Publications by authors named "Sandra Gemma"

107 Publications

Selective Fatty Acid Amide Hydrolase Inhibitors as Potential Novel Antiepileptic Agents.

ACS Chem Neurosci 2021 May 23;12(9):1716-1736. Epub 2021 Apr 23.

Laboratory of Neurophysiology, Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, MSD2080 Msida, Malta.

Temporal lobe epilepsy is the most common form of epilepsy, and current antiepileptic drugs are ineffective in many patients. The endocannabinoid system has been associated with an on-demand protective response to seizures. Blocking endocannabinoid catabolism would elicit antiepileptic effects, devoid of psychotropic effects. We herein report the discovery of selective anandamide catabolic enzyme fatty acid amide hydrolase (FAAH) inhibitors with promising antiepileptic efficacy, starting from a further investigation of our prototypical inhibitor . When tested in two rodent models of epilepsy, reduced the severity of the pilocarpine-induced status epilepticus and the elongation of the hippocampal maximal dentate activation. Notably, did not affect hippocampal dentate gyrus long-term synaptic plasticity. These data prompted our further endeavor aiming at discovering new antiepileptic agents, developing a new set of FAAH inhibitors (-). Biological studies highlighted and as the best performing analogues to be further investigated. In cell-based studies, using a neuroblastoma cell line, and could reduce the oxinflammation state by decreasing DNA-binding activity of NF-kB p65, devoid of cytotoxic effect. Unwanted cardiac effects were excluded for (Langendorff perfused rat heart). Finally, the new analogue reduced the severity of the pilocarpine-induced status epilepticus as observed for .
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http://dx.doi.org/10.1021/acschemneuro.1c00192DOI Listing
May 2021

Synthesis and biological evaluation of benzhydryl-based antiplasmodial agents possessing Plasmodium falciparum chloroquine resistance transporter (PfCRT) inhibitory activity.

Eur J Med Chem 2021 Apr 6;215:113227. Epub 2021 Feb 6.

Department of Biotechnology, Chemistry and Pharmacy (DoE 2018-2022), University of Siena, Via Aldo Moro 2, 53100 Siena, Italy; Centro Interuniversitario di Ricerche Sulla Malaria (CIRM), University of Milan, Milano, Italy.

Due to the surge in resistance to common therapies, malaria remains a significant concern to human health worldwide. In chloroquine (CQ)-resistant (CQ-R) strains of Plasmodium falciparum, CQ and related drugs are effluxed from the parasite's digestive vacuole (DV). This process is mediated by mutant isoforms of a protein called CQ resistance transporter (PfCRT). CQ-R strains can be partially re-sensitized to CQ by verapamil (VP), primaquine (PQ) and other compounds, and this has been shown to be due to the ability of these molecules to inhibit drug transport via PfCRT. We have previously developed a series of clotrimazole (CLT)-based antimalarial agents that possess inhibitory activity against PfCRT (4a,b). In our endeavor to develop novel PfCRT inhibitors, and to perform a structure-activity relationship analysis, we synthesized a new library of analogues. When the benzhydryl system was linked to a 4-aminoquinoline group (5a-f) the resulting compounds exhibited good cytotoxicity against both CQ-R and CQ-S strains of P. falciparum. The most potent inhibitory activity against the PfCRT-mediated transport of CQ was obtained with compound 5k. When compared to the reference compound, benzhydryl analogues of PQ (5i,j) showed a similar activity against blood-stage parasites, and a stronger in vitro potency against liver-stage parasites. Unfortunately, in the in vivo transmission blocking assays, 5i,j were inactive against gametocytes.
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http://dx.doi.org/10.1016/j.ejmech.2021.113227DOI Listing
April 2021

Spiroindoline-Capped Selective HDAC6 Inhibitors: Design, Synthesis, Structural Analysis, and Biological Evaluation.

ACS Med Chem Lett 2020 Nov 29;11(11):2268-2276. Epub 2020 Sep 29.

Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323, United States.

Histone deacetylase inhibitors (HDACi) have emerged as promising therapeutics for the treatment of neurodegeneration, cancer, and rare disorders. Herein, we report the development of a series of spiroindoline-based HDAC6 isoform-selective inhibitors based on the X-ray crystal studies of the hit . We identified compound as the most potent and selective HDAC6 inhibitor of the series. Biological investigation of compounds , , and demonstrated their antiproliferative activity against several cancer cell lines. Western blotting studies indicated that they were able to increase tubulin acetylation, without significant variation in histone acetylation state, and induced PARP cleavage indicating their apoptotic potential at the molecular level. induced HDAC6-dependent pSTAT3 inhibition.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667836PMC
November 2020

Novel quinolone-based potent and selective HDAC6 inhibitors: Synthesis, molecular modeling studies and biological investigation.

Eur J Med Chem 2021 Feb 7;212:112998. Epub 2020 Nov 7.

Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy. Electronic address:

In this work we describe the synthesis of potent and selective quinolone-based histone deacetylase 6 (HDAC6) inhibitors. The quinolone moiety has been exploited as an innovative bioactive cap-group for HDAC6 inhibition; its synthesis was achieved by applying a multicomponent reaction. The optimization of potency and selectivity of these products was performed by employing computational studies which led to the discovery of the diethylaminomethyl derivatives 7g and 7k as the most promising hit molecules. These compounds were investigated in cellular studies to evaluate their anticancer effect against colon (HCT-116) and histiocytic lymphoma (U9347) cancer cells, showing good to excellent potency, leading to tumor cell death by apoptosis induction. The small molecules 7a, 7g and 7k were able to strongly inhibit the cytoplasmic and slightly the nuclear HDAC enzymes, increasing the acetylation of tubulin and of the lysine 9 and 14 of histone 3, respectively. Compound 7g was also able to increase Hsp90 acetylation levels in HCT-116 cells, thus further supporting its HDAC6 inhibitory profile. Cytotoxicity and mutagenicity assays of these molecules showed a safe profile; moreover, the HPLC analysis of compound 7k revealed good solubility and stability profile.
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http://dx.doi.org/10.1016/j.ejmech.2020.112998DOI Listing
February 2021

Modulation of the Innate Immune Response by Targeting Toll-like Receptors: A Perspective on Their Agonists and Antagonists.

J Med Chem 2020 11 15;63(22):13466-13513. Epub 2020 Sep 15.

Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022, University of Siena, via Aldo Moro 2, 53100, Siena, Italy.

Toll-like receptors (TLRs) are a class of proteins that recognize pathogen-associated molecular patterns (PAMPs) and damaged-associated molecular patterns (DAMPs), and they are involved in the regulation of innate immune system. These transmembrane receptors, localized at the cellular or endosomal membrane, trigger inflammatory processes through either myeloid differentiation primary response 88 (MyD88) or TIR-domain-containing adapter-inducing interferon-β (TRIF) signaling pathways. In the last decades, extensive research has been performed on TLR modulators and their therapeutic implication under several pathological conditions, spanning from infections to cancer, from metabolic disorders to neurodegeneration and autoimmune diseases. This Perspective will highlight the recent discoveries in this field, emphasizing the role of TLRs in different diseases and the therapeutic effect of their natural and synthetic modulators, and it will discuss insights for the future exploitation of TLR modulators in human health.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01049DOI Listing
November 2020

(+)-(R)- and (-)-(S)-Perhexiline maleate: Enantioselective synthesis and functional studies on Schistosoma mansoni larval and adult stages.

Bioorg Chem 2020 09 30;102:104067. Epub 2020 Jun 30.

Department of Biotechnology, Chemistry and Pharmacy, University of Siena, via Aldo Moro 2, 53100 Siena, Italy. Electronic address:

Schistosomiasis is a neglected tropical disease mainly affecting the poorest tropical and subtropical areas of the world with the impressive number of roughly 200 million infections per year. Schistosomes are blood trematode flukes of the genus Schistosoma causing symptoms in humans and animals. Organ morbidity is caused by the accumulation of parasite eggs and subsequent development of fibrosis. If left untreated, schistosomiasis can result in substantial morbidity and even mortality. Praziquantel (PZQ) is the most effective and widely used compound for the treatment of the disease, in prevention and control programs in the last 30 years. Unfortunately, it has no effect on juvenile immature schistosomes and cannot prevent reinfection or interfere with the schistosome life cycle; moreover drug-resistance represents a serious threat. The search for an alternative or complementary treatment is urgent and drug repurposing could accelerate a solution. The anti-anginal drug perhexiline maleate (PHX) has been previously shown to be effective on larval, juvenile, and adult stages of S. mansoni and to impact egg production in vitro. Since PHX is a racemic mixture of R-(+)- and S-(-)-enantiomers, we designed and realized a stereoselective synthesis of both PHX enantiomers and developed an analytical procedure for the direct quantification of the enantiomeric excess also suitable for semipreparative separation of PHX enantiomers. We next investigated the impact of each enantiomer on viability of newly transformed schistosomula (NTS) and worm pairs of S. mansoni as well as on egg production and vitellarium morphology by in vitro studies. Our results indicate that the R-(+)-PHX is mainly driving the anti-schistosomal activity but that also the S-(-)-PHX possesses a significant activity towards S. mansoni in vitro.
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http://dx.doi.org/10.1016/j.bioorg.2020.104067DOI Listing
September 2020

Structure-Based Design of Biologically Active Compounds.

Authors:
Sandra Gemma

Molecules 2020 Jul 8;25(14). Epub 2020 Jul 8.

Department of Biotechnology, Chemistry and Pharmacy, University of Siena, via Aldo Moro 2, 53100 Siena, Italy.

The past decades have witnessed tremendous progress in the detailed structural knowledge of proteins as potential or validated drug targets and the discovery of new drugs based on this wealth of knowledge progressed in parallel [...].
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http://dx.doi.org/10.3390/molecules25143115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397263PMC
July 2020

Retinitis Pigmentosa and Retinal Degenerations: Deciphering Pathways and Targets for Drug Discovery and Development.

ACS Chem Neurosci 2020 08 9;11(15):2173-2191. Epub 2020 Jul 9.

Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022, University of Siena, via Aldo Moro 2, 53100 Siena, Italy.

Inherited retinal diseases (IRDs) are a group of retinopathies generally caused by genetic mutations. Retinitis pigmentosa (RP) represents one of the most studied IRDs. RP leads to intense vision loss or blindness resulting from the degeneration of photoreceptor cells. To date, RP is mainly treated with palliative supplementation of vitamin A and retinoids, gene therapies, or surgical interventions. Therefore, a pharmacologically based therapy is an urgent need requiring a medicinal chemistry approach, to validate molecular targets able to deal with retinal degeneration. This Review aims at outlining the recent research efforts in identifying new drug targets for RP, especially focusing on the neuroprotective role of the Wnt/β-catenin/GSK3β pathway and apoptosis modulators (in particular PARP-1) but also on growth factors such as VEGF and BDNF. Furthermore, the role of spatiotemporally expressed G protein-coupled receptors (GPR124) in the retina and the emerging function of histone deacetylase inhibitors in promoting retinal neuroprotection will be discussed.
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http://dx.doi.org/10.1021/acschemneuro.0c00358DOI Listing
August 2020

Ionotropic Glutamate Receptor GluA2 in Complex with Bicyclic Pyrimidinedione-Based Compounds: When Small Compound Modifications Have Distinct Effects on Binding Interactions.

ACS Chem Neurosci 2020 06 5;11(12):1791-1800. Epub 2020 Jun 5.

Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 162, DK-2100 Copenhagen, Denmark.

()-2-Amino-3-(5-methyl-3-hydroxyisoxazol-4-yl)propanoic acid (AMPA) receptors comprise an important class of ionotropic glutamate receptors activated by glutamate in the central nervous system. These receptors have been shown to be involved in brain diseases, for example, Alzheimer's disease and epilepsy. To understand the functional role of AMPA receptors at the molecular level and their potential as targets for drugs, development of tool compounds is essential. We have previously reported the synthesis of six bicyclic pyrimidinedione-based analogues of willardiine with differences limited to the pyrimidinedione-fused five-membered rings. Despite minor molecular differences, we observed >500-fold difference in binding affinity of the compounds at full-length GluA2. Here, we report binding affinities and the binding mode of these compounds at the ligand-binding domain of GluA2 using X-ray crystallography. The structures revealed similar binding modes, with distinct differences in the interaction between GluA2 and the compounds. The methylene () and sulfur () containing compounds showed the greatest binding affinities. Changing the dihydrothiophene () into pyrrolidine (), -methyl pyrrolidine (), or dihydrofuran () induced flexibility in the position of a binding-site water molecule and changes in the hydrogen-bonding network between compound, water, and GluA2. This might be essential for explaining the reduced binding affinity of these compounds. The weakest binding affinity was observed when the aliphatic oxygen containing dihydrofuran () was changed into an aromatic furan system (). Molecular docking studies revealed two possible orientations of , whereas only one binding mode was observed for the other analogues. This could likely contribute to the weakest binding affinity of at GluA2.
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http://dx.doi.org/10.1021/acschemneuro.0c00195DOI Listing
June 2020

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes-6.

Molecules 2019 Dec 28;25(1). Epub 2019 Dec 28.

Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências, Químicas, Faculdade de Farmácia, Universidade do Porto, Rua Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal.

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of Editorials that is published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal [...].
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http://dx.doi.org/10.3390/molecules25010119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983133PMC
December 2019

Telomerase-based Cancer Therapeutics: A Review on their Clinical Trials.

Curr Top Med Chem 2020 ;20(6):433-457

Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022, via Aldo Moro 2, I- 53100 Siena, University of Siena, Siena, Italy.

Telomeres are protective chromosomal ends that shield the chromosomes from DNA damage, exonucleolytic degradation, recombination, and end-to-end fusion. Telomerase is a ribonucleoprotein that adds TTAGGG tandem repeats to the telomeric ends. It has been observed that 85 to 90% of human tumors express high levels of telomerase, playing a crucial role in the development of cancers. Interestingly, the telomerase activity is generally absent in normal somatic cells. This selective telomerase expression has driven scientists to develop novel anti-cancer therapeutics with high specificity and potency. Several advancements have been made in this area, which is reflected by the enormous success of the anticancer agent Imetelstat. Since the discovery of Imetelstat, several research groups have contributed to enrich the therapeutic arsenal against cancer. Such contributions include the application of new classes of small molecules, peptides, and hTERT-based immunotherapeutic agents (p540, GV1001, GRNVAC1 or combinations of these such as Vx-001). Many of these therapeutic tools are under different stages of clinical trials and have shown promising outcomes. In this review, we highlight the current status of telomerase-based cancer therapeutics and the outcome of these investigations.
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http://dx.doi.org/10.2174/1568026620666200102104930DOI Listing
December 2020

A Repurposing Approach for Uncovering the Anti-Tubercular Activity of FDA-Approved Drugs with Potential Multi-Targeting Profiles.

Molecules 2019 Nov 29;24(23). Epub 2019 Nov 29.

Department of Biotechnology (DoE 2018-2022), Chemistry and Pharmacy (DoE 2018-2022), University of Siena, via Aldo Moro 2, 53100 Siena, Italy.

Tuberculosis (TB) is one of the top 10 causes of death worldwide. This scenario is further complicated by the insurgence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. The identification of appropriate drugs with multi-target affinity profiles is considered to be a widely accepted strategy to overcome the rapid development of resistance. The aim of this study was to discover Food and Drug Administration (FDA)-approved drugs possessing antimycobacterial activity, potentially coupled to an effective multi-target profile. An integrated screening platform was implemented based on computational procedures (high-throughput docking techniques on the target enzymes peptide deformylase and Zmp1) and in vitro phenotypic screening assays using two models to evaluate the activity of the selected drugs against (), namely, growth of H37Rv and of two clinical isolates in axenic media, and infection of peripheral blood mononuclear cells with . Starting from over 3000 FDA-approved drugs, we selected 29 marketed drugs for submission to biological evaluation. Out of 29 drugs selected, 20 showed antimycobacterial activity. Further characterization suggested that five drugs possessed promising profiles for further studies. Following a repurposing strategy, by combining computational and biological efforts, we identified marketed drugs with relevant antimycobacterial profiles.
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http://dx.doi.org/10.3390/molecules24234373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930672PMC
November 2019

Autophagy modulators for the treatment of oral and esophageal squamous cell carcinomas.

Med Res Rev 2020 05 19;40(3):1002-1060. Epub 2019 Nov 19.

Department of Biotechnology, Chemistry, and Pharmacy, Department of Excellence 2018-2022, University of Siena, Siena, Italy.

Oral squamous cell carcinomas (OSCC) and esophageal squamous cell carcinomas (ESCC) exhibit a survival rate of less than 60% and 40%, respectively. Late-stage diagnosis and lack of effective treatment strategies make both OSCC and ESCC a significant health burden. Autophagy, a lysosome-dependent catabolic process, involves the degradation of intracellular components to maintain cell homeostasis. Targeting autophagy has been highlighted as a feasible therapeutic strategy with clinical utility in cancer treatment, although its associated regulatory mechanisms remain elusive. The detection of relevant biomarkers in biological fluids has been anticipated to facilitate early diagnosis and/or prognosis for these tumors. In this context, recent studies have indicated the presence of specific proteins and small RNAs, detectable in circulating plasma and serum, as biomarkers. Interestingly, the interplay between biomarkers (eg, exosomal microRNAs) and autophagic processes could be exploited in the quest for targeted and more effective therapies for OSCC and ESCC. In this review, we give an overview of the available biomarkers and innovative targeted therapeutic strategies, including the application of autophagy modulators in OSCC and ESCC. Additionally, we provide a viewpoint on the state of the art and on future therapeutic perspectives combining the early detection of relevant biomarkers with drug discovery for the treatment of OSCC and ESCC.
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http://dx.doi.org/10.1002/med.21646DOI Listing
May 2020

Screening and Phenotypical Characterization of Histone Deacetylase 8 (HDAC8) Inhibitors as Multistage Antischistosomal Agents.

ACS Infect Dis 2020 01 12;6(1):100-113. Epub 2019 Nov 12.

Institute of Biochemistry and Cell Biology (IBBC) , National Research Council (CNR) , Campus A. Buzzati-Traverso, via E. Ramarini 32 , 00015 Monterotondo ( Rome ), Italy.

Schistosomiasis (also known as bilharzia) is a neglected tropical disease caused by platyhelminths of the genus . The disease is endemic in tropical and subtropical areas of the world where water is infested by the intermediate parasite host, the snail. More than 800 million people live in endemic areas and more than 200 million are infected and require treatment. Praziquantel (PZQ) is the drug of choice for schistosomiasis treatment and transmission control being safe and very effective against adult worms of all the clinically relevant species. Unfortunately, it is ineffective on immature, juvenile worms; therefore, it does not prevent reinfection. Moreover, the risk of development and spread of drug resistance because of the widespread use of a single drug in such a large population represents a serious threat. Therefore, research aimed at identifying novel drugs to be used alone or in combination with PZQ are needed. histone deacetylase 8 (HDAC8) is a class I zinc-dependent HDAC, which is abundantly expressed in all stages of its life cycle, thus representing an interesting target for drug discovery. Through virtual screening and phenotypical characterization of selected hits, we discovered two main chemical classes of compounds characterized by the presence of a hydroxamate-based metal binding group coupled to a spiroindoline or a tricyclic thieno[3,2-]indole core as capping groups. Some of the compounds of both classes were deeply investigated and showed to impair viability of larval, juvenile, and adult schistosomes, to impact egg production and/or to induce morphological alterations of the adult schistosome reproductive systems. Noteworthy, all of them inhibit the recombinant form of HDAC8 enzyme . Overall, we identified very interesting scaffolds, paving the way to the development of effective antischistosomal agents.
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http://dx.doi.org/10.1021/acsinfecdis.9b00224DOI Listing
January 2020

Development of novel multipotent compounds modulating endocannabinoid and dopaminergic systems.

Eur J Med Chem 2019 Dec 4;183:111674. Epub 2019 Sep 4.

Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, University of Siena, via Aldo Moro 2, 53100, Siena, Italy.

Polypharmacology approaches may help the discovery of pharmacological tools for the study or the potential treatment of complex and multifactorial diseases as well as for addictions and also smoke cessation. In this frame, following our interest in the development of molecules able to modulate either the endocannabinoid or the dopaminergic system, and given the multiple and reciprocal interconnections between them, we decided to merge the pharmacophoric elements of some of our early leads for identifying new molecules as tools able to modulate both systems. We herein describe the synthesis and biological characterization of compounds 5a-j inspired by the structure of our potent and selective fatty acid amide hydrolase (FAAH) inhibitors (3a-c) and ligands of dopamine D or D receptor subtypes (4a,b). Notably, the majority of the new molecules showed a nanomolar potency of interaction with the targets of interest. The drug-likeliness of the developed compounds (5a-j) was investigated in silico while hERG affinity, selectivity profile (for some proteins of the endocannabinoid system), cytotoxicity profiles (on fibroblast and astrocytes), and mutagenicity (Ames test) were experimentally determined. Metabolic studies also served to complement the preliminary drug-likeliness profiling for compounds 3a and 5c. Interestingly, after assessing the lack of toxicity for the neuroblastoma cell line (IMR 32), we demonstrated a potential anti-inflammatory profile for 3a and 5c in the same cell line.
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http://dx.doi.org/10.1016/j.ejmech.2019.111674DOI Listing
December 2019

Identification of Novel 3-Hydroxy-pyran-4-One Derivatives as Potent HIV-1 Integrase Inhibitors Using Structure-Based Combinatorial Library Design Approach.

Front Chem 2019 13;7:574. Epub 2019 Aug 13.

Department of Pharmacy, Department of Excellence 2018-2022, University of Naples Federico II, Naples, Italy.

We describe herein the development and experimental validation of a computational protocol for optimizing a series of 3-hydroxy-pyran-4-one derivatives as HIV integrase inhibitors (HIV INIs). Starting from a previously developed micromolar inhibitors of HIV integrase (HIV IN), we performed an in-depth investigation based on an structure-based combinatorial library designing approach. This method allowed us to combine a combinatorial library design and side chain hopping with Quantum Polarized Ligand Docking (QPLD) studies and Molecular Dynamics (MD) simulation. The combinatorial library design allowed the identification of the best decorations for our promising scaffold. The resulting compounds were assessed by the mentioned QPLD methodology using a homology model of full-length binary HIV IN/DNA for retrieving the best performing compounds acting as HIV INIs. Along with the prediction of physico-chemical properties, we were able to select a limited number of drug-like compounds potentially displaying potent HIV IN inhibition. From this final set, based on the synthetic accessibility, we further shortlisted three representative compounds for the synthesis. The compounds were experimentally assessed for evaluating overall HIV-1 IN inhibition, HIV-1 IN strand transfer activity inhibition, HIV-1 activity inhibition and cellular toxicity. Gratifyingly, all of them showed relevant inhibitory activity in the tests along with no toxicity. Among them represents the most promising compound as potential anti-HIV agent, showing inhibitory activity against HIV IN in the low nanomolar range, comparable to that found for Raltegravir, and relevant potency in inhibiting HIV-1 replication and HIV-1 IN strand transfer activity. In summary, our results outline as a useful optimized hit for the potential treatment of HIV-1 infection by targeting HIV IN.
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http://dx.doi.org/10.3389/fchem.2019.00574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700280PMC
August 2019

Old but Gold: Tracking the New Guise of Histone Deacetylase 6 (HDAC6) Enzyme as a Biomarker and Therapeutic Target in Rare Diseases.

J Med Chem 2020 01 27;63(1):23-39. Epub 2019 Aug 27.

Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022 , University of Siena , via Aldo Moro 2 , 53100 , Siena , Italy.

Epigenetic regulation orchestrates many cellular processes and greatly influences key disease mechanisms. Histone deacetylase (HDAC) enzymes play a crucial role either as biomarkers or therapeutic targets owing to their involvement in specific pathophysiological pathways. Beyond their well-characterized role as histone modifiers, HDACs also interact with several nonhistone substrates and their increased expression has been highlighted in specific diseases. The HDAC6 isoform, due to its unique cytoplasmic localization, modulates the acetylation status of tubulin, HSP90, TGF-β, and peroxiredoxins. HDAC6 also exerts noncatalytic activities through its interaction with ubiquitin. Both catalytic and noncatalytic functions of HDACs are being actively studied in the field of specific rare disorders beyond the well-established role in carcinogenesis. This Perspective outlines the application of HDAC(6) inhibitors in rare diseases, such as Rett syndrome, inherited retinal disorders, idiopathic pulmonary fibrosis, and Charcot-Marie-Tooth disease, highlighting their therapeutic potential as innovative and targeted disease-modifying agents.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00924DOI Listing
January 2020

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes-5.

Molecules 2019 Jun 30;24(13). Epub 2019 Jun 30.

Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII, 27-31, E-08028 Barcelona, Spain.

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of Editorials which is published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal [...].
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http://dx.doi.org/10.3390/molecules24132415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650823PMC
June 2019

Bridged bicyclic 2,3-dioxabicyclo[3.3.1]nonanes as antiplasmodial agents: Synthesis, structure-activity relationships and studies on their biomimetic reaction with Fe(II).

Bioorg Chem 2019 08 31;89:103020. Epub 2019 May 31.

Department of Biotechnology, Chemistry and Pharmacy (DoE 2018-2022), University of Siena, via Aldo Moro 2, 53100 Siena, Italy.

Despite recent advancements in its control, malaria is still a deadly parasitic disease killing millions of people each year. Progresses in combating the infection have been made by using the so-called artemisinin combination therapies (ACTs). Natural and synthetic peroxides are an important class of antimalarials. Here we describe a new series of peroxides synthesized through a new elaboration of the scaffold of bicyclic-fused/bridged synthetic endoperoxides previously developed by us. These peroxides are produced by a straightforward synthetic protocol and are characterized by submicromolar potency when tested against both chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains. To investigate their mode of action, the biomimetic reaction of the representative compound 6w with Fe(II) was studied by EPR and the reaction products were characterized by NMR. Rationalization of the observed structure-activity relationship studies was performed by molecular docking. Taken together, our data robustly support the hypothesized mode of activation of peroxides 6a-cc and led to the definition of the key structural requirements responsible for the antiplasmodial potency. These data will pave the way in future to the rational design of novel optimized antimalarials suitable for in vivo investigation.
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http://dx.doi.org/10.1016/j.bioorg.2019.103020DOI Listing
August 2019

Raising the bar in anticancer therapy: recent advances in, and perspectives on, telomerase inhibitors.

Drug Discov Today 2019 07 25;24(7):1370-1388. Epub 2019 May 25.

University of Siena, Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, via Aldo Moro 2, I-53100 Siena, Italy. Electronic address:

Telomerase is a ribonucleic reverse transcriptase enzyme that uses an integral RNA component as a template to add tandem telomeric DNA repeats, TTAGGG, at the 3' end of the chromosomes. 85-90% of human tumors and their derived cell lines predominantly express high levels of telomerase, therefore contributing to cancer cell development. However, in normal cells, telomerase activity is almost always absent except in germ cells and stem cells. This differential expression has been exploited to develop highly specific and potent cancer therapeutics. In this review, we outline recent advances in the development of telomerase inhibitors as anticancer agents.
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http://dx.doi.org/10.1016/j.drudis.2019.05.015DOI Listing
July 2019

Dietary polyphenols rutin, taxifolin and quercetin related compounds target Leishmania amazonensis arginase.

Food Funct 2019 Jun;10(6):3172-3180

Departamento de Medicina Veterinária, Faculdade de Zootecnia e Engenharia de Alimentos, Universidade de São Paulo, Avenida Duque de Caxias Norte, 225, 13635-900 Pirassununga, SP, Brazil.

Quercetin related compounds were tested against Leishmania amazonensis arginase, a potential target for the development of new approaches in treating leishmaniasis. The IC50 and kinetic analysis were performed to determine the dissociation constant Ki and the inhibition mechanism of the parasite's arginase enzyme. The best arginase inhibition was obtained from taxifolin (dihydroquercetin) with IC50 = 1.6 ± 0.1 μM. This study showed for the first time that rutin (IC50 = 10.4 ± 0.8 μM), and human metabolite quercetin-3-O-glucuronide (IC50 = 8.2 ± 0.4 μM), target L. amazonensis arginase. In addition, computational studies applying molecular docking simulations were performed to gain insight into the molecular basis for arginase inhibition by the competitive inhibitors. Our results suggest that these compounds could be exploited to develop new approaches for treating leishmaniasis through molecular nutrition supplement in a drug-based therapy.
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http://dx.doi.org/10.1039/c9fo00265kDOI Listing
June 2019

A light in the dark: state of the art and perspectives in optogenetics and optopharmacology for restoring vision.

Future Med Chem 2019 03 25;11(5):463-487. Epub 2019 Mar 25.

Department of Biotechnology, Chemistry & Pharmacy, Department of Excellence 2018-2022, University of Siena, Via A. Moro 2, 53100 Siena, Italy.

In the last decade, innovative therapeutic strategies against inherited retinal degenerations (IRDs) have emerged. In particular, chemical- and opto-genetics approaches or a combination of them have been identified for modulating neuronal/optical activity in order to restore vision in blinding diseases. The 'chemical-genetics approach' (optopharmacology) uses small molecules (exogenous photoswitches) for restoring light sensitivity by activating ion channels. The 'opto-genetics approach' employs light-activated photosensitive proteins (exogenous opsins), introduced by viral vectors in injured tissues, to restore light response. These approaches offer control of neuronal activities with spatial precision and limited invasiveness, although with some drawbacks. Currently, a combined therapeutic strategy (optogenetic pharmacology) is emerging. This review describes the state of the art and provides an overview of the future perspectives in vision restoration.
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http://dx.doi.org/10.4155/fmc-2018-0315DOI Listing
March 2019

Synthesis, Molecular Modelling and Biological Studies of 3-hydroxypyrane- 4-one and 3-hydroxy-pyridine-4-one Derivatives as HIV-1 Integrase Inhibitors.

Med Chem 2019 ;15(7):755-770

Department of Chemistry, Faculty of Sciences, University of Isfahan, 81746-73441 Isfahan, Iran.

Background: Despite the progress in the discovery of antiretroviral compounds for treating HIV-1 infection by targeting HIV integrase (IN), a promising and well-known drug target against HIV-1, there is a growing need to increase the armamentarium against HIV, for avoiding the drug resistance issue.

Objective: To develop novel HIV-1 IN inhibitors, a series of 3-hydroxy-pyrane-4-one (HP) and 3- hydroxy-pyridine-4-one (HPO) derivatives have been rationally designed and synthesized.

Methods: To provide a significant characterization of the novel compounds, in-depth computational analysis was performed using a novel HIV-1 IN/DNA binary 3D-model for investigating the binding mode of the newly conceived molecules in complex with IN. The 3D-model was generated using the proto-type foamy virus (PFV) DNA as a structural template, positioning the viral polydesoxyribonucleic chain into the HIV-1 IN homology model. Moreover, a series of in vitro tests were performed including HIV-1 activity inhibition, HIV-1 IN activity inhibition, HIV-1 IN strand transfer activity inhibition and cellular toxicity.

Results: Bioassay results indicated that most of HP analogues including HPa, HPb, HPc, HPd, HPe and HPg, showed favorable inhibitory activities against HIV-1-IN in the low micromolar range. Particularly halogenated derivatives (HPb and HPd) offered the best biological activities in terms of reduced toxicity and optimum inhibitory activities against HIV-1 IN and HIV-1 in cell culture.

Conclusion: Halogenated derivatives, HPb and HPd, displayed the most promising anti-HIV profile, paving the way to the optimization of the presented scaffolds for developing new effective antiviral agents.
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http://dx.doi.org/10.2174/1573406415666181219113225DOI Listing
December 2019

Structure-activity relationships, biological evaluation and structural studies of novel pyrrolonaphthoxazepines as antitumor agents.

Eur J Med Chem 2019 Jan 3;162:290-320. Epub 2018 Nov 3.

Department of Precision Medicine, University of Campania Luigi Vanvitelli, Vico L. de Crecchio 7, 80138, Naples, Italy.

Microtubule-targeting agents (MTAs) are a class of clinically successful anti-cancer drugs. The emergence of multidrug resistance to MTAs imposes the need for developing new MTAs endowed with diverse mechanistic properties. Benzoxazepines were recently identified as a novel class of MTAs. These anticancer agents were thoroughly characterized for their antitumor activity, although, their exact mechanism of action remained elusive. Combining chemical, biochemical, cellular, bioinformatics and structural efforts we developed improved pyrrolonaphthoxazepines antitumor agents and their mode of action at the molecular level was elucidated. Compound 6j, one of the most potent analogues, was confirmed by X-ray as a colchicine-site MTA. A comprehensive structural investigation was performed for a complete elucidation of the structure-activity relationships. Selected pyrrolonaphthoxazepines were evaluated for their effects on cell cycle, apoptosis and differentiation in a variety of cancer cells, including multidrug resistant cell lines. Our results define compound 6j as a potentially useful optimized hit for the development of effective compounds for treating drug-resistant tumors.
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http://dx.doi.org/10.1016/j.ejmech.2018.11.004DOI Listing
January 2019

Expansion of the object of surveillance for occupational accidents: history and challenges underwent by a reference center aiming at prevention.

Cien Saude Colet 2018 Sep;23(9):3055-3066

Faculdade de Medicina, Universidade Estadual Paulista (UNESP). Botucatu SP Brasil.

The Surveillance System for Occupational Accidents (Sistema de Vigilância em Acidentes de Trabalho - SIVAT) established by Reference Center for Workers' Health (Centro de Referência em Saúde do Trabalhador - CEREST-Piracicaba) in 2003 represents an experience consolidated according to the guidelines formulated by the National Network for Integral Care of the Workers' Health (Rede Nacional de Atenção Integral à Saúde do Trabalhador - RENAST). The present article analyzes the history and development of SIVAT at CEREST - Piracicaba from the perspective of cultural-historical activity theory. The historical data comprise interviews, documents and observations performed by the researchers. Analysis showed that the studied activity underwent two cycles of expansion. During the first cycle, CEREST actions sought to adequate the targeted companies to the legislation in vigor. During the second cycle, actions aimed at introducing changes relative to organizational determinants in the targeted companies that CEREST staff identified as causes of accidents. A new modality of formative intervention, called Change Laboratory (CL), seems to be useful to attain the goal of prevention; it involves analysis of the causes of accidents, activity remodeling and implantation of solutions by developing agency in the targeted organizations.
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http://dx.doi.org/10.1590/1413-81232018239.21952016DOI Listing
September 2018

Cinnamic acids derived compounds with antileishmanial activity target Leishmania amazonensis arginase.

Chem Biol Drug Des 2019 02 10;93(2):139-146. Epub 2018 Oct 10.

Universidade Anhembi Morumbi, São Paulo, Brazil.

This study describes the activity of five natural hydroxycinnamic acids and derived compound: caffeic (1), rosmarinic (2), chlorogenic (3), and cryptochlorogenic (4), acids and isoverbascoside (5). All compounds inhibited Leishmania amazonensis arginase with IC -in range of 1.5-11 μM. Compounds 2 and 5 also showed activity against promastigotes of L. amazonensis with IC  = 61 (28-133) μM and IC  = 14 (9-24) μM, respectively. Further computational studies applying molecular docking simulations were performed on the competitive inhibitors to gain insight into the molecular basis for arginase inhibition and could be exploited to the development of new antileishmanials drug targeting parasite arginase.
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http://dx.doi.org/10.1111/cbdd.13391DOI Listing
February 2019

Novel spiroindoline HDAC inhibitors: Synthesis, molecular modelling and biological studies.

Eur J Med Chem 2018 Sep 31;157:127-138. Epub 2018 Jul 31.

European Research Centre for Drug Discovery and Development (NatSynDrugs) and Department of Biotechnology, Chemistry, and Pharmacy, Department of Excellence 2018-2022, University of Siena, via Aldo Moro 2, 53100, Siena, Italy.

This paper describes the rational development of a series of novel spiroindoline derivatives endowed with selective inhibitory activity on the HDAC6 isoform. A convenient multicomponent one-pot protocol was applied for the assembly of the desired N1-substituted spiroindoline core which allowed a straightforward analoging. Computational studies and in vitro determination of inhibitory potency for the developed compounds against HDAC6 and HDAC1 isoforms were flanked by cell-based studies on histone H3 and α-tubulin acetylation. The effects on cancer cell cycle and apoptosis of the best performing derivatives were assessed on cancer cell lines highlighting a promising antitumor potential. In view of cell-based data and calculated drug-like properties, the selective HDAC6 inhibitor 5b, with a spiroindoline-based hydroxamate bearing a tert-butyl carbamate functionality, was selected to be further investigated for its potential in inhibiting tumor cells migration. It was able to potently inhibit cell migration in SH-SY5Y neuroblastoma cells and did not display toxicity in NIH3T3 mouse fibroblasts. Taken together, these data foster further investigation and optimization for this class of compounds as novel anticancer agents.
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http://dx.doi.org/10.1016/j.ejmech.2018.07.069DOI Listing
September 2018

Development of Potent Inhibitors of Fatty Acid Amide Hydrolase Useful for the Treatment of Neuropathic Pain.

ChemMedChem 2018 10 30;13(19):2090-2103. Epub 2018 Aug 30.

European Research Centre for Drug Discovery and Development (NatSynDrugs), Department of Biotechnology, Chemistry, and Pharmacy (DoE 2018-2020), University of Siena, Via Aldo Moro 2, 53100, Siena, Italy.

The unique role of fatty acid amide hydrolase (FAAH) in terminating endocannabinoid (EC) signaling supports its relevance as a therapeutic target. Inhibition of EC metabolizing enzymes elicits indirect agonism of cannabinoid receptors (CBRs) and therapeutic efficacy devoid of psychotropic effects. Based on our previous ligands, and aiming at the discovery of new selective FAAH inhibitors, we developed a series of 12 new compounds characterized by functionalized tricyclic scaffolds. All the developed compounds display negligible activity on monoacylglycerol lipase (MAGL) and CBRs. The most potent FAAH inhibitors of the newly developed series, 6-oxo-5,6-dihydro-4H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-9-yl-6-phenylhexylcarbamate (5 h) and 4-oxo-5,6-dihydro-4H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-9-yl-(6-phenylhexyl)carbamate (5 i) (nanomolar FAAH inhibitors, the latter of which also shows micromolar affinity at the CB R), were selected for further studies. Results of cell-based studies on a neuroblastoma cell line (IMR32) demonstrated 5 h, 5 i, and our reference compound 3 ([3-(3-carbamoylpyrrol-1-yl)phenyl] N-(5-phenylpentyl)carbamate) to lack any cytotoxic effect, while all three showed the ability to decrease oxidative stress by reducing the expression of the redox-sensitive transcription factor NF-κB. Encouraged by these data, these compounds were studied in vivo and were dosed orally in a mouse model of neuropathic pain. At 10 mg kg all the compounds were able to relieve the hypersensitivity induced by oxaliplatin.
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http://dx.doi.org/10.1002/cmdc.201800397DOI Listing
October 2018

Antimalarial agents against both sexual and asexual parasites stages: structure-activity relationships and biological studies of the Malaria Box compound 1-[5-(4-bromo-2-chlorophenyl)furan-2-yl]-N-[(piperidin-4-yl)methyl]methanamine (MMV019918) and analogues.

Eur J Med Chem 2018 Apr 10;150:698-718. Epub 2018 Mar 10.

Department of Biotechnology, Chemistry and Pharmacy, Dipartimento di Eccellenza 2018-2022, University of Siena, Via Aldo Moro 2, 53100, Siena, Italy; European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena, Via Aldo Moro 2, 53100, Siena, Italy; Centro Interuniversitario di Ricerche sulla Malaria (CIRM), University of Perugia, Perugia, Italy.

Therapies addressing multiple stages of Plasmodium falciparum life cycle are highly desirable for implementing malaria elimination strategies. MMV019918 (1, 1-[5-(4-bromo-2-chlorophenyl)furan-2-yl]-N-[(piperidin-4-yl)methyl]methanamine) was selected from the MMV Malaria Box for its dual activity against both asexual stages and gametocytes. In-depth structure-activity relationship studies and cytotoxicity evaluation led to the selection of 25 for further biological investigation. The potential transmission blocking activity of 25 versus P. falciparum was confirmed through the standard membrane-feeding assay. Both 1 and 25 significantly prolonged atrioventricular conduction time in Langendorff-isolated rat hearts, and showed inhibitory activity of Ba current through Ca1.2 channels. An in silico target-fishing study suggested the enzyme phosphoethanolamine methyltransferase (PfPMT) as a potential target. However, compound activity against PfPMT did not track with the antiplasmodial activity, suggesting the latter activity relies on a different molecular target. Nevertheless, 25 showed interesting activity against PfPMT, which could be an important starting point for the identification of more potent inhibitors active against both sexual and asexual stages of the parasite.
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http://dx.doi.org/10.1016/j.ejmech.2018.03.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5902032PMC
April 2018

( S)-2-Amino-3-(5-methyl-3-hydroxyisoxazol-4-yl)propanoic Acid (AMPA) and Kainate Receptor Ligands: Further Exploration of Bioisosteric Replacements and Structural and Biological Investigation.

J Med Chem 2018 03 26;61(5):2124-2130. Epub 2018 Feb 26.

Department of Drug Design and Pharmacology , University of Copenhagen , Jagtvej 162 , DK-2100 Copenhagen , Denmark.

Starting from 1-4 and 7 structural templates, analogues based on bioisosteric replacements (5a-c vs 1, 2 and 6 vs 7) were synthesized for completing the SAR analysis. Interesting binding properties at GluA2, GluK1, and GluK3 receptors were discovered. The requirements for GluK3 interaction were elucidated by determining the X-ray structures of the GluK3-LBD with 2 and 5c and by computational studies. Antinociceptive potential was demonstrated for GluK1 partial agonist 3 and antagonist 7 (2 mg/kg ip).
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http://dx.doi.org/10.1021/acs.jmedchem.8b00099DOI Listing
March 2018