Isabella Fiorini

Publications (32)123.99 Total impact

• Source

  Available from: Simone Brogi

  Dataset: movieS1

  Sandra Gemma, Caterina Camodeca, Margherita Brindisi, Simone Brogi, Gagan Kukreja, Sanil Kunjir, Emanuele Gabellieri, Leonardo Lucantoni, Annette Habluetzel, Donatella Taramelli, [......], Maria Rosa Moncelli, Rowena E Martin, Robert L Summers, Stefania Lamponi, Luisa Savini, Isabella Fiorini, Massimo Valoti, Ettore Novellino, Giuseppe Campiani, Stefania Butini
• Source

  Available from: Simone Brogi

  Dataset: movieS2

  Sandra Gemma, Caterina Camodeca, Margherita Brindisi, Simone Brogi, Gagan Kukreja, Sanil Kunjir, Emanuele Gabellieri, Leonardo Lucantoni, Annette Habluetzel, Donatella Taramelli, [......], Maria Rosa Moncelli, Rowena E Martin, Robert L Summers, Stefania Lamponi, Luisa Savini, Isabella Fiorini, Massimo Valoti, Ettore Novellino, Giuseppe Campiani, Stefania Butini
• Article: Mimicking the Intramolecular Hydrogen Bond: Synthesis, Biological Evaluation, and Molecular Modeling of Benzoxazines and Quinazolines as Potential Antimalarial Agents.

  Sandra Gemma, Caterina Camodeca, Margherita Brindisi, Simone Brogi, Gagan Kukreja, Sanil Kunjir, Emanuele Gabellieri, Leonardo Lucantoni, Annette Habluetzel, Donatella Taramelli, [......], Maria Rosa Moncelli, Rowena E Martin, Robert L Summers, Stefania Lamponi, Luisa Savini, Isabella Fiorini, Massimo Valoti, Ettore Novellino, Giuseppe Campiani, Stefania Butini
  [show abstract] [hide abstract]
  ABSTRACT: The intramolecular hydrogen bond formed between a protonated amine and a neighbouring H-bond acceptor group in the side chain of amodiaquine and isoquine is thought to play an important role in their antimalarial activities. Here we describe isoquine-based compounds in which the intramolecular H-bond is mimicked by a methylene linker. The antimalarial activities of the resulting benzoxazines, their isosteric tetrahydroquinazoline derivatives, and febrifugine-based 1,3-quinazolin-4-ones were examined in vitro (against Plasmodium falciparum) and in vivo (against P. berghei). Compounds 6b,c caused modest inhibition of chloroquine transport via the parasite's 'chloroquine resistance transporter' (PfCRT) in a Xenopus laevis oocyte expression system. In silico predictions and experimental evaluation of selected drug-like properties were also performed on compounds 6b,c. Compound 6c emerged from this work as the most promising scaffold of the series; it possessed low toxicity and good antimalarial activity when administered orally to P. berghei-infected mice.
  Journal of Medicinal Chemistry 11/2012; · 4.80 Impact Factor
• Article: Quinolylhydrazones as novel inhibitors of Plasmodium falciparum serine protease PfSUB1.

  Sandra Gemma, Simone Giovani, Margherita Brindisi, Pierangela Tripaldi, Simone Brogi, Luisa Savini, Isabella Fiorini, Ettore Novellino, Stefania Butini, Giuseppe Campiani, Maria Penzo, Michael J Blackman
  [show abstract] [hide abstract]
  ABSTRACT: Plasmodium falciparum subtilisin-like protease 1 (PfSUB1) is a serine protease that plays key roles in the egress of the parasite from red blood cells and in preparing the released merozoites for the subsequent invasion of new erythrocytes. The development of potent and selective PfSUB1 inhibitors could pave the way to the discovery of potential antimalarial drugs endowed with an innovative mode of action and consequently able to overcome the current problems of resistance to established chemotherapies. Through the screening of a proprietary library of compounds against PfSUB1, we identified hydrazone 2 as a hit compound. Here we report a preliminary investigation of the structure-activity relationships for a class of PfSUB1 inhibitors related to our identified hit.
  Bioorganic & medicinal chemistry letters 06/2012; 22(16):5317-21. · 2.65 Impact Factor
• Article: Enantioselective binding of second generation pyrrolobenzoxazepinones to the catalytic ternary complex of HIV-1 RT wild-type and L100I and K103N drug resistant mutants.

  Stefania Butini, Sandra Gemma, Margherita Brindisi, Giuseppe Borrelli, Isabella Fiorini, Alberta Samuele, Aristotele Karytinos, Marcella Facchini, Andrea Lossani, Samantha Zanoli, Giuseppe Campiani, Ettore Novellino, Federico Focher, Giovanni Maga
  [show abstract] [hide abstract]
  ABSTRACT: We investigated some pyrrolobenzoxazepinone (PBOs, 3e-i) analogues of early described effective non-nucleoside inhibitors of HIV-1 reverse transcriptase (RT). Enzymological studies of 3e-i enantiomers, with wild type (wt) RT and some drug-resistant mutants, revealed a stereoselective mode of action and selectivity for RT ternary complex. Unexpectedly (+)-3g was found more potent towards the L100I mutant than towards the wt RT, whereas (+)-3h inhibited the K103N mutant and RT wt with comparable potency.
  Bioorganic & medicinal chemistry letters 07/2011; 21(13):3935-8. · 2.65 Impact Factor
• Article: Pyrroloquinoxaline hydrazones as fluorescent probes for amyloid fibrils.

  Sandra Gemma, Laura Colombo, Gianluigi Forloni, Luisa Savini, Claudia Fracasso, Silvio Caccia, Mario Salmona, Margherita Brindisi, Bhupendra P Joshi, Pierangela Tripaldi, Gianluca Giorgi, Orazio Taglialatela-Scafati, Ettore Novellino, Isabella Fiorini, Giuseppe Campiani, Stefania Butini
  [show abstract] [hide abstract]
  ABSTRACT: Here we describe the identification and preliminary characterization of a new class of pyrrolo(imidazo)quinoxaline hydrazones as florescent probes for Aβ(1-42) fibrils. All the newly developed compounds were able to bind amyloid fibrils formed in vitro and some of them displayed an increase of their fluorescence upon binding. When tested on brain tissue preparations presenting Aβ deposits, the described hydrazones selectively stained amyloid structures and did not display aspecific binding. The hydrazones did not show antifibrillogenic activity and electron microscopy analysis revealed that they do not interfere with fibrils structure. The described pyrrolo(imidazo)quinoxalines could be useful for studying amyloid structures in vitro. Moreover, their experimentally proven ability to cross the blood-brain barrier in mouse opens the possibility of developing these compounds as potential amyloid imaging agents for in vivo applications.
  Organic & Biomolecular Chemistry 06/2011; 9(14):5137-48. · 3.70 Impact Factor
• Article: Non-nucleoside inhibitors of human adenosine kinase: synthesis, molecular modeling, and biological studies.

  Stefania Butini, Sandra Gemma, Margherita Brindisi, Giuseppe Borrelli, Andrea Lossani, Anna Maria Ponte, Andrea Torti, Giovanni Maga, Luciana Marinelli, Valeria La Pietra, Isabella Fiorini, Stefania Lamponi, Giuseppe Campiani, Daniela M Zisterer, Seema-Maria Nathwani, Stefania Sartini, Concettina La Motta, Federico Da Settimo, Ettore Novellino, Federico Focher
  [show abstract] [hide abstract]
  ABSTRACT: Adenosine kinase (AK) catalyzes the phosphorylation of adenosine (Ado) to AMP by means of a kinetic mechanism in which the two substrates Ado and ATP bind the enzyme in a binary and/or ternary complex, with distinct protein conformations. Most of the described inhibitors have Ado-like structural motifs and are nonselective, and some of them (e.g., the tubercidine-like ligands) are characterized by a toxic profile. We have cloned and expressed human AK (hAK) and searched for novel non-substrate-like inhibitors. Our efforts to widen the structural diversity of AK inhibitors led to the identification of novel non-nucleoside, noncompetitive allosteric modulators characterized by a unique molecular scaffold. Among the pyrrolobenzoxa(thia)zepinones (4a-qq) developed, 4a was identified as a non-nucleoside prototype hAK inhibitor. 4a has proapoptotic efficacy, slight inhibition of short-term RNA synthesis, and cytostatic activity on tumor cell lines while showing low cytotoxicity and no significant adverse effects on short-term DNA synthesis in cells.
  Journal of Medicinal Chemistry 02/2011; 54(5):1401-20. · 4.80 Impact Factor
• Article: Discovery of potent nucleotide-mimicking competitive inhibitors of hepatitis C virus NS3 helicase.

  Sandra Gemma, Stefania Butini, Giuseppe Campiani, Margherita Brindisi, Samantha Zanoli, Maria Pia Romano, Pierangela Tripaldi, Luisa Savini, Isabella Fiorini, Giuseppe Borrelli, Ettore Novellino, Giovanni Maga
  [show abstract] [hide abstract]
  ABSTRACT: Among the enzymes involved in the life cycle of HCV, the non-structural protein NS3, with its double function of protease and NTPase/helicase, is essential for the virus replication. Exploiting our previous knowledge in the development of nucleotide-mimicking NS3 helicase (NS3h) inhibitors endowed with key structural and electronic features necessary for an optimal ligand-enzyme interaction, we developed the tetrahydroacridinyl derivative 3a as the most potent NS3h competitive inhibitor reported to date (HCV NS3h K(i)=20 nM).
  Bioorganic & medicinal chemistry letters 09/2010; 21(9):2776-9. · 2.65 Impact Factor
• Article: Discovery of bishomo(hetero)arylpiperazines as novel multifunctional ligands targeting dopamine D(3) and serotonin 5-HT(1A) and 5-HT(2A) receptors.

  Stefania Butini, Giuseppe Campiani, Silvia Franceschini, Francesco Trotta, Vinod Kumar, Egeria Guarino, Giuseppe Borrelli, Isabella Fiorini, Ettore Novellino, Caterina Fattorusso, Marco Persico, Nausicaa Orteca, Karin Sandager-Nielsen, Thomas Amos Jacobsen, Kim Madsen, Jorgen Scheel-Kruger, Sandra Gemma
  [show abstract] [hide abstract]
  ABSTRACT: As a continuation of our efforts to develop innovative ligands for D(3), 5-HT(1A), and 5-HT(2A) receptors with low propensity to block hERG channels, we propose a series bishetero(homo)arylpiperazines 5a-m as novel and potent multifunctional ligands characterized by low occupancy at D(2) and 5-HT(2C) receptors.
  Journal of Medicinal Chemistry 06/2010; 53(12):4803-7. · 4.80 Impact Factor
• Article: Discovery of Bishomo(hetero)arylpiperazines as Novel Multifunctional Ligands Targeting Dopamine D3 and Serotonin 5-HT1A and 5-HT2A Receptors

  Stefania Butini, Giuseppe Campiani, Silvia Franceschini, Francesco Trotta, Vinod Kumar, Egeria Guarino, Giuseppe Borrelli, Isabella Fiorini, Ettore Novellino, Caterina Fattorusso, Marco Persico, Nausicaa Orteca, Karin Sandager-Nielsen, Thomas Amos Jacobsen, Kim Madsen, Jorgen Scheel-Kruger, Sandra Gemma
  [show abstract] [hide abstract]
  ABSTRACT: As a continuation of our efforts to develop innovative ligands for D3, 5-HT1A, and 5-HT2A receptors with low propensity to block hERG channels, we propose a series bishetero(homo)arylpiperazines 5a−m as novel and potent multifunctional ligands characterized by low occupancy at D2 and 5-HT2C receptors.
  05/2010;
• Article: Novel, potent, and selective quinoxaline-based 5-HT(3) receptor ligands. 1. Further structure-activity relationships and pharmacological characterization.

  Stefania Butini, Roberta Budriesi, Michel Hamon, Elena Morelli, Sandra Gemma, Margherita Brindisi, Giuseppe Borrelli, Ettore Novellino, Isabella Fiorini, Pierfranco Ioan, Alberto Chiarini, Alfredo Cagnotto, Tiziana Mennini, Claudia Fracasso, Silvio Caccia, Giuseppe Campiani
  [show abstract] [hide abstract]
  ABSTRACT: We investigated the pharmacological profile of a novel series of quinoxaline-based 5-HT(3) receptor ligands bearing an extra basic moiety on the piperazine N-4. High affinity and selectivity were dependent on the electronic properties of the substituents, and at cardiac level 3a and 3c modulated chronotropy but not inotropy. In von Bezold-Jarisch reflex test 3a-c were partial agonists while 3i was a full agonist. Preliminary pharmacokinetic studies indicated that 3a is a brain penetrating agent.
  Journal of Medicinal Chemistry 11/2009; 52(21):6946-50. · 4.80 Impact Factor
• Source

  Available from: Tiziana Mennini

  Article: Specific targeting of peripheral serotonin 5-HT(3) receptors. Synthesis, biological investigation, and structure-activity relationships.

  Elena Morelli, Sandra Gemma, Roberta Budriesi, Giuseppe Campiani, Ettore Novellino, Caterina Fattorusso, Bruno Catalanotti, Salvatore Sanna Coccone, Sindu Ros, Giuseppe Borrelli, [......], Vito Nacci, Pierfranco Ioan, Alberto Chiarini, Michel Hamon, Alfredo Cagnotto, Tiziana Mennini, Claudia Fracasso, Milena Colovic, Silvio Caccia, Stefania Butini
  [show abstract] [hide abstract]
  ABSTRACT: The synthesis and the biological characterization of novel highly selective pyrroloquinoxaline 5-HT(3) receptor (5-HT(3)R) ligands are described. In functional and in vivo biological studies the novel quinoxalines modulated cardiac parameters by direct interaction with myocardial 5-HT(3)Rs. The potent 5-HT(3)R ligands 4h and 4n modulate chronotropy (right atrium) but not inotropy (left atrium) at the cardiac level, being antagonist and partial agonist, respectively. Preliminary pharmacokinetic studies indicate that (S)-4n and 4a, representatives of the novel 5-HT(3)R ligands, possess poor blood-brain barrier permeability, being the prototypes of peripherally acting 5-HT(3)R modulators endowed with a clear-cut pharmacological activity at the cardiac level. The unique properties of 4h and 4n, compared to their previously described centrally active N-methyl analogue 5a, are mainly due to the hydrophilic groups at the distal piperazine nitrogen. These analogues represent novel pharmacological tools for investigating the role of peripheral 5-HT(3)R in the modulation of cardiac parameters.
  Journal of Medicinal Chemistry 06/2009; 52(11):3548-62. · 4.80 Impact Factor
• Article: Combining 4-aminoquinoline- and clotrimazole-based pharmacophores toward innovative and potent hybrid antimalarials.

  Sandra Gemma, Giuseppe Campiani, Stefania Butini, Bhupendra P Joshi, Gagan Kukreja, Salvatore Sanna Coccone, Matteo Bernetti, Marco Persico, Vito Nacci, Isabella Fiorini, [......], Vanessa Yardley, Simon Croft, Sonja Keller-Maerki, Matthias Rottmann, Reto Brun, Massimiliano Coletta, Stefano Marini, Giovanna Guiso, Silvio Caccia, Caterina Fattorusso
  [show abstract] [hide abstract]
  ABSTRACT: Antimalarial agents structurally based on novel pharmacophores, synthesized by low-cost synthetic procedures and characterized by low potential for developing resistance are urgently needed. Recently, we developed an innovative class of antimalarials based on a polyaromatic pharmacophore. Hybridizing the 4-aminoquinoline or the 9-aminoacridine system of known antimalarials with the clotrimazole-like pharmacophore, characterized by a polyarylmethyl group, we describe herein the development of a unique class (4a-l and 5a-c) of antimalarials selectively interacting with free heme and interfering with Plasmodium falciparum (Pf) heme metabolism. Combination of the polyarylmethyl system, able to form and stabilize radical intermediates, with the iron-complexing and conjugation-mediated electron transfer properties of the 4(9)-aminoquinoline(acridine) system led to potent antimalarials in vitro against chloroquine sensitive and resistant Pf strains. Among the compounds synthesized, 4g was active in vivo against P. chabaudi and P. berghei after oral administration and, possessing promising pharmacokinetic properties, it is a candidate for further preclinical development.
  Journal of Medicinal Chemistry 01/2009; 52(2):502-13. · 4.80 Impact Factor
• Source

  Available from: Tiziana Mennini

  Article: Discovery of a new class of potential multifunctional atypical antipsychotic agents targeting dopamine D3 and serotonin 5-HT1A and 5-HT2A receptors: design, synthesis, and effects on behavior.

  Stefania Butini, Sandra Gemma, Giuseppe Campiani, Silvia Franceschini, Francesco Trotta, Marianna Borriello, Nicoletta Ceres, Sindu Ros, Salvatore Sanna Coccone, Matteo Bernetti, [......], Vito Nacci, Isabella Fiorini, Ettore Novellino, Alfredo Cagnotto, Tiziana Mennini, Karin Sandager-Nielsen, Jesper Tobias Andreasen, Jorgen Scheel-Kruger, Jens D Mikkelsen, Caterina Fattorusso
  [show abstract] [hide abstract]
  ABSTRACT: Dopamine D(3) antagonism combined with serotonin 5-HT(1A) and 5-HT(2A) receptor occupancy may represent a novel paradigm for developing innovative antipsychotics. The unique pharmacological features of 5i are a high affinity for dopamine D(3), serotonin 5-HT(1A) and 5-HT(2A) receptors, together with a low affinity for dopamine D(2) receptors (to minimize extrapyramidal side effects), serotonin 5-HT(2C) receptors (to reduce the risk of obesity under chronic treatment), and for hERG channels (to reduce incidence of torsade des pointes). Pharmacological and biochemical data, including specific c-fos expression in mesocorticolimbic areas, confirmed an atypical antipsychotic profile of 5i in vivo, characterized by the absence of catalepsy at antipsychotic dose.
  Journal of Medicinal Chemistry 01/2009; 52(1):151-69. · 4.80 Impact Factor
• Article: 1H-cyclopentapyrimidine-2,4(1H,3H)-dione-related ionotropic glutamate receptors ligands. structure-activity relationships and identification of potent and Selective iGluR5 modulators.

  Stefania Butini, Darryl S Pickering, Elena Morelli, Salvatore Sanna Coccone, Francesco Trotta, Meri De Angelis, Egeria Guarino, Isabella Fiorini, Giuseppe Campiani, Ettore Novellino, Arne Schousboe, Jeppe K Christensen, Sandra Gemma
  [show abstract] [hide abstract]
  ABSTRACT: (S)-CPW399 ((S)-1) is a potent and excitotoxic AMPA receptor partial agonist. Modifying the cyclopentane ring of (S)-1, we developed two of the most potent and selective functional antagonists (5 and 7) for kainate receptor (KA-R) subunit iGluR5. Derivatives 5 and 7, with their unique pharmacological profile, may lead to a better understanding of the different roles and modes of action of iGluR1-5 subunits, paving the way for the synthesis of new potent, subunit selective iGluR5 modulators.
  Journal of Medicinal Chemistry 10/2008; 51(20):6614-8. · 4.80 Impact Factor
• Article: An efficient approach to chiral C8/C9-piperazino-substituted 1,4-benzodiazepin-2-ones as peptidomimetic scaffolds.

  Stefania Butini, Emanuele Gabellieri, Paul Brady Huleatt, Giuseppe Campiani, Silvia Franceschini, Margherita Brindisi, Sindu Ros, Salvatore Sanna Coccone, Isabella Fiorini, Ettore Novellino, Gianluca Giorgi, Sandra Gemma
  [show abstract] [hide abstract]
  ABSTRACT: A promising way to interfere with biological processes is through the modulation of protein-protein interactions by means of small molecules acting as peptidomimetics. The 1,4-benzodiazepine scaffold has been widely reported as a peptide-mimicking, pharmacogenic system. While several synthetic pathways to C6-8 substituted benzodiazepines have been disclosed, few 1,4-benzodiazepines substituted at C9 have been reported. Herein, we describe a versatile approach to introduce cyclic, protonatable functionality at C8/C9. Introduction of the piperazine system at C8 and C9 gave access to a unique functionalization of the versatile benzodiazepine skeleton, broadening tailoring options on the benzofused side of the molecule, and the possibility of discovering novel peptidomimetics potentially able to modulate protein-protein interactions. Coupling of activated amino acids with poorly reactive anilines under mild conditions, while avoiding racemization, gave easy access to these compounds. Efficient amino acid activation was obtained by exploiting the rapid formation of acid chlorides under low temperature and acid/base free conditions, using triphenylphosphine and hexachloroacetone. This procedure successfully resulted in high reaction yields, did not produce racemization (ee > 98%, as demonstrated by using chiral solvating agents), and was compatible with the acid sensitive protecting groups present in the substrates.
  The Journal of Organic Chemistry 10/2008; 73(21):8458-68. · 4.45 Impact Factor
• Article: Tacrine based human cholinesterase inhibitors: synthesis of peptidic-tethered derivatives and their effect on potency and selectivity.

  Stefania Butini, Egeria Guarino, Giuseppe Campiani, Margherita Brindisi, Salvatore Sanna Coccone, Isabella Fiorini, Ettore Novellino, Tatyana Belinskaya, Ashima Saxena, Sandra Gemma
  [show abstract] [hide abstract]
  ABSTRACT: Tacrine based reversible inhibitors of cholinesterases (ChEIs) containing peptidic tethers were synthesized to interact with specific regions at the gorge level, and their potency was determined with human (h) acetylcholinesterase and butyrylcholinesterase. Analogues 3i,j and 3l,m were identified as promising hits and may pave the way for the development of a new series of tacrine based enzyme selective hChEIs.
  Bioorganic & medicinal chemistry letters 09/2008; 18(19):5213-6. · 2.65 Impact Factor
• Article: Exploiting protein fluctuations at the active-site gorge of human cholinesterases: further optimization of the design strategy to develop extremely potent inhibitors.

  Stefania Butini, Giuseppe Campiani, Marianna Borriello, Sandra Gemma, Alessandro Panico, Marco Persico, Bruno Catalanotti, Sindu Ros, Margherita Brindisi, Marianna Agnusdei, Isabella Fiorini, Vito Nacci, Ettore Novellino, Tatyana Belinskaya, Ashima Saxena, Caterina Fattorusso
  [show abstract] [hide abstract]
  ABSTRACT: Protein conformational fluctuations are critical for biological functions, although the relationship between protein motion and function has yet to be fully explored. By a thorough bioinformatics analysis of cholinesterases (ChEs), we identified specific hot spots, responsible for protein fluctuations and functions, and those active-site residues that play a role in modulating the cooperative network among the key substructures. This drew the optimization of our design strategy to discover potent and reversible inhibitors of human acetylcholinesterase and butyrylcholinesterase (hAChE and hBuChE) that selectively interact with specific protein substructures. Accordingly, two tricyclic moieties differently spaced by functionalized linkers were investigated as molecular yardsticks to probe the finest interactions with specific hot spots in the hChE gorge. A number of SAR trends were identified, and the multisite inhibitors 3a and 3d were found to be the most potent inhibitors of hBuChE and hAChE known to date.
  Journal of Medicinal Chemistry 07/2008; 51(11):3154-70. · 5.25 Impact Factor
• Article: Clotrimazole scaffold as an innovative pharmacophore towards potent antimalarial agents: design, synthesis, and biological and structure-activity relationship studies.

  Sandra Gemma, Giuseppe Campiani, Stefania Butini, Gagan Kukreja, Salvatore Sanna Coccone, Bhupendra P Joshi, Marco Persico, Vito Nacci, Isabella Fiorini, Ettore Novellino, [......], Luisa Savini, Donatella Taramelli, Nicoletta Basilico, Silvia Parapini, Giulia Morace, Vanessa Yardley, Simon Croft, Massimiliano Coletta, Stefano Marini, Caterina Fattorusso
  [show abstract] [hide abstract]
  ABSTRACT: We describe herein the design, synthesis, biological evaluation, and structure-activity relationship (SAR) studies of an innovative class of antimalarial agents based on a polyaromatic pharmacophore structurally related to clotrimazole and easy to synthesize by low-cost synthetic procedures. SAR studies delineated a number of structural features able to modulate the in vitro and in vivo antimalarial activity. A selected set of antimalarials was further biologically investigated and displayed low in vitro toxicity on a panel of human and murine cell lines. In vitro, the novel compounds proved to be selective for free heme, as demonstrated in the beta-hematin inhibitory activity assay, and did not show inhibitory activity against 14-alpha-lanosterol demethylase (a fungal P450 cytochrome). Compounds 2, 4e, and 4n exhibited in vivo activity against P. chabaudi after oral administration and thus represent promising antimalarial agents for further preclinical development.
  Journal of Medicinal Chemistry 04/2008; 51(5):1278-94. · 5.25 Impact Factor
• Article: Specific targeting highly conserved residues in the HIV-1 reverse transcriptase primer grip region. Design, synthesis, and biological evaluation of novel, potent, and broad spectrum NNRTIs with antiviral activity.

  Caterina Fattorusso, Sandra Gemma, Stefania Butini, Paul Huleatt, Bruno Catalanotti, Marco Persico, Meri De Angelis, Isabella Fiorini, Vito Nacci, Anna Ramunno, Manuela Rodriquez, Giovanni Greco, Ettore Novellino, Alberto Bergamini, Stefano Marini, Massimo Coletta, Giovanni Maga, Silvio Spadari, Giuseppe Campiani
  [show abstract] [hide abstract]
  ABSTRACT: Pyrrolobenzoxazepinones (PBOs) represent a new class of human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) whose prototype is 5. Molecular modeling studies based on the X-ray structures of HIV-1 RT prompted the synthesis of novel analogues which were tested as anti-HIV agents. The PBO derivatives specifically designed to target the highly conserved amino acid residues within the beta12-beta13 hairpin, namely primer grip, proved to be very potent against the most common mutant enzymes, including the highly resistant K103N mutant strain. Structure-activity relationships (SARs) are discussed in terms of a possible interaction with the RT binding site, depending on the nature of the substituents at C-6. Among the pyrrolobenzoxazepines investigated, 15c appeared to be the most promising NNRTI of the series characterized by potent antiviral activity, broad spectrum, and low cytotoxicity. 15c showed synergistic antiviral activity with AZT.
  Journal of Medicinal Chemistry 12/2005; 48(23):7153-65. · 5.25 Impact Factor