Publications by authors named "Sandro Cosconati"

115 Publications

A novel smaller β-defensin-derived peptide is active against multidrug-resistant bacterial strains.

FASEB J 2021 12;35(12):e22026

Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Naples, Italy.

Antibiotic resistance is becoming a severe obstacle in the fight against acute and chronic infectious diseases that accompany most degenerative illnesses from neoplasia to osteo-arthritis and obesity. Currently, the race is on to identify pharmaceutical molecules or combinations of molecules able to prevent or reduce the insurgence and/or progression of infectivity. Attempts to substitute antibiotics with antimicrobial peptides have, thus far, met with little success against multidrug-resistant (MDR) bacterial strains. During the last decade, we designed and studied the activity and features of human β-defensin analogs, which are salt-resistant, and hence active also under high salt concentrations as, for instance, in cystic fibrosis. Herein, we describe the design, synthesis, and major features of a new 21 aa long molecule, peptide γ2. The latter derives from the γ-core of the β-defensin natural molecules, a small fragment of these molecules still bearing high antibacterial activity. We found that peptide γ2, which contains only one disulphide bond, recapitulates most of the biological properties of natural human β-defensins and can also counteract both Gram-positive and Gram-negative MDR bacterial strains and biofilm formation. Moreover, it has great stability in human serum thereby enhancing its antibacterial presence and activity without cytotoxicity in human cells. In conclusion, peptide γ2 is a promising new weapon also in the battle against intractable infectious diseases.
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http://dx.doi.org/10.1096/fj.202002330RRDOI Listing
December 2021

FEPrepare: A Web-Based Tool for Automating the Setup of Relative Binding Free Energy Calculations.

J Chem Inf Model 2021 09 14;61(9):4131-4138. Epub 2021 Sep 14.

Biomedical Research Foundation, Academy of Athens, 4 Soranou Ephessiou, 11527 Athens, Greece.

Relative binding free energy calculations in drug design are becoming a useful tool in facilitating lead binding affinity optimization in a cost- and time-efficient manner. However, they have been limited by technical challenges such as the manual creation of large numbers of input files to set up, run, and analyze free energy simulations. In this Application Note, we describe FEPrepare, a novel web-based tool, which automates the setup procedure for relative binding FEP calculations for the dual-topology scheme of NAMD, one of the major MD engines, using OPLS-AA force field topology and parameter files. FEPrepare provides the user with all necessary files needed to run a FEP/MD simulation with NAMD. FEPrepare can be accessed and used at https://feprepare.vi-seem.eu/.
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http://dx.doi.org/10.1021/acs.jcim.1c00215DOI Listing
September 2021

Carbonic anhydrase activation profile of indole-based derivatives.

J Enzyme Inhib Med Chem 2021 Dec;36(1):1783-1797

Department of Pharmacy, University of Pisa, Pisa, Italy.

Carbonic Anhydrase Activators (CAAs) could represent a novel approach for the treatment of Alzheimer's disease, ageing, and other conditions that require remedial achievement of spatial learning and memory therapy. Within a research project aimed at developing novel CAAs selective for certain isoforms, three series of indole-based derivatives were investigated. Enzyme activation assay on human CA I, II, VA, and VII isoforms revealed several effective micromolar activators, with promising selectivity profiles towards the brain-associated cytosolic isoform hCA VII. Molecular modelling studies suggested a theoretical model of the complex between hCA VII and the new activators and provide a possible explanation for their modulating as well as selectivity properties. Preliminary biological evaluations demonstrated that one of the most potent CAA is not cytotoxic and is able to increase the release of the brain-derived neurotrophic factor (BDNF) from human microglial cells, highlighting its possible application in the treatment of CNS-related disorders.
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http://dx.doi.org/10.1080/14756366.2021.1959573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344252PMC
December 2021

Tetrahydroquinazole-based secondary sulphonamides as carbonic anhydrase inhibitors: synthesis, biological evaluation against isoforms I, II, IV, and IX, and computational studies.

J Enzyme Inhib Med Chem 2021 Dec;36(1):1874-1883

Department of Pharmacy, University of Pisa, Pisa, Italy.

A library of variously decorated -phenyl secondary sulphonamides featuring the bicyclic tetrahydroquinazole scaffold was synthesised and biologically evaluated for their inhibitory activity against human carbonic anhydrase (hCA) I, II, IV, and IX. Of note, several compounds were identified showing submicromolar potency and excellent selectivity for the tumour-related hCA IX isoform. Structure-activity relationship data attained for various substitutions were rationalised by molecular modelling studies in terms of both inhibitory activity and selectivity.
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http://dx.doi.org/10.1080/14756366.2021.1956913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344263PMC
December 2021

PyRMD: A New Fully Automated AI-Powered Ligand-Based Virtual Screening Tool.

J Chem Inf Model 2021 08 16;61(8):3835-3845. Epub 2021 Jul 16.

DiSTABiF, University of Campania Luigi Vanvitelli, Via Vivaldi 43, 81100 Caserta, Italy.

Artificial intelligence (AI) algorithms are dramatically redefining the current drug discovery landscape by boosting the efficiency of its various steps. Still, their implementation often requires a certain level of expertise in AI paradigms and coding. This often prevents the use of these powerful methodologies by non-expert users involved in the design of new biologically active compounds. Here, the random matrix discriminant (RMD) algorithm, a high-performance AI method specifically tailored for the identification of new ligands, was implemented in a new fully automated tool, PyRMD. This ligand-based virtual screening tool can be trained using target bioactivity data directly downloaded from the ChEMBL repository without manual intervention. The software automatically splits the available training compounds into active and inactive sets and learns the distinctive chemical features responsible for the compounds' activity/inactivity. PyRMD was designed to easily screen millions of compounds in hours through an automated workflow and intuitive input files, allowing fine tuning of each parameter of the calculation. Additionally, PyRMD features a wealth of benchmark metrics, to accurately probe the model performance, which were used here to gauge its predictive potential and limitations. PyRMD is freely available on GitHub (https://github.com/cosconatilab/PyRMD) as an open-source tool.
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http://dx.doi.org/10.1021/acs.jcim.1c00653DOI Listing
August 2021

Quinolinonyl Non-Diketo Acid Derivatives as Inhibitors of HIV-1 Ribonuclease H and Polymerase Functions of Reverse Transcriptase.

J Med Chem 2021 06 9;64(12):8579-8598. Epub 2021 Jun 9.

Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma, p.le Aldo Moro 5, I-00185 Rome, Italy.

Novel anti-HIV agents are still needed to overcome resistance issues, in particular inhibitors acting against novel viral targets. The ribonuclease H (RNase H) function of the reverse transcriptase (RT) represents a validated and promising target, and no inhibitor has reached the clinical pipeline yet. Here, we present rationally designed non-diketo acid selective RNase H inhibitors (RHIs) based on the quinolinone scaffold starting from former dual integrase (IN)/RNase H quinolinonyl diketo acids. Several derivatives were synthesized and tested against RNase H and viral replication and found active at micromolar concentrations. Docking studies within the RNase H catalytic site, coupled with site-directed mutagenesis, and Mg titration experiments demonstrated that our compounds coordinate the Mg cofactor and interact with amino acids of the RNase H domain that are highly conserved among naïve and treatment-experienced patients. In general, the new inhibitors influenced also the polymerase activity of RT but were selective against RNase H vs the IN enzyme.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279492PMC
June 2021

Inhibition studies on carbonic anhydrase isoforms I, II, IV and IX with N-arylsubstituted secondary sulfonamides featuring a bicyclic tetrahydroindazole scaffold.

Eur J Med Chem 2021 Aug 24;220:113490. Epub 2021 Apr 24.

Department of Pharmacy, University of Pisa, Pisa, Italy.

Carbonic Anhydrases (CAs) are pharmaceutically relevant targets for the treatment of several disease conditions. The ubiquitous localization of these enzymes and the high homology shared by the different isoforms represent substantial impediments for the discovery of potential drugs devoid of off-target side effects. As a consequence, substantial efforts are still needed to allow for the full realization of the pharmacological potential of CA modulators. In this contribution, starting from our previous studies, we describe the synthesis of a set of new bicyclic tetrahydroindazoles featuring a secondary sulfonamide. Biological evaluation of the inhibitory activity against the hCA I, II, IV, and IX isoforms allowed drawing a structure-activity relationship profile that was rationalized through theoretical studies. This allowed dissecting the new molecules into the single portions influencing the zinc chelation properties and the selectivity profile thereby offering a new platform for the discovery of new isotype selective CA inhibitors.
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http://dx.doi.org/10.1016/j.ejmech.2021.113490DOI Listing
August 2021

Lead Discovery of SARS-CoV-2 Main Protease Inhibitors through Covalent Docking-Based Virtual Screening.

J Chem Inf Model 2021 04 30;61(4):2062-2073. Epub 2021 Mar 30.

DiSTABiF, University of Campania Luigi Vanvitelli, Via Vivaldi 43, Caserta 81100, Italy.

During almost all 2020, coronavirus disease 2019 (COVID-19) pandemic has constituted the major risk for the worldwide health and economy, propelling unprecedented efforts to discover drugs for its prevention and cure. At the end of the year, these efforts have culminated with the approval of vaccines by the American Food and Drug Administration (FDA) and the European Medicines Agency (EMA) giving new hope for the future. On the other hand, clinical data underscore the urgent need for effective drugs to treat COVID-19 patients. In this work, we embarked on a virtual screening campaign against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) M chymotrypsin-like cysteine protease employing our in-house database of peptide and non-peptide ligands characterized by different types of warheads acting as Michael acceptors. To this end, we employed the AutoDock4 docking software customized to predict the formation of a covalent adduct with the target protein. verification of the inhibition properties of the most promising candidates allowed us to identify two new lead inhibitors that will deserve further optimization. From the computational point of view, this work demonstrates the predictive power of AutoDock4 and suggests its application for the screening of large chemical libraries of potential covalent binders against the SARS-CoV-2 M enzyme.
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http://dx.doi.org/10.1021/acs.jcim.1c00184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8029447PMC
April 2021

Structure-Activity Relationship Studies on Oxazolo[3,4-]pyrazine Derivatives Leading to the Discovery of a Novel Neuropeptide S Receptor Antagonist with Potent Activity.

J Med Chem 2021 04 18;64(7):4089-4108. Epub 2021 Mar 18.

Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Via Luigi Borsari 46, 44121 Ferrara, Italy.

Neuropeptide S modulates important neurobiological functions including locomotion, anxiety, and drug abuse through interaction with its G protein-coupled receptor known as neuropeptide S receptor (NPSR). NPSR antagonists are potentially useful for the treatment of substance abuse disorders against which there is an urgent need for new effective therapeutic approaches. Potent NPSR antagonists have been discovered which, however, require further optimization of their pharmacological profile. This work describes a new series of NPSR antagonists of the oxazolo[3,4-]pyrazine class. The guanidine derivative exhibited nanomolar activity and 5-fold improved potency compared to , a reference pharmacological tool in this field. Compound can be considered a new tool for research studies on the translational potential of the NPSergic system. An in-depth molecular modeling investigation was also performed to gain new insights into the observed structure-activity relationships and provide an updated model of ligand/NPSR interactions.
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http://dx.doi.org/10.1021/acs.jmedchem.0c02223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041306PMC
April 2021

Olive Leaves and Hibiscus Flowers Extracts-Based Preparation Protect Brain from Oxidative Stress-Induced Injury.

Antioxidants (Basel) 2020 Sep 1;9(9). Epub 2020 Sep 1.

Dipartimento di Scienze della Vita, Università di Siena, Via Aldo Moro, 2, 53100 Siena, Italy.

Oxidative stress (OS) arising from tissue redox imbalance, critically contributes to the development of neurodegenerative disorders. Thus, natural compounds, owing to their antioxidant properties, have promising therapeutic potential. (PRES) is a nutraceutical product composed of leaves- and flowers-extracts of L. and L., respectively, the composition of which has been characterized by HPLC coupled to a UV-Vis and QqQ-Ms detector. As PRES possess antioxidant, antiapoptotic and anti-inflammatory properties, the aim of this study was to assess its neuroprotective effects in human neuroblastoma SH-SY5Y cells and in rat brain slices subjected to OS. PRES (1-50 µg/mL) reverted the decrease in viability as well as the increase in sub-diploid-, DAPI-and annexin V-positive-cells, reduced ROS formation, recovered the mitochondrial potential and caspase-3 and 9 activity changes caused by OS. PRES (50-100 µg/mL) neuroprotective effects occurred also in rat brain slices subjected to HO challenge. Finally, as the neuroprotective potential of PRES is strictly related to its penetration into the brain and a relatively good pharmacokinetic profile, an in-silico prediction of its components drug-like properties was carried out. The present results suggest the possibility of PRES as a nutraceutical, which could help in preventing neurodegenerative diseases.
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http://dx.doi.org/10.3390/antiox9090806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555463PMC
September 2020

Disulfide Bond Replacement with 1,4- and 1,5-Disubstituted [1,2,3]-Triazole on C-X-C Chemokine Receptor Type 4 (CXCR4) Peptide Ligands: Small Changes that Make Big Differences.

Chemistry 2020 Aug 20;26(44):10113-10125. Epub 2020 Jul 20.

DiSTABiF, University of Campania "Luigi Vanvitelli", Via Vivaldi 43, 81100, Caserta, Italy.

Here we investigated the structural and biological effects ensuing from the disulfide bond replacement of a potent and selective C-X-C chemokine receptor type 4 (CXCR4) peptide antagonist, with 1,4- and 1,5- disubstituted 1,2,3-triazole moieties. Both strategies produced candidates that showed high affinity and selectivity against CXCR4. Notably, when assessed for their ability to modulate the CXCL12-mediated cell migration, the 1,4-triazole variant conserved the antagonistic effect in the low-mid nanomolar range, while the 1,5-triazole one displayed the ability to activate the migration, becoming the first in class low-molecular-weight CXCR4 peptide agonist. By combining NMR and computational studies, we provided a valuable model that highlighted differences in the interactions of the two peptidomimetics with the receptor that could account for their different functional profile. Finally, we envisage that our findings could be translated to different GPCR-interacting peptides for the pursuit of novel chemical probes that could assist in dissecting the complex puzzle of this fundamental class of transmembrane receptors.
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http://dx.doi.org/10.1002/chem.202002468DOI Listing
August 2020

Peptidyl Vinyl Ketone Irreversible Inhibitors of Rhodesain: Modifications of the P2 Fragment.

ChemMedChem 2020 08 7;15(16):1552-1561. Epub 2020 Jul 7.

Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Annunziata, 98168, Messina, Italy.

In this paper, we report the design, synthesis and biological investigation of a series of peptidyl vinyl ketones obtained by modifying the P2 fragment of previously reported highly potent inhibitors of rhodesain, the main cysteine protease of Trypanosoma brucei rhodesiense. Investigation of the structure-activity relationship led us to identify new rhodesain inhibitors endowed with an improved selectivity profile (a selectivity index of up to 22 000 towards the target enzyme), and/or an improved antitrypanosomal activity in the sub-micromolar range.
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http://dx.doi.org/10.1002/cmdc.202000360DOI Listing
August 2020

Pyrrolyl Pyrazoles as Non-Diketo Acid Inhibitors of the HIV-1 Ribonuclease H Function of Reverse Transcriptase.

ACS Med Chem Lett 2020 May 5;11(5):798-805. Epub 2020 Mar 5.

Dipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, "Sapienza" Università di Roma, p.le Aldo Moro 5, I-00185 Roma, Italy.

Due to the biological liability of diketo acid (DKA) chain, we transferred this element of our previously reported anti-HIV-1 pyrrolyl derivatives to a non-DKA scaffold, obtaining a series of pyrrolyl-pyrazole carboxylic acids as new RNase H inhibitors. Among the newly synthesized derivatives, oxyphenylpyrrolyl-pyrazoles demonstrated inhibitory activities within the low micromolar/submicromolar range with compound being the most potent. Interestingly, all tested compounds showed up to 2 orders of magnitude of selectivity for RNase H vs integrase. Docking studies within the RNase H catalytic site, coupled with site-directed mutagenesis, showed the key structural features that could confer the ability to establish specific interactions within RNase H. Furthermore, they proved the ability of our compounds to interact with amino acids highly conserved among HIV-1 subspecies isolated among patients carrying drug-resistant variants. In the end, the newly discovered pyrazole carboxylic acid derivatives feature promising serum stability with respect to their corresponding DKAs.
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http://dx.doi.org/10.1021/acsmedchemlett.9b00617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236236PMC
May 2020

Development of Novel Benzodiazepine-Based Peptidomimetics as Inhibitors of Rhodesain from Trypanosoma brucei rhodesiense.

ChemMedChem 2020 06 5;15(11):995-1001. Epub 2020 May 5.

Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Annunziata, 98168, Messina, Italy.

Starting from the reversible rhodesain inhibitors 1 a-c, which have K values towards the target protease in the low-micromolar range, we have designed a series of peptidomimetics, 2 a-g, that contain a benzodiazepine scaffold as a β-turn mimetic; they are characterized by a specific peptide sequence for the inhibition of rhodesain. Considering that irreversible inhibition is strongly desirable in the case of a parasitic target, a vinyl ester moiety acting as Michael-acceptor was introduced as the warhead; this portion was functionalized in order to evaluate the size of corresponding enzyme pocket that could accommodate this substituent. With this investigation, we identified an irreversible rhodesain inhibitor (i. e., 2 g) with a k value of 90 000 M  min that showed antitrypanosomal activity in the low-micromolar range (EC =1.25 μM), this may be considered a promising lead compound in the drug-discovery process for treating human African trypanosomiasis (HAT).
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http://dx.doi.org/10.1002/cmdc.202000158DOI Listing
June 2020

Two novel SIRT1 activators, SCIC2 and SCIC2.1, enhance SIRT1-mediated effects in stress response and senescence.

Epigenetics 2020 Jun - Jul;15(6-7):664-683. Epub 2020 Jan 16.

Dipartimento di Medicina di Precisione, Università degli Studi della Campania "Luigi Vanvitelli" Napoli , Napoli, Italy.

SIRT1, a NAD-dependent deacetylase, is the most well-studied member of class III histone deacetylases. Due to its wide range of activities and substrate targets, this enzyme has emerged as a major regulator of different physiological processes. However, SIRT1-mediated alterations are also implicated in the pathogenesis of several conditions, including metabolic and neurodegenerative disorders, and cancer. Current evidence highlights the potential role of SIRT1 as an attractive therapeutic target for disease prevention and treatment strategies, thus propelling the development of new pharmacological agents. By high-throughput screening of a large library of compounds, we identified SCIC2 as an effective SIRT1 activator. This small molecule showed enzymatic activity of 135.8% at 10 μM, an AC value of 50 ± 1.8 µM, and bound SIRT1 with a K of 26.4 ± 0.6 μM. In order to potentiate its SIRT1-activating ability, SCIC2 was subjected to modelling studies, leading to the identification of a more potent derivative, SCIC2.1. SCIC2.1 displayed higher SIRT1 activity (175%; AC = 36.83 ± 2.23 µM), stronger binding to SIRT1, and greater cell permeability than SCIC2. At cellular level, both molecules did not alter the cell cycle progression of cancer cells and normal cells, and were able to strengthen SIRT1-mediated effects in stress response. Finally, SCIC2 and SCIC2.1 attenuated induction of senescence by reducing senescence-associated β-galactosidase activity. Our findings warrant further investigation of these two novel SIRT1 activators in and human studies.
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http://dx.doi.org/10.1080/15592294.2019.1704349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574383PMC
May 2021

Inhibition of Histone Demethylases LSD1 and UTX Regulates ERα Signaling in Breast Cancer.

Cancers (Basel) 2019 Dec 16;11(12). Epub 2019 Dec 16.

Department of Precision Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy.

In breast cancer, Lysine-specific demethylase-1 (LSD1) and other lysine demethylases (KDMs), such as Lysine-specific demethylase 6A also known as Ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX), are co-expressed and co-localize with estrogen receptors (ERs), suggesting the potential use of hybrid (epi)molecules to target histone methylation and therefore regulate/redirect hormone receptor signaling. Here, we report on the biological activity of a dual-KDM inhibitor (MC3324), obtained by coupling the chemical properties of tranylcypromine, a known LSD1 inhibitor, with the 2OG competitive moiety developed for JmjC inhibition. MC3324 displays unique features not exhibited by the single moieties and well-characterized mono-pharmacological inhibitors. Inhibiting LSD1 and UTX, MC3324 induces significant growth arrest and apoptosis in hormone-responsive breast cancer model accompanied by a robust increase in H3K4me2 and H3K27me3. MC3324 down-regulates ERα in breast cancer at both transcriptional and non-transcriptional levels, mimicking the action of a selective endocrine receptor disruptor. MC3324 alters the histone methylation of ERα-regulated promoters, thereby affecting the transcription of genes involved in cell surveillance, hormone response, and death. MC3324 reduces cell proliferation in ex vivo breast cancers, as well as in breast models with acquired resistance to endocrine therapies. Similarly, MC3324 displays tumor-selective potential in vivo, in both xenograft mice and chicken embryo models, with no toxicity and good oral efficacy. This epigenetic multi-target approach is effective and may overcome potential mechanism(s) of resistance in breast cancer.
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http://dx.doi.org/10.3390/cancers11122027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966629PMC
December 2019

Discovery of dihydroxyindole-2-carboxylic acid derivatives as dual allosteric HIV-1 Integrase and Reverse Transcriptase associated Ribonuclease H inhibitors.

Antiviral Res 2020 02 5;174:104671. Epub 2019 Dec 5.

Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria SS554, 09042, Monserrato (CA), Italy.

The management of Human Immunodeficiency Virus type 1 (HIV-1) infection requires life-long treatment that is associated with chronic toxicity and possible selection of drug-resistant strains. A new opportunity for drug intervention is offered by antivirals that act as allosteric inhibitors targeting two viral functions (dual inhibitors). In this work, we investigated the effects of 5,6-dihydroxyindole-2-carboxylic acid (DHICA) derivatives on both HIV-1 Integrase (IN) and Reverse Transcriptase associated Ribonuclease H (RNase H) activities. Among the tested compounds, the dihydroxyindole-carboxamide 5 was able to inhibit in the low micromolar range (1-18 μM) multiple functions of IN, including functional IN-IN interactions, IN-LEDGF/p75 binding and IN catalytic activity. Docking and site-directed mutagenesis studies have suggested that compound 5 binds to a previously described HIV-1 IN allosteric pocket. These observations indicate that 5 is structurally and mechanistically distinct from the published allosteric HIV-1 IN inhibitors. Moreover, compound 5 also inhibited HIV-1 RNase H function, classifying this molecule as a dual HIV-1 IN and RNase H inhibitor able to impair the HIV-1 virus replication in cell culture. Overall, we identified a new scaffold as a suitable platform for the development of novel dual HIV-1 inhibitors.
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http://dx.doi.org/10.1016/j.antiviral.2019.104671DOI Listing
February 2020

Optimization Strategy of Novel Peptide-Based Michael Acceptors for the Treatment of Human African Trypanosomiasis.

J Med Chem 2019 12 27;62(23):10617-10629. Epub 2019 Nov 27.

Department of Chemical, Biological, Pharmaceutical and Environmental Sciences , University of Messina, Italy , Viale Annunziata , 98168 Messina , Italy.

This paper describes an optimization strategy of the highly active vinyl ketone which was recognized as a strong inhibitor of rhodesain of , endowed with a value of 67 × 10 M min coupled with a high binding affinity ( = 38 pM). We now report a new structure-activity relationship study based on structural variations on the P3, P2, and P1' sites which led us to identify two potent lead compounds, i.e., vinyl ketones and . Vinyl ketone showed an impressive potency toward rhodesain ( = 8811 × 10) coupled to a good antiparasitic activity (EC = 3.6 μM), while vinyl ketone proved to possess the highest binding affinity toward the trypanosomal protease ( = 0.6 pM) and a submicromolar antiparasitic activity (EC = 0.67 μM), thus representing new lead compounds in the drug discovery process for the treatment of Human African Trypanosomiasis.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00908DOI Listing
December 2019

Novel 2-substituted-benzimidazole-6-sulfonamides as carbonic anhydrase inhibitors: synthesis, biological evaluation against isoforms I, II, IX and XII and molecular docking studies.

J Enzyme Inhib Med Chem 2019 Dec;34(1):1697-1710

Department of Pharmacy, Universy of Pisa , Pisa , Italy.

Inhibition of Carbonic Anhydrases (CAs) has been clinically exploited for many decades for a variety of therapeutic applications. Within a research project aimed at developing novel classes of CA inhibitors (CAIs) with a proper selectivity for certain isoforms, a series of derivatives featuring the 2-substituted-benzimidazole-6-sulfonamide scaffold, conceived as frozen analogs of Schiff bases and secondary amines previously reported in the literature as CAIs, were investigated. Enzyme inhibition assays on physiologically relevant human CA I, II, IX and XII isoforms revealed a number of potent CAIs, showing promising selectivity profiles towards the transmembrane tumor-associated CA IX and XII enzymes. Computational studies were attained to clarify the structural determinants behind the activities and selectivity profiles of the novel inhibitors.
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http://dx.doi.org/10.1080/14756366.2019.1666836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6758606PMC
December 2019

Boosting Fmoc Solid-Phase Peptide Synthesis by Ultrasonication.

Org Lett 2019 08 30;21(16):6378-6382. Epub 2019 Jul 30.

DiSTABiF , Università degli Studi della Campania "Luigi Vanvitelli" , via A. Vivaldi 43 , 81100 Caserta , Italy.

We investigated the ultrasonication-mediated effects on the Fmoc-based solid-phase peptide synthesis (SPPS). Our study culminated with the development of an ultrasound-assisted strategy (US-SPPS) that allowed for the synthesis of different biologically active peptides (up to 44-mer), with a remarkable savings of material and reaction time. Noteworthy, ultrasonic irradiation did not exacerbate the main side reactions and improved the synthesis of peptides endowed with "difficult sequences", placing the US-SPPS among the current high-efficient peptide synthetic strategies.
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http://dx.doi.org/10.1021/acs.orglett.9b02283DOI Listing
August 2019

Unbinding of Translocator Protein 18 kDa (TSPO) Ligands: From in Vitro Residence Time to in Vivo Efficacy via in Silico Simulations.

ACS Chem Neurosci 2019 08 3;10(8):3805-3814. Epub 2019 Jul 3.

DiSTABiF , University of Campania "Luigi Vanvitelli" , Via Vivaldi 43 , 81100 Caserta , Italy.

Translocator protein 18 kDa (TSPO) is a validated pharmacological target for the development of new treatments for neurological disorders. ,-Dialkyl-2-phenylindol-3-ylglyoxylamides (PIGAs) are effective TSPO modulators and potentially useful therapeutics for the treatment of anxiety, central nervous system pathologies featuring astrocyte loss, and inflammatory-based neuropathologies. For this class of compounds, no correlation exists between the TSPO binding affinity and the corresponding functional efficacy. Rather, their biological effectiveness correlates with the kinetics of the unbinding events and more specifically with the residence time (RT). So far, the structural reasons for the different recorded RT of congeneric PIGAs remain elusive. Here, to understand the different kinetics of PIGAs, their unbinding paths were studied by employing enhanced-sampling molecular dynamics simulations. Results of these studies revealed how subtle structural differences between PIGAs have a substantial effect on the unbinding energetics. In particular, during the egress from the TSPO binding site, slow-dissociating PIGAs find tight interactions with the protein LP1 region thereby determining a long RT. Further support to these findings was achieved by in vivo studies, which demonstrated how the anxiolytic effect observed for the inspected PIGAs correlated with their RT to TSPO.
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http://dx.doi.org/10.1021/acschemneuro.9b00300DOI Listing
August 2019

Identification of novel indole derivatives acting as inhibitors of the Keap1-Nrf2 interaction.

J Enzyme Inhib Med Chem 2019 Dec;34(1):1152-1157

c Dipartimento di Salute della Donna e del Bambino , Università di Padova , Padua , Italy.

Nine indole derivatives () were tested as potential inhibitors of the Keap1-Nrf2 interaction. This class of compounds increases the intracellular levels of the transcription factor Nrf2 and the consequent expression of enzymes encoded by genes containing the antioxidant response element (ARE). In the ARE-luciferase reporter assay only - revealed to be remarkably more active than -butylhydroxyquinone (-BHQ), with standing out as the best performing compound. While and are weak acids, is an ampholyte prevailing as a zwitterion in neutral aqueous solutions. The ability of to significantly increase levels of Nrf2, NADPH:quinone oxidoreductase 1, and transketolase (TKT) gave further support to the hypothesis that these compounds act as inhibitors of the Keap1-Nrf2 interaction. Docking simulations allowed us to elucidate the nature of the putative interactions between and Keap1.
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http://dx.doi.org/10.1080/14756366.2019.1623209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567006PMC
December 2019

Discovery of Pyrido[3',2':5,6]thiopyrano[4,3-]pyrimidine-Based Antiproliferative Multikinase Inhibitors.

ACS Med Chem Lett 2019 Apr 17;10(4):457-462. Epub 2019 Jan 17.

Dipartimento di Scienze del Farmaco, Università di Padova, Via Marzolo 5, 35131 Padova, Italy.

Protein kinases dysregulation is extremely common in cancer cells, and the development of new agents able to simultaneously target multiple kinase pathways involved in angiogenesis and tumor growth may offer several advantages in the treatment of cancer. Herein we report the discovery of new pyridothiopyranopyrimidine derivatives (-) showing high potencies in VEGFR-2 KDR inhibition as well as antiproliferative effect on a panel of human tumor cell lines. Investigation on the selectivity profile of the representative 2-anilino-substituted compounds , , and revealed a multiplicity of kinase targets that should account for the potent antiproliferative effect produced by these pyridothiopyranopyrimidine derivatives.
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http://dx.doi.org/10.1021/acsmedchemlett.8b00499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466516PMC
April 2019

4-Imidazo[2,1-b]thiazole-1,4-DHPs and neuroprotection: preliminary study in hits searching.

Eur J Med Chem 2019 May 4;169:89-102. Epub 2019 Mar 4.

Department of Pharmacy and Biotecnology (FaBit), Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy. Electronic address:

In the present work we describe the synthesis, characterization and evaluation of neuroprotective effects of a focused library of 4-imidazo[2,1-b]thiazole-1,4-dihydropyridines. Furthermore, the new dihydropyridines were subjected to functional in vitro assays in cardiac tissues and vascular smooth muscle to determine their possible selectivity in counteracting the effects of neurodegeneration. In particular the strategy adopted for designing the compounds involves the imidazo[2,1-b]thiazole nucleus. The observed properties show that substituents at C2 and C6 of the bicyclic scaffold are able to influence the cardiovascular parameters and the neuroprotective activity. In comparison to nifedipine, a set of derivatives such as compound 6, showed a neuroprotective profile of particular interest.
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http://dx.doi.org/10.1016/j.ejmech.2019.02.075DOI Listing
May 2019

Discovery of a Novel Chemotype of Histone Lysine Methyltransferase EHMT1/2 (GLP/G9a) Inhibitors: Rational Design, Synthesis, Biological Evaluation, and Co-crystal Structure.

J Med Chem 2019 03 26;62(5):2666-2689. Epub 2019 Feb 26.

Department of Molecular and Cellular Oncology , The University of Texas MD Anderson Cancer Center , Houston , Texas 77030 , United States.

Since the discovery of compound BIX01294 over 10 years ago, only a very limited number of nonquinazoline inhibitors of H3K9-specific methyltransferases G9a and G9a-like protein (GLP) have been reported. Herein, we report the identification of a novel chemotype for G9a/GLP inhibitors, based on the underinvestigated 2-alkyl-5-amino- and 2-aryl-5-amino-substituted 3 H-benzo[ e][1,4]diazepine scaffold. Our research efforts resulted in the identification 12a (EML741), which not only maintained the high in vitro and cellular potency of its quinazoline counterpart, but also displayed improved inhibitory potency against DNA methyltransferase 1, improved selectivity against other methyltransferases, low cell toxicity, and improved apparent permeability values in both parallel artificial membrane permeability assay (PAMPA) and blood-brain barrier-specific PAMPA, and therefore might potentially be a better candidate for animal studies. Finally, the co-crystal structure of GLP in complex with 12a provides the basis for the further development of benzodiazepine-based G9a/GLP inhibitors.
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http://dx.doi.org/10.1021/acs.jmedchem.8b02008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430049PMC
March 2019

Tailoring a lead-like compound targeting multiple G-quadruplex structures.

Eur J Med Chem 2019 Feb 27;163:295-306. Epub 2018 Nov 27.

Department of Chemical Sciences, University of Naples Federico II, 80126, Naples, Italy. Electronic address:

A focused library of analogs of a lead-like G-quadruplex (G4) targeting compound (4), sharing a furobenzoxazine naphthoquinone core and differing for the pendant groups on the N-atom of the oxazine ring, has been here analyzed with the aim of developing more potent and selective ligands. These molecules have been tested vs. topologically different G4s by the G4-CPG assay, an affinity chromatography-based method for screening putative G4 ligands. The obtained results showed that all these compounds were able to bind several G4 structures, both telomeric and extra-telomeric, thus behaving as multi-target ligands, and two of them fully discriminated G4 vs. duplex DNA. Biological assays proved that almost all the compounds produced effective DNA damage, showing marked antiproliferative effects on tumor cells in the low μM range. Combined analysis of the G4-CPG binding assays and biological data led us to focus on compound S4-5, proved to be less cytotoxic than the parent compound 4 on normal cells. An in-depth biophysical characterization of the binding of S4-5 to different G4s showed that the here identified ligand has higher affinity for the G4s and higher ability to discriminate G4 vs. duplex DNA than 4. Molecular docking studies, in agreement with the NMR data, suggest that S4-5 interacts with the accessible grooves of the target G4 structures, giving clues for its increased G4 vs. duplex selectivity.
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http://dx.doi.org/10.1016/j.ejmech.2018.11.058DOI Listing
February 2019

Studies on enantioselectivity of chiral 4-acetylamino-6-alkyloxy-2-alkylthiopyrimidines acting as antagonists of the human A adenosine receptor.

Medchemcomm 2018 Jan 9;9(1):81-86. Epub 2017 Nov 9.

Dipartimento di Farmacia , Università di Pisa , Via Bonanno Pisano 6 , 56126 Pisa , Italy.

Three A adenosine receptor (AR) antagonists () selected from 4-acylamino-6-alkyloxy-2-alkylthiopyrimidines previously investigated by us were modified by inserting a methyl group on their ether or thioether side chains. These compounds gave us the chance to evaluate whether their higher lipophilicity, reduced conformational freedom and chirality might improve the potency towards the A AR. Racemic mixtures of were resolved using chiral HPLC methods and the absolute configurations of the enantiomers were assigned by chiroptical spectroscopy and density functional theory calculations. We measured the affinity for human A, A, A and A ARs of the racemic mixtures and the pure enantiomers of by radioligand competition binding experiments. Cell-based assays of the most potent enantiomers confirmed their A AR antagonist profiles. Our research led to the identification of ()- with high potency (0.5 nM) and selectivity as an A AR antagonist. Moreover we built a docking-model useful to design new pyrimidine derivatives.
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http://dx.doi.org/10.1039/c7md00375gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072526PMC
January 2018

4-Substituted Benzenesulfonamides Incorporating Bi/Tricyclic Moieties Act as Potent and Isoform-Selective Carbonic Anhydrase II/IX Inhibitors.

J Med Chem 2018 07 27;61(13):5765-5770. Epub 2018 Jun 27.

Dipartimento di Farmacia , Università di Pisa , Via Bonanno 6 , 56126 Pisa , Italy.

As a part of our efforts to expand chemical diversity in the carbonic anhydrases inhibitors (CAIs), three small series of polyheterocyclic compounds (4-6) featuring the primary benzenesulfonamide moiety linked to bi/tricyclic scaffolds were investigated. Highly effective inhibitors against the target tumor-associated hCA IX (low nanomolar/subnanomolar potency levels) showing significant functional selectivity profile toward hCA I, II, and IV isozymes were identified. Molecular docking studies clarified the reasons behind the activity and selectivity of the new compounds.
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http://dx.doi.org/10.1021/acs.jmedchem.8b00670DOI Listing
July 2018

Antitumor efficacy of Kisspeptin in human malignant mesothelioma cells.

Oncotarget 2018 Apr 10;9(27):19273-19282. Epub 2018 Apr 10.

Oncologia Medica, Dipartimento di Internistica Clinica e Sperimentale "F. Magrassi", Università degli Studi della Campania Luigi Vanvitelli, Naples, Italy.

Purpose: Kisspeptin signaling, its receptors GPR54, could be an essential players in the inhibition of mesothelioma progression, invasion and metastasis formation. The loss of KiSS1 by tumor cells has been associated with a metastatic phenotype but the mechanistic insights of this process are still unknown.

Experimental Design: The blockade of the metastatic process at early stage is a hot topic in cancer research. We studied the role of KiSS1 on proliferation, invasiveness, migration abilities of mesothelioma cell lines focusing on the effect on epithelial-to-mesenchymal transition (EMT).

Results: Treatment with the KiSS1 peptide or with a synthesis peptide with longer half-life, the FTM080, significantly inhibited cell proliferation, migration and invasion of mesothelioma cell lines; the same treatment reduced the activity of MMP-2 and MMP-9 determining consequently a marked reduction in the invasiveness of primary tumors and metastases. Thespecificexpression of EMT markers, as E-caderin, Vimentin, Slug and Snail, suggested the inhibition of EMT after treatment with KiSS1 as well as the preservation of epithelial components.

Conclusion: Our results support anti-proliferative effect of KiSS1 in cancer cells and suggest that targeting the KiSS1/GPR54 system may represent a novel therapeutic approach for mesothelioma.
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http://dx.doi.org/10.18632/oncotarget.25018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922395PMC
April 2018

Cationic nucleopeptides as novel non-covalent carriers for the delivery of peptide nucleic acid (PNA) and RNA oligomers.

Bioorg Med Chem 2018 05 7;26(9):2539-2550. Epub 2018 Apr 7.

Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Via Vivaldi 43, 81100 Caserta, Italy. Electronic address:

Cationic nucleopeptides belong to a family of synthetic oligomers composed by amino acids and nucleobases. Their capability to recognize nucleic acid targets and to cross cellular membranes provided the basis for considering them as novel non-covalent delivery agents for nucleic acid pharmaceuticals. Herein, starting from a 12-mer nucleopeptide model, the number of cationic residues was modulated in order to obtain new nucleopeptides endowed with high solubility in acqueous medium, acceptable bio-stability, low cytotoxicity and good capability to bind nucleic acid. Two candidates were selected to further investigate their potential as nucleic acid carriers, showing higher efficiency to deliver PNA in comparison with RNA. Noteworthy, this study encourages the development of nucleopeptides as new carriers to extend the known strategies for those nucleic acid analogues, especially PNA, that still remain difficult to drive into the cells.
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http://dx.doi.org/10.1016/j.bmc.2018.04.017DOI Listing
May 2018
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