeier K , Frigui W , Valenti P , Dos Santos S , Duthoy S , Lacroix C , Garcia-Pelayo C , Inwald JK , Golby P , Garcia JN , Hewinson RG , Behr MA , Quail MA , Churcher C , Barrell BG , Parkhill J , Cole ST
Ref : Proc Natl Acad Sci U S A , 104 :5596 , 2007
Abstract : To understand the evolution, attenuation, and variable protective efficacy of bacillus Calmette-Guerin (BCG) vaccines, Mycobacterium bovis BCG Pasteur 1173P2 has been subjected to comparative genome and transcriptome analysis. The 4,374,522-bp genome contains 3,954 protein-coding genes, 58 of which are present in two copies as a result of two independent tandem duplications, DU1 and DU2. DU1 is restricted to BCG Pasteur, although four forms of DU2 exist; DU2-I is confined to early BCG vaccines, like BCG Japan, whereas DU2-III and DU2-IV occur in the late vaccines. The glycerol-3-phosphate dehydrogenase gene, glpD2, is one of only three genes common to all four DU2 variants, implying that BCG requires higher levels of this enzyme to grow on glycerol. Further amplification of the DU2 region is ongoing, even within vaccine preparations used to immunize humans. An evolutionary scheme for BCG vaccines was established by analyzing DU2 and other markers. Lesions in genes encoding sigma-factors and pleiotropic transcriptional regulators, like PhoR and Crp, were also uncovered in various BCG strains; together with gene amplification, these affect gene expression levels, immunogenicity, and, possibly, protection against tuberculosis. Furthermore, the combined findings suggest that early BCG vaccines may even be superior to the later ones that are more widely used.
ESTHER : Brosch_2007_Proc.Natl.Acad.Sci.U.S.A_104_5596
PubMedSearch : Brosch_2007_Proc.Natl.Acad.Sci.U.S.A_104_5596
PubMedID: 17372194
Gene_locus related to this paper: myctu-a85a , myctu-a85b , myctu-a85c , myctu-bpoC , myctu-cut3 , myctu-cutas2 , myctu-d5yk66 , myctu-ephB , myctu-ephc , myctu-ephd , myctu-ephE , myctu-hpx , myctu-linb , myctu-lipG , myctu-lipJ , myctu-LIPS , myctu-lipv , myctu-LPQC , myctu-LPQP , myctu-MBTB , myctu-metx , myctu-mpt51 , myctu-MT1628 , myctu-p71654 , myctu-p95011 , myctu-PKS6 , myctu-PKS13 , myctu-ppe42 , myctu-ppe63 , myctu-Rv1430 , myctu-RV0045C , myctu-Rv0077c , myctu-Rv0151c , myctu-Rv0152c , myctu-Rv0159c , myctu-Rv0160c , myctu-rv0183 , myctu-Rv0217c , myctu-Rv0220 , myctu-Rv0272c , myctu-RV0293C , myctu-RV0457C , myctu-RV0519C , myctu-RV0774C , myctu-RV0782 , myctu-RV0840C , myctu-Rv1069c , myctu-Rv1076 , myctu-RV1123C , myctu-Rv1184c , myctu-Rv1191 , myctu-RV1192 , myctu-RV1215C , myctu-Rv1399c , myctu-Rv1400c , myctu-Rv1426c , myctu-RV1639C , myctu-RV1683 , myctu-RV1758 , myctu-Rv1800 , myctu-Rv1833c , myctu-Rv2045c , myctu-RV2054 , myctu-Rv2284 , myctu-RV2296 , myctu-Rv2385 , myctu-Rv2485c , myctu-RV2627C , myctu-RV2672 , myctu-RV2695 , myctu-RV2765 , myctu-RV2800 , myctu-RV2854 , myctu-Rv2970c , myctu-Rv3084 , myctu-Rv3097c , myctu-rv3177 , myctu-Rv3312c , myctu-RV3452 , myctu-RV3473C , myctu-Rv3487c , myctu-Rv3569c , myctu-Rv3591c , myctu-RV3724 , myctu-Rv3802c , myctu-Rv3822 , myctu-y0571 , myctu-y963 , myctu-Y1834 , myctu-y1835 , myctu-y2079 , myctu-yc88 , myctu-ym23 , myctu-ym24 , myctu-YR15 , myctu-yt28

Title : Cholinesterase inhibitors: xanthostigmine derivatives blocking the acetylcholinesterase-induced beta-amyloid aggregation - Belluti_2005_J.Med.Chem_48_4444
Author(s) : Belluti F , Rampa A , Piazzi L , Bisi A , Gobbi S , Bartolini M , Andrisano V , Cavalli A , Recanatini M , Valenti P
Ref : Journal of Medicinal Chemistry , 48 :4444 , 2005
Abstract : In continuing research that led us to identify a new class of carbamate derivatives acting as potent (Rampa et al. J. Med. Chem. 1998, 41, 3976) and long-lasting (Rampa et al. J. Med. Chem. 2001, 44, 3810) acetylcholinesterase (AChE) inhibitors, we obtained some analogues able to simultaneously block both the catalytic and the beta-amyloid (Abeta) proaggregatory activities of AChE. The key feature of these derivatives is a 2-arylidenebenzocycloalkanone moiety that provides the ability to bind at the AChE peripheral site responsible for promoting the Abeta aggregation. The new carbamates were tested in vitro for the inhibition of both cholinesterases and also for the ability to prevent the AChE-induced Abeta aggregation. All of the compounds had AChE IC(50) values in the nanomolar range and showed the ability to block the AChE-induced Abeta aggregation, thus supporting the feasibility of this new strategy in the search of compounds for the treatment of Alzheimer's disease.
ESTHER : Belluti_2005_J.Med.Chem_48_4444
PubMedSearch : Belluti_2005_J.Med.Chem_48_4444
PubMedID: 15974596

Title : Acetylcholinesterase inhibitors as a starting point towards improved Alzheimer's disease therapeutics - Recanatini_2004_Curr.Pharm.Des_10_3157
Author(s) : Recanatini M , Valenti P
Ref : Curr Pharm Des , 10 :3157 , 2004
Abstract : The knowledge about the pathogenesis and the development of the neurodegeneration associated with Alzheimer's disease (AD) has been organised throughout the years into two theories, namely the cholinergic and the amyloid hypotheses. The loss of cholinergic neurotransmission and the abnormal aggregation and deposition of the amyloid-beta peptide (A beta) in the brain are retained as the central events by the two theories, respectively. These phenomena and their pathological consequences are the main targets of the drug discovery strategies based on each hypothesis. However, the two paradigms share some common aspects as shown by several experimental evidences, such that they might even fit into a unifying scenario of neuropathology and neurodegeneration. In this context, in a perspective of drug discovery, the enzyme acetylcholinesterase (AChE) holds a key position, as it is a main target for cholinomimetic AD drugs being responsible for the breakdown of the neurotransmitter, and it is also involved in the aggregation of A beta and the formation of the neurotoxic fibrils. Following this view, in recent years, a drug design strategy has emerged, directed to finding molecules able to inhibit both of these actions exerted by AChE. In this review, we will briefly introduce the biological basis of this strategy, and then will account for the early results obtained in this field in our and in other laboratories. The main focus will be on potential lead compounds for which some experimental evidence exists supporting the hypothesis of their dual action, as AChE inhibitors and blockers of the AChE-induced A beta aggregation.
ESTHER : Recanatini_2004_Curr.Pharm.Des_10_3157
PubMedSearch : Recanatini_2004_Curr.Pharm.Des_10_3157
PubMedID: 15544505

Title : 3-(4-[[Benzyl(methyl)amino]methyl]phenyl)-6,7-dimethoxy-2H-2-chromenone (AP2238) inhibits both acetylcholinesterase and acetylcholinesterase-induced beta-amyloid aggregation: a dual function lead for Alzheimer's disease therapy - Piazzi_2003_J.Med.Chem_46_2279
Author(s) : Piazzi L , Rampa A , Bisi A , Gobbi S , Belluti F , Cavalli A , Bartolini M , Andrisano V , Valenti P , Recanatini M
Ref : Journal of Medicinal Chemistry , 46 :2279 , 2003
Abstract : In recent years, the investigation of acetylcholinesterase (AChE) inhibitors has gained further interest, because the involvement of the peripheral site of the enzyme in the beta-amyloid (Abeta) aggregation process has been disclosed. We present here, for the first time, a direct evidence of the Abeta antiaggregating action of an AChE inhibitor (AP2238) purposely designed to bind at both the catalytic and the peripheral sites of the human enzyme.
ESTHER : Piazzi_2003_J.Med.Chem_46_2279
PubMedSearch : Piazzi_2003_J.Med.Chem_46_2279
PubMedID: 12773032

Title : Acetylcholinesterase Inhibitors: SAR and Kinetic Studies on omega-[N-Methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxyaryl Derivatives - Rampa_2001_J.Med.Chem_44_3810
Author(s) : Rampa A , Piazzi L , Belluti F , Gobbi S , Bisi A , Bartolini M , Andrisano V , Cavrini V , Cavalli A , Recanatini M , Valenti P
Ref : Journal of Medicinal Chemistry , 44 :3810 , 2001
Abstract : In this work, we further investigated a class of carbamic cholinesterase inhibitors introduced in a previous paper (Rampa et al. J. Med. Chem. 1998, 41, 3976). Some new omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxyaryl analogues were designed, synthesized, and evaluated for their inhibitory activity against both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The structure of the lead compound (xanthostigmine) was systematically varied with the aim to optimize the different parts of the molecule. Moreover, such a structure-activity relationships (SAR) study was integrated with a kinetic analysis of the mechanism of AChE inhibition for two representative compounds. The structural modifications lead to a compound (12b) showing an IC(50) value for the AChE inhibition of 0.32 +/- 0.09 nM and to a group of BuChE inhibitors also active at the nanomolar level, the most potent of which (15d) was characterized by an IC(50) value of 3.3 +/- 0.4 nM. The kinetic analysis allowed for clarification of the role played by different molecular moieties with regard to the rate of AChE carbamoylation and the duration of inhibition. On the basis of the results presented here, it was concluded that the cholinesterase inhibitors of this class possess promising characteristics in view of a potential development as drugs for the treatment of Alzheimer's disease.
ESTHER : Rampa_2001_J.Med.Chem_44_3810
PubMedSearch : Rampa_2001_J.Med.Chem_44_3810
PubMedID: 11689067

Title : SAR of 9-amino-1,2,3,4-tetrahydroacridine-based acetylcholinesterase inhibitors: synthesis, enzyme inhibitory activity, QSAR, and structure-based CoMFA of tacrine analogues - Recanatini_2000_J.Med.Chem_43_2007
Author(s) : Recanatini M , Cavalli A , Belluti F , Piazzi L , Rampa A , Bisi A , Gobbi S , Valenti P , Andrisano V , Bartolini M , Cavrini V
Ref : Journal of Medicinal Chemistry , 43 :2007 , 2000
Abstract : In this study, we attempted to derive a comprehensive SAR picture for the class of acetylcholinesterase (AChE) inhibitors related to tacrine, a drug currently in use for the treatment of the Alzheimer's disease. To this aim, we synthesized and tested a series of 9-amino-1,2,3,4-tetrahydroacridine derivatives substituted in the positions 6 and 7 of the acridine nucleus and bearing selected groups on the 9-amino function. By means of the Hansch approach, QSAR equations were obtained, quantitatively accounting for both the detrimental steric effect of substituents in position 7 and the favorable electron-attracting effect exerted by substituents in positions 6 and 7 of the 9-amino-1,2,3,4-tetrahydroacridine derivatives. The three-dimensional (3D) properties of the inhibitors were taken into consideration by performing a CoMFA analysis on the series of AChE inhibitors made by 12 9-amino-1,2,3, 4-tetrahydroacridines and 13 11H-indeno[1,2-b]quinolin-10-ylamines previously developed in our laboratory. The alignment of the molecules to be submitted to the CoMFA procedure was carried out by taking advantage of docking models calculated for the interactions of both the unsubstituted 9-amino-1,2,3,4-tetrahydroacridine and 11H-indeno[1,2-b]quinolin-10-ylamine with the target enzyme. A highly significant CoMFA model was obtained using the steric field alone, and the features of such a 3D QSAR model were compared with the classical QSAR equations previously calculated. The two models appeared consistent, the main aspects they had in common being (a) the individuation of the strongly negative contribution of the substituents in position 7 of tacrine and (b) a tentative assignment of the hydrophobic character to the favorable effect exerted by the substituents in position 6. Finally, a new previously unreported tacrine derivative designed on the basis of both the classical and the 3D QSAR equations was synthesized and kinetically evaluated, to test the predictive ability of the QSAR models. The 6-bromo-9-amino-1,2,3,4-tetrahydroacridine was predicted to have a pIC(50) value of 7.31 by the classical QSAR model and 7.40 by the CoMFA model, while its experimental IC(50) value was equal to 0.066 (+/-0.009) microM, corresponding to a pIC(50) of 7.18, showing a reasonable agreement between predicted and observed AChE inhibition data.
ESTHER : Recanatini_2000_J.Med.Chem_43_2007
PubMedSearch : Recanatini_2000_J.Med.Chem_43_2007
PubMedID: 10821713

Title : Acetylcholinesterase inhibitors for potential use in Alzheimer's disease: molecular modeling, synthesis and kinetic evaluation of 11H-indeno-[1,2-b]-quinolin-10-ylamine derivatives - Rampa_2000_Bioorg.Med.Chem_8_497
Author(s) : Rampa A , Bisi A , Belluti F , Gobbi S , Valenti P , Andrisano V , Cavrini V , Cavalli A , Recanatini M
Ref : Bioorganic & Medicinal Chemistry , 8 :497 , 2000
Abstract : Continuing our work on tetracyclic tacrine analogues, we synthesized a series of acetylcholinesterase (AChE) inhibitors of 11H-indeno-[1,2-b]-quinolin-10-ylaminic structure. Selected substituents were placed in synthetically accessible positions of the tetracyclic nucleus, in order to explore the structure-activity relationships (SAR) and the mode of action of this class of anticholinesterases. A molecular modeling investigation of the binding interaction of the lead compound (1a) with the AChE active site was performed, from which it resulted that, despite the rather wide and rigid structure of 1a, there may still be the possibility to introduce some small substituent in some positions of the tetracycle. However, from the examination of the experimental IC50 values, it derived that the indenoquinoline nucleus probably represents the maximum allowable molecular size for rigid compounds binding to AChE. In fact, only a fluorine atom in position 2 maintains the AChE inhibitory potency of the parent compound, and, actually, increases the AChE-selectivity with respect to the butyrylcholinesterase inhibition. By studying the kinetics of AChE inhibition for two representative compounds of the series, it resulted that the lead compound (1a) shows an inhibition of mixed type, binding to both the active and the peripheral sites, while the more sterically hindered analogue 2n seems to interact only at the external binding site of the enzyme. This finding seems particularly important in the context of Alzheimer's disease research in the light of recent observations showing that peripheral AChE inhibitors might decrease the aggregating effects of the enzyme on the beta-amyloid peptide (betaA).
ESTHER : Rampa_2000_Bioorg.Med.Chem_8_497
PubMedSearch : Rampa_2000_Bioorg.Med.Chem_8_497
PubMedID: 10732965

Title : Acetylcholinesterase Inhibitors: Synthesis and Structure-Activity Relationships of omega-[N-Methyl-N-(3-alkylcarbamoyloxyphenyl)- methyl]aminoalkoxyheteroaryl Derivatives - Rampa_1998_J.Med.Chem_41_3976
Author(s) : Rampa A , Bisi A , Valenti P , Recanatini M , Cavalli A , Andrisano V , Cavrini V , Fin L , Buriani A , Giusti P
Ref : Journal of Medicinal Chemistry , 41 :3976 , 1998
Abstract : Acetylcholinesterase (AChE) inhibitors are one of the most actively investigated classes of compounds in the search for an effective treatment of Alzheimer's disease. This work describes the synthesis, AChE inhibitory activity, and structure-activity relationships of some compounds related to a recently discovered series of AChE inhibitors: the omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxy xanthen-9-ones. The influence of structural variations on the inhibitory potency was carefully investigated by modifying different parts of the parent molecule, and a theoretical model of the binding of one representative compound to the enzyme was developed. The biological properties of the series were investigated in some detail by considering not only the activity on isolated enzyme but the selectivity with respect to butyrylcholinesterase (BCHE) and the in vitro inhibitory activity on rat cerebral cortex as well. Some of the newly synthesized derivatives, when tested on isolated and/or AChE-enriched rat brain cortex fraction, displayed a selective inhibitory activity and were more active than physostigmine. In particular, compound 13, an azaxanthone derivative, displayed the best rat cortex AChE inhibition (190-fold higher than physostigmine), as well as a high degree of enzyme selectivity (over 60-fold more selective for AChE than for BCHE). When tested in the isolated enzyme, compound 13 was less active, suggesting some differences either in drug availability/biotransformation or in the inhibitor-sensitive residues of the enzyme when biologically positioned in rat brain membranes.
ESTHER : Rampa_1998_J.Med.Chem_41_3976
PubMedSearch : Rampa_1998_J.Med.Chem_41_3976
PubMedID: 9767635

Title : Chemiluminescence imaging in bioanalysis - Pasini_1998_J.Pharm.Biomed.Anal_18_555
Author(s) : Pasini P , Musiani M , Russo C , Valenti P , Aicardi G , Crabtree JE , Baraldini M , Roda A
Ref : J Pharm Biomed Anal , 18 :555 , 1998
Abstract : The development, analytical performance and applications of chemiluminescence imaging as a tool for quantitative analyte localization in target biological specimens are described. The detection of acetylcholinesterase activity both in array format and on a target surface are described. A proposed application of the method is a 384 well microtiter format assay for high throughput screening of acetylcholinesterase inhibitors such as tacrine, a drug widely used in the treatment of Alzheimer's disease, and two recently developed analogues. The chemiluminescent system in conjunction with optical microscopy allowed localization of acetylcholinesterase in brain tissue sections. We also describe the chemiluminescent immunohistochemical localization of interleukin 8 in Helicobacter pylori infected gastric mucosa cryosections and an in situ hybridization assay for the detection of herpes simplex virus DNA in single cells.
ESTHER : Pasini_1998_J.Pharm.Biomed.Anal_18_555
PubMedSearch : Pasini_1998_J.Pharm.Biomed.Anal_18_555
PubMedID: 9919955