Publications by authors named "Simone Carradori"

177 Publications

Carbonic Anhydrases: New Perspectives on Protein Functional Role and Inhibition in .

Front Microbiol 2021 19;12:629163. Epub 2021 Mar 19.

Department of Biology, Agriculture and Food Sciences, National Research Council (CNR), Institute of Biosciences and Bioresources, Naples, Italy.

Our understanding of the function of bacterial carbonic anhydrases (CAs, EC 4.2.1.1) has increased significantly in the last years. CAs are metalloenzymes able to modulate CO, HCO and H concentration through their crucial role in catalysis of reversible CO hydration (CO + HO ⇄ HCO + H). In all living organisms, CA activity is linked to physiological processes, such as those related to the transport and supply of CO or HCO, pH homeostasis, secretion of electrolytes, biosynthetic processes and photosynthesis. These important processes cannot be ensured by the very low rate of the non-catalyzed reaction of CO hydration. It has been recently shown that CAs are important biomolecules for many bacteria involved in human infections, such as , , , , and . In these species, CA activity promotes microorganism growth and adaptation in the host, or modulates bacterial toxin production and virulence. In this review, recent literature in this research field and some of the above-mentioned issues are discussed, namely: () the implication of CAs from bacterial pathogens in determining the microorganism growth and virulence; () the druggability of these enzymes using classical CA inhibitors (CAIs) of the sulfonamide-type as examples; () the role played by CAs in the acid tolerance/adaptation of the microbe within the human abdomen; () the role of CAs played in the outer membrane vesicles spawned by in its planktonic and biofilm phenotypes; () the possibility of using CAIs in combination with probiotic strains as a novel anti-ulcer treatment approach. The latter approach may represent an innovative and successful strategy to fight gastric infections in the era of increasing resistance of pathogenic bacteria to classical antibiotics.
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http://dx.doi.org/10.3389/fmicb.2021.629163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017301PMC
March 2021

Synthesis and Evaluation of Thymol-Based Synthetic Derivatives as Dual-Action Inhibitors against Different Strains of and AGS Cell Line.

Molecules 2021 Mar 24;26(7). Epub 2021 Mar 24.

Department of Innovative Technologies in Medicine and Dentistry, "G. d'Annunzio" University of Chieti-Pescara, 66100 Chieti, Italy.

Following a similar approach on carvacrol-based derivatives, we investigated the synthesis and the microbiological screening against eight strains of , and the cytotoxic activity against human gastric adenocarcinoma (AGS) cells of a new series of ether compounds based on the structure of thymol. Structural analysis comprehended elemental analysis and H/C/F NMR spectra. The analysis of structure-activity relationships within this molecular library of 38 structurally-related compounds reported that some chemical modifications of the OH group of thymol led to broad-spectrum growth inhibition on all isolates. Preferred substitutions were benzyl groups compared to alkyl chains, and the specific presence of functional groups at position of the benzyl moiety such as 4-CN and 4-Ph endowed the most anti- activity toward all the strains with minimum inhibitory concentration (MIC) values up to 4 µg/mL. Poly-substitution on the benzyl ring was not essential. Moreover, several compounds characterized by the lowest minimum inhibitory concentration/minimum bactericidal concentration (MIC/MBC) values against were also tested in order to verify a cytotoxic effect against AGS cells with respect to 5-fluorouracil and carvacrol. Three derivatives can be considered as new lead compounds alternative to current therapy to manage infection, preventing the occurrence of severe gastric diseases. The present work confirms the possibility to use natural compounds as templates for the medicinal semi-synthesis.
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http://dx.doi.org/10.3390/molecules26071829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037164PMC
March 2021

Chemical and Bioinformatics Analyses of the Anti-Leishmanial and Anti-Oxidant Activities of Hemp Essential Oil.

Biomolecules 2021 Feb 12;11(2). Epub 2021 Feb 12.

Department of Pharmacy, University of Lahore, Islamabad Campus, Islamabad 54590, Pakistan.

Industrial hemp is a multiuse crop that has been widely cultivated to produce fibers and nutrients. The capability of the essential oil (EO) from inflorescences as antimicrobial agent has been reported. However, literature data are still lacking about the hemp EO antiprotozoal efficacy in vivo. The present study aims to unravel this concern through the evaluation of the efficacy of hemp EOs (2.5 mL/kg, intraperitoneally) of three different cultivars, namely , and , in mice intraperitoneally infected with . A detailed description of EO composition and targets-components analysis is reported. Myrcene, α-pinene and -caryophyllene were the main components of the EOs, as indicated by the gas-chromatographic analysis. However, a prominent position in the scenario of the theoretical interactions underlying the bio-pharmacological activity was also occupied by selina-3,7(11)-diene, which displayed affinities in the micromolar range (5.4-28.9) towards proliferator-activated receptor α, cannabinoid CB2 receptor and acetylcholinesterase. The content of this compound was higher in and , in accordance with their higher scavenging/reducing properties and efficacy against the tissue wound, induced by . Overall, the present study recommends hemp female inflorescences, as sources of biomolecules with potential pharmacological applications, especially towards infective diseases.
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http://dx.doi.org/10.3390/biom11020272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917915PMC
February 2021

Synthesis, Cytotoxicity and Anti-Proliferative Activity Against AGS Cells of New 3(2)-Pyridazinone Derivatives Endowed with a Piperazinyl Linker.

Pharmaceuticals (Basel) 2021 Feb 25;14(3). Epub 2021 Feb 25.

Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi 682 041, India.

Novel twenty-three 3(2)-pyridazinone derivatives were designed and synthesized based on the chemical requirements related to the anti-proliferative effects previously demonstrated within this scaffold. The introduction of a piperazinyl linker between the pyridazinone nucleus and the additional (un)substituted phenyl group led to some compounds endowed with a limited cytotoxicity against human gingival fibroblasts (HGFs) and good anti-proliferative effects against gastric adenocarcinoma cells (AGS) as evaluated by MTT and LDH assays, using doxorubicin as a positive control. Successive analyses revealed that the two most promising representative compounds ( and ) could exert their effects by inducing oxidative stress as demonstrated by the hydrogen peroxide release and the morphological changes (cell blebbing) revealed by light microscopy analysis after the haematoxylin-eosin staining. Moreover, to further assess the apoptotic process induced by compounds and , Bax expression was measured by flow cytometry. These findings enlarged our knowledge of the structural requirements in this scaffold to display valuable biological effects against cancerous cell lines.
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http://dx.doi.org/10.3390/ph14030183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996573PMC
February 2021

Reconsidering anion inhibitors in the general context of drug design studies of modulators of activity of the classical enzyme carbonic anhydrase.

J Enzyme Inhib Med Chem 2021 Dec;36(1):561-580

Neurofarba Department, Pharmaceutical and Nutraceutical Section, University of Florence, Florence, Italy.

Inorganic anions inhibit the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) generally by coordinating to the active site metal ion. Cyanate was reported as a non-coordinating CA inhibitor but those erroneous results were subsequently corrected by another group. We review the anion CA inhibitors (CAIs) in the more general context of drug design studies and the discovery of a large number of inhibitor classes and inhibition mechanisms, including zinc binders (sulphonamides and isosteres, dithiocabamates and isosteres, thiols, selenols, benzoxaboroles, ninhydrins, etc.); inhibitors anchoring to the zinc-coordinated water molecule (phenols, polyamines, sulfocoumarins, thioxocoumarins, catechols); CAIs occluding the entrance to the active site (coumarins and derivatives, lacosamide), as well as compounds that bind outside the active site. All these new chemotypes integrated with a general procedure for obtaining isoform-selective compounds (the tail approach) has resulted, through the guidance of rigorous X-ray crystallography experiments, in the development of highly selective CAIs for all human CA isoforms with many pharmacological applications.
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http://dx.doi.org/10.1080/14756366.2021.1882453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901698PMC
December 2021

Dual Acting Carbon Monoxide Releasing Molecules and Carbonic Anhydrase Inhibitors Differentially Modulate Inflammation in Human Tenocytes.

Biomedicines 2021 Feb 1;9(2). Epub 2021 Feb 1.

Department of Pharmacy, University "G. d'Annunzio" of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy.

Sustained oxidative stress and inflammation have been reported as the major factors responsible for the failure of tendon healing during rotator cuff tears (RCTs) and rotator cuff disease (RCD). Although, their therapeutic management remains still challenging. Carbonic anhydrases (CAs) are involved in many pathological conditions, and the overexpression of both CA9 and 12 in inflamed joints has been recently reported. Consequently, a selective CA9/12 inhibition could be a feasible strategy for improving tendon recovery after injury. In addition, since carbon monoxide (CO) has been proven to have an important role in modulating inflammation, CO releasing molecules (CORMs) can be also potentially suitable compounds. The present study aims at evaluating five newly synthesized dual-mode acting CA inhibitors (CAIs)-CORMs compounds, belonging to two chemical scaffolds, on tendon-derived human primary cells under HO stimulation in comparison with Meloxicam. Our results show that compounds and are the most promising of the series in counteracting oxidative stress-induced cytotoxicity and display a better profile in terms of enhanced viability, decreased LDH release, and augmented tenocyte proliferation compared to Meloxicam. Moreover, compound , as a potent superoxide scavenger, exerts its action inhibiting NF-ĸB translocation and downregulating iNOS, whereas compound is more effective in increasing collagen I deposition. Taken together, our data highlight a potential role of CA in RCTs and RCD and the prospective effectiveness of compounds acting as CAI-CORM during inflammation.
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http://dx.doi.org/10.3390/biomedicines9020141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912830PMC
February 2021

Dual Carbonic Anhydrase IX/XII Inhibitors and Carbon Monoxide Releasing Molecules Modulate LPS-Mediated Inflammation in Mouse Macrophages.

Antioxidants (Basel) 2021 Jan 5;10(1). Epub 2021 Jan 5.

Department of Pharmacy, "G. d'Annunzio" University of Chieti-Pescara, via dei Vestini 31, 66100 Chieti, Italy.

Low concentrations of carbon monoxide (CO) were reported to exhibit anti-inflammatory effects when administered in cells by suitable chemotypes such as CO releasing molecules (CO-RMs). In addition, the pH-modulating abilities of specific carbonic anhydrase isoforms played a crucial role in different models of inflammation and neuropathic pain. Herein, we report a series of chemical hybrids consisting of a Carbonic Anhydrase (CA) inhibitor linked to a CO-RM tail (CAI/CO-RMs). All compounds and their precursors were first tested in vitro for their inhibition activity against the human CA I, II, IX, and XII isoforms as well their CO releasing properties, aiming at corroborating the data by means of molecular modelling techniques. Then, their impact on metabolic activity modulation of RAW 264.7 mouse macrophages for 24 and 48 h was assessed with or without lipopolysaccharide (LPS) stimulation. The compounds were shown to counteract the inflammatory stimulus as also indicated by the reduced tumor necrosis factor alpha (TNF-α) release after treatment. All the biological results were compared to those of -acetylcysteine (NAC) as a reference antioxidant compound. Within the series, two CAI/CO-RM hybrids ( and ), bearing both the well-known scaffold able to inhibit CAs (acesulfame) and the cobalt-based CO releasing portion, induced a higher anti-inflammatory effect up to 48 h at concentrations lower than NAC.
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http://dx.doi.org/10.3390/antiox10010056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824903PMC
January 2021

Metabolomic Profile and Antioxidant/Anti-Inflammatory Effects of Industrial Hemp Water Extract in Fibroblasts, Keratinocytes and Isolated Mouse Skin Specimens.

Antioxidants (Basel) 2021 Jan 1;10(1). Epub 2021 Jan 1.

Department of Pharmacy, Università Degli Studi "Gabriele d'Annunzio", Via dei Vestini 31, 66100 Chieti, Italy.

Industrial hemp is a multiuse crop whose phytocomplex includes terpenophenolics and flavonoids. In the present study, the phenolic and terpenophenolic compounds were assayed in the water extract of the hemp variety Futura 75. Protective effects were also investigated in human fibroblast and keratinocytes and isolate mouse skin specimens, which were exposed to hydrogen peroxide and/or to the extract (1-500 µg/mL). The results of phytochemical analysis suggested the cannabidiol, cannabidiolic acid and rutin as the prominent phytocompounds. In the in vitro system represented by human keratinocytes and fibroblasts, the hemp extract was found to be able to protect cells from cytotoxicity and apoptosis induced by oxidative stress. Moreover, modulatory effects on IL-6, a key mediator in skin proliferation, were found. In isolated rat skin, the extract reduced hydrogen peroxide-induced l-dopa turnover, prostaglandin-E2 production and the ratio kynurenine/tryptpophan, thus corroborating anti-inflammatory/antioxidant effects. The in silico docking studies also highlighted the putative interactions between cannabidiol, cannabidiolic acid and rutin with tyrosinase and indoleamine-2,3-dioxygenase, involved in l-dopa turnover and tryptophan conversion in kynurenine, respectively. In conclusion, the present findings showed the efficacy of hemp water extract as a skin protective agent. This could be partly related to the extract content in cannabidiol, cannabidiolic acid and rutin.
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http://dx.doi.org/10.3390/antiox10010044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823476PMC
January 2021

Natural Products Database Screening for the Discovery of Naturally Occurring SARS-Cov-2 Spike Glycoprotein Blockers.

ChemistrySelect 2020 Nov 16;5(42):13309-13317. Epub 2020 Nov 16.

Department of Pharmaceutical Chemistry Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus Kochi 682 041 India.

SARS-CoV-2 coronavirus has been recognized the causative agent of the recent and ongoing pandemic. Effective and specific antiviral agents or vaccines are still missing, despite a large plethora of compounds have been proposed and tested worldwide. New compounds are requested urgently and virtual screening can offer fast and robust predictions to investigate. Moreover, natural compounds were shown to exert antiviral effects and can be endowed with limited side effects and wide availability. Our approach consisted in the validation of a docking protocol able to refine the most suitable candidates, within the 31000 natural compounds of the natural product activity and species source (NPASS) library, interacting with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein. After the refinement process two natural compounds, castanospermine and karuquinone B, were shown to be the best-in-class derivatives able to target an essential structure of the virus and to act in the early stage of infection.
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http://dx.doi.org/10.1002/slct.202003349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753608PMC
November 2020

Optimization of Ultrasonic Extraction to Obtain Erinacine A and Polyphenols with Antioxidant Activity from the Fungal Biomass of .

Foods 2020 Dec 18;9(12). Epub 2020 Dec 18.

Department of Pharmacy, "G. d'Annunzio" University of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy.

is a medicinal fungal species that produces the active biological metabolite erinacine A with strong antioxidant activity. The classical extraction techniques used to date to obtain metabolites from this fungal species require high consumption of resources and energy and, in the end, prove to be expensive and inefficient, especially on a biomedical scale. The aim of this research is based on the development of an ultrasonic extraction (UE) method for the identification and extraction of biological compounds with high antioxidant activity from the mycelia of biomass developed through a solid cultivation process. The extraction process was optimized by varying parameters to determine the best extraction yield of metabolites involved in such antioxidant activity, using the response surface methodology (RSM). The physicochemical analyses were oriented towards the investigation of polyphenols, flavonoids, and the diterpenoid erinacine A. It is highlighted that there is a very good mutual connection between the concentration of polyphenols and flavonoids in the extracts studied and the diterpenoid erinacine A. Also, this study describes an efficient and qualitative extraction method for extracting natural antioxidants from the mushroom, since toxic solvents were not used in the developed extraction procedure. This biomass can be used both as a food source and as a possible phytotherapeutic tool in the prevention or treatment of various neurodegenerative disorders that require drugs with strong antioxidant activity.
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http://dx.doi.org/10.3390/foods9121889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766035PMC
December 2020

Response to Perspectives on the Classical Enzyme Carbonic Anhydrase and the Search for Inhibitors.

Biophys J 2021 01 8;120(1):178-181. Epub 2020 Dec 8.

Neurofarba Department, Pharmaceutical and Nutraceutical Section, University of Florence, Sesto Fiorentino, Florence, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.bpj.2020.11.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820713PMC
January 2021

Synthesis and Biological Evaluation of Carvacrol-Based Derivatives as Dual Inhibitors of Strains and AGS Cell Proliferation.

Pharmaceuticals (Basel) 2020 Nov 19;13(11). Epub 2020 Nov 19.

Department of Medical, Oral, and Biotechnological Sciences, "G. d'Annunzio" University of Chieti-Pescara, 66100 Chieti, Italy.

This study reports on the synthesis, structural assessment, microbiological screening against several strains of and antiproliferative activity against human gastric adenocarcinoma (AGS) cells of a large series of carvacrol-based compounds. Structural analyses consisted of elemental analysis, H/C/F NMR spectra and crystallographic studies. The structure-activity relationships evidenced that among ether derivatives the substitution with specific electron-withdrawing groups (CF and NO) especially in the para position of the benzyl ring led to an improvement of the antimicrobial activity, whereas electron-donating groups on the benzyl ring and ethereal alkyl chains were not tolerated with respect to the parent compound (MIC/MBC = 64/64 µg/mL). Ester derivatives (coumarin-carvacrol hybrids) displayed a slight enhancement of the inhibitory activity up to MIC values of 8-16 µg/mL. The most interesting compounds exhibiting the lowest MIC/MBC activity against (among others, compounds and endowed with MIC/MBC values ranging between 2/2 to 32/32 µg/mL against all the evaluated strains) were also assayed for their ability to reduce AGS cell growth with respect to 5-Fluorouracil. Some derivatives can be regarded as new lead compounds able to reduce growth and to counteract the proliferation of AGS cells, both contributing to the occurrence of gastric cancer.
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http://dx.doi.org/10.3390/ph13110405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699384PMC
November 2020

Correlation between the Antimicrobial Activity and Metabolic Profiles of Cell Free Supernatants and Membrane Vesicles Produced by DSM 17938.

Microorganisms 2020 Oct 24;8(11). Epub 2020 Oct 24.

Department of Pharmacy, "G. d'Annunzio" University of Chieti-Pescara, 66100 Chieti, Italy.

The aim of the work is to assess the antimicrobial activities of Cell Free Supernatants (CFS) and Membrane Vesicles (MVs), produced by DSM 17938, versus Gram-positive and Gram-negative bacteria and investigate their metabolic profiles. The Minimum Inhibitory Concentration was determined through the broth microdilution method and cell proliferation assay and the Minimum Bactericidal Concentration was determined by Colony Forming Units counts. The characteristics of the antimicrobial compounds were evaluated by pH adjustments, proteinase treatment, and size fractionation of the CFS. The cytotoxicity of CFS was tested on two human cell lines. A detailed snapshot of the . metabolism was attained through an untargeted metabolic profiling by means of high resolution Fourier Transform Ion Cyclotron Resonance Mass Spectrometry (FT-ICR MS) coupled with Electrospray Ionization Source (ESI). The results showed (i) a greater efficacy of CFS and its fractions towards Gram-negative compared to Gram-positive bacteria; (ii) an antimicrobial effect related to pH-dependent compounds but not to MVs; (iii) a molecular weight < 3 KDa as well as an a non-proteinaceous nature of the antimicrobial compounds; and (iv) more than 200 and 500 putative metabolites annotated in MVs and supernatants, covering several classes of metabolites, including amino acids, lipids, fatty and organic acids, polyalcohols, nucleotides, and vitamins. Some putative compounds were proposed not only as characteristic of specific fractions, but also possibly involved in antimicrobial activity.
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http://dx.doi.org/10.3390/microorganisms8111653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692313PMC
October 2020

A Comprehensive Overview of Colon Cancer- A Grim Reaper of the 21st Century

Curr Med Chem 2020 10 26. Epub 2020 Oct 26.

Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi-682 041, India

A few decades ago, the incidence of colorectal cancer (CRC) was low and is now the fourth in the list of deadly cancers producing nearly a million deaths annually. A population that is aging along with risk factors such as smoking, obesity, sedentary lifestyle with little or no physical activity, and non-healthy food habits of developed countries can increase the risk of colorectal cancer. The balance in gut microbiota and the metabolites produced during bacterial fermentation within the host plays a significant role in regulating intestinal diseases as well as colorectal cancer development. Recent progress in the understanding of illness resulted in multiple treatment options such as surgery, radiation, and chemotherapy, including targeted therapy and multitherapies. The treatment plan for CRC depends on the location, stage and grade of cancer as well as genomic biomarker tests. Despite all the advancements made in the genetic and molecular aspects of the disease, the knowledge seems inadequate as the drug action as well as the wide variation in drug response did not appear strongly correlated with the individual molecular and genetic characteristics, which suggests the requirement of comprehensive molecular understanding of this complex heterogeneous disease. Furthermore, multitherapies or a broad spectrum approach, which is an amalgamation of the various promising as well as effective therapeutic strategies that can tackle heterogeneity and act on several targets of the disease, need to be validated in clinical studies. The latest treatment options have significantly increased the survival of up to three years in the case of advanced disease. The fact that colorectal cancer is developed from a polypoid precursor, as well as the symptoms of the disease that occur at an advanced stage, underlines how screening programs can help early detection and decrease mortality as well as morbidity from CRC.
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http://dx.doi.org/10.2174/0929867327666201026143757DOI Listing
October 2020

Carbonic Anhydrase Inhibitors Targeting Metabolism and Tumor Microenvironment.

Metabolites 2020 Oct 14;10(10). Epub 2020 Oct 14.

Neurofarba Department, Pharmaceutical and Nutraceutical Section, University of Florence, Via Ugo Schiff 6, Sesto Fiorentino, 50019 Florence, Italy.

The tumor microenvironment is crucial for the growth of cancer cells, triggering particular biochemical and physiological changes, which frequently influence the outcome of anticancer therapies. The biochemical rationale behind many of these phenomena resides in the activation of transcription factors such as hypoxia-inducible factor 1 and 2 (HIF-1/2). In turn, the HIF pathway activates a number of genes including those involved in glucose metabolism, angiogenesis, and pH regulation. Several carbonic anhydrase (CA, EC 4.2.1.1) isoforms, such as CA IX and XII, actively participate in these processes and were validated as antitumor/antimetastatic drug targets. Here, we review the field of CA inhibitors (CAIs), which selectively inhibit the cancer-associated CA isoforms. Particular focus was on the identification of lead compounds and various inhibitor classes, and the measurement of CA inhibitory on-/off-target effects. In addition, the preclinical data that resulted in the identification of SLC-0111, a sulfonamide in Phase Ib/II clinical trials for the treatment of hypoxic, advanced solid tumors, are detailed.
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http://dx.doi.org/10.3390/metabo10100412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602163PMC
October 2020

Novel insights on saccharin- and acesulfame-based carbonic anhydrase inhibitors: design, synthesis, modelling investigations and biological activity evaluation.

J Enzyme Inhib Med Chem 2020 Dec;35(1):1891-1905

Neurofarba Department, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Sesto Fiorentino, Italy.

A large library of saccharin and acesulfame derivatives has been synthesised and evaluated against four isoforms of human carbonic anhydrase, the two off-targets hCA I/II and the tumour related isoforms hCA IX/XII. Different strategies of scaffold modification have been attempted on both saccharin as well as acesulfame core leading to the obtainment of 60 compounds. Some of them exhibited inhibitory activity in the nanomolar range, albeit some of the performed changes led to either micromolar activity or to its absence, against hCA IX/XII. Molecular modelling studies focused the attention on the binding mode of these compounds to the enzyme. The proposed inhibition mechanism is the anchoring to zinc-bound water molecule. Docking studies along with molecular dynamics also underlined the importance of the compounds flexibility (e.g. achieved through the insertion of methylene group) which favoured potent and selective hCA inhibition.
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http://dx.doi.org/10.1080/14756366.2020.1828401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580763PMC
December 2020

Catechols: a new class of carbonic anhydrase inhibitors.

Chem Commun (Camb) 2020 Nov 1;56(85):13033-13036. Epub 2020 Oct 1.

Istituto di Biostrutture e Bioimmagini-CNR, Naples, Italy.

To date, catechols have been only poorly investigated as carbonic anhydrase (CA) inhibitors. Here we report the first structural information on the CA inhibition mechanism of these molecules, showing that they adopt a peculiar binding mode to the enzyme active site which involves the zinc-bound water molecule and the "deep water".
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http://dx.doi.org/10.1039/d0cc05172aDOI Listing
November 2020

Biofilm and Quorum Sensing inhibitors: the road so far.

Expert Opin Ther Pat 2020 Dec 10;30(12):917-930. Epub 2020 Oct 10.

Dipartimento di Scienze Biomediche, Chirurgiche ed Odontoiatriche, University of Milan , Milan, Italy.

Introduction: Biofilm is a complex aggregation of microorganisms characterized by the presence of a dynamic, adhesive and protective extracellular matrix composed of polysaccharides, proteins and nucleic acids. It is estimated that the vast majority of human infections are related to the biofilm in which the microorganisms reside and communicate with each other (Quorum Sensing), surviving in hostile environmental conditions.

Areas Covered: This review provides a comprehensive focus on the development state of promising strategies against biofilm production and eradication describing chemical structures, results, administration routes, pharmaceutical compositions, and SARs as well as their shortcomings within the 2019-2020 range.

Expert Opinion: New pharmacological targets have been explored in the past years, allowing a broader therapeutic arsenal against biofilm-related pathologies. The Quorum Sensing system was targeted as well in order to avoid the development of intrinsically antibiotic-resistant bacteria and to enhance a proper host defense.
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http://dx.doi.org/10.1080/13543776.2020.1830059DOI Listing
December 2020

Chalcones: Unearthing their therapeutic possibility as monoamine oxidase B inhibitors.

Eur J Med Chem 2020 Nov 23;205:112650. Epub 2020 Jul 23.

Department of Pharmacy, "G. D'Annunzio" University of Chieti-Pescara, Via Dei Vestini 31, 66100, Chieti, Italy. Electronic address:

In the last years the continuous efforts in the development of novel and effective inhibitors of human monoamine oxidases (hMAOs) promoted the discovery of new agents able to effectively and selectively bound one of the two isoforms (hMAO-A and hMAO-B). However, the parent chalcone scaffold still covers an important role in hMAOs inhibition. In the present work, we focused our attention on the researches performed in the last five years, involving chalcones or compounds that can be correlated to them. We classified the chalcones into different groups depending on their structural characteristics or common molecular properties. In this regard, we also considered chalcones based on heterocycles and compounds endowed with scaffolds containing a masked chalcone motif. When structural attributes could not be used, we took advantage of enzymatic activity to arrange compounds in a group. We followed this approach for the multitarget agents. Finally, we also analysed the naturally occurring chalcones. All the sections were discussed exhaustively and the structure-activity relationship (SAR) analyses were sustained by means of detailed images describing the effects related to the substituents or structural changes.
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http://dx.doi.org/10.1016/j.ejmech.2020.112650DOI Listing
November 2020

2-substituted benzothiazoles as antiproliferative agents: Novel insights on structure-activity relationships.

Eur J Med Chem 2020 Dec 21;207:112762. Epub 2020 Aug 21.

Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad de Sevilla, C/Profesor García González, 2, 41012, Sevilla, Spain.

Given the wide spectrum of biological activities, benzothiazoles represent privileged scaffolds in medicinal chemistry, useful in drug discovery programs to modulate biological activities of lead compounds. A large body of knowledge about benzothiazoles has been reported in scientific literature, describing their antimicrobial, anticonvulsant, neuroprotective, anti-inflammatory, and antiproliferative effects. This review summarizes the results obtained in the structure-activity relationship studies on antiproliferative benzothiazoles, focusing on 2-substituted derivatives and on mechanism of action responsible for the antitumor effects of this class of compounds.
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http://dx.doi.org/10.1016/j.ejmech.2020.112762DOI Listing
December 2020

Antimicrobial and Antibiofilm Activities of New Synthesized Silver Ultra-NanoClusters (SUNCs) Against .

Front Microbiol 2020 31;11:1705. Epub 2020 Jul 31.

Department of Medical, Oral, and Biotechnological Sciences, "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy.

colonizes approximately 50% of the world's population, and it is the cause of chronic gastritis, peptic ulcer disease, and gastric cancer. The increase of antibiotic resistance is one of the biggest challenges of our century due to its constant increase. In order to identify an alternative or adjuvant strategy to the standard antibiotic therapy, the activity of newly synthesized Silver Ultra-NanoClusters (SUNCs), characterized by an average size inferior to 5 nm, against clinical strains of , with different antibiotic susceptibilities, was evaluated in this study. MICs and MBCs were determined by the broth microdilution method, whereas the effect of drug combinations was determined by the checkerboard assay. The Minimum Biofilm Eradication Concentration (MBEC) was measured using AlamarBlue (AB) assay and colony-forming unit (CFU) counts. The cytotoxicity was evaluated by performing the MTT assay on the AGS cell line. The inhibitory activity was expressed in terms of bacteriostatic and bactericidal potential, with MIC, MIC, and MBC of 0.33 mg/L against planktonic strains. Using the fractional inhibitory concentration index (FICI), SUNCs showed potential synergism with metronidazole and clarithromycin. The biofilm eradication was obtained after treatment with 2×, 3×, and 4× MIC values. Moreover, SUNCs showed low toxicity on human cells and were effective in eradicating a mature biofilm produced by . The data presented in this study demonstrate that SUNCs could represent a novel strategy for the treatment of infections either alone or in combination with metronidazole.
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http://dx.doi.org/10.3389/fmicb.2020.01705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411087PMC
July 2020

Effects of Processing on Polyphenolic and Volatile Composition and Fruit Quality of Clery Strawberries.

Antioxidants (Basel) 2020 Jul 17;9(7). Epub 2020 Jul 17.

Department of Drug Chemistry and Technologies, University "Sapienza" of Rome, P.le Aldo Moro 5, 00185 Rome, Italy.

Strawberries belonging to cultivar Clery ( (Duchesne ex Weston)), cultivated in central Italy were subjected to a multi-methodological experimental study. Fresh and defrosted strawberries were exposed to different processing methods, such as homogenization, thermal and microwave treatments. The homogenate samples were submitted to CIEL*a*b* color analysis and Head-Space GC/MS analysis to determine the impact of these procedures on phytochemical composition. Furthermore, the corresponding strawberry hydroalcoholic extracts were further analyzed by HPLC-DAD for secondary metabolites quantification and by means of spectrophotometric in vitro assays to evaluate their total phenolic and total flavonoid contents and antioxidant activity. These chemical investigations confirmed the richness in bioactive metabolites supporting the extraordinary healthy potential of this fruit as a food ingredient, as well as functional food, highlighting the strong influence of the processing steps which could negatively impact on the polyphenol composition. Despite a more brilliant red color and aroma preservation, non-pasteurized samples were characterized by a lower content of polyphenols and antioxidant activity with respect to pasteurized samples, as also suggested by the PCA analysis of the collected data.
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http://dx.doi.org/10.3390/antiox9070632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402087PMC
July 2020

The Chronicle of COVID-19 and Possible Strategies to Curb the Pandemic

Curr Med Chem 2020 07 2. Epub 2020 Jul 2.

Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi-682 041, India

COVID-19, a type of infection that emerged in Wuhan, has become a pandemic affecting people worldwide and is rapidly spreading and evolving. Day by day, the confirmed cases and deaths are increasing many folds. SARS-CoV-2 is a novel virus; therefore, limited data are available to curb the disease. Epidemiological approaches, such as isolation, quarantine, social distancing, lockdown, and curfew, are being employed to halt the spread of the disease. Individual and joint efforts all over the world are producing a wealth of data and information which are expected to produce therapeutic strategies against COVID-19. Current research focuses on the utilization of antiviral drugs, repurposing strategies, vaccine development, as well as basic to advanced research about the organism and the infection. The review focuses on its life cycle, targets, and possible therapeutic strategies, which can lead to further research and development of COVID-19 therapy.
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http://dx.doi.org/10.2174/0929867327666200702151018DOI Listing
July 2020

Synthesis and evaluation of a large library of nitroxoline derivatives as pancreatic cancer antiproliferative agents.

J Enzyme Inhib Med Chem 2020 Dec;35(1):1331-1344

Department of Pharmacy, "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy.

Pancreatic cancer (PC) is one of the deadliest carcinomas and in most cases, which are diagnosed with locally advanced or metastatic disease, current therapeutic options are highly unsatisfactory. Based on the anti-proliferative effects shown by nitroxoline, an old urinary antibacterial agent, we explored a large library of newly synthesised derivatives to unravel the importance of the OH moiety and pyridine ring of the parent compound. The new derivatives showed a valuable anti-proliferative effect and some displayed a greater effect as compared to nitroxoline against three pancreatic cancer cell lines with different genetic profiles. In particular, pharmacokinetic data, clonogenicity assays and selectivity indexes of the most promising compounds showed several advantages for such derivatives, as compared to nitroxoline. Moreover, some of these novel compounds had stronger effects on cell viability and/or clonogenic capacity in PC cells as compared to erlotinib, a targeted agent approved for PC treatment.
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http://dx.doi.org/10.1080/14756366.2020.1780228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470072PMC
December 2020

Inhibition of lysine acetyltransferases impairs tumor angiogenesis acting on both endothelial and tumor cells.

J Exp Clin Cancer Res 2020 Jun 5;39(1):103. Epub 2020 Jun 5.

Preclinical Models and New Therapeutic Agents Unit, Department of Research and Advanced Technologies, IRCCS Regina Elena National Cancer Institute, Rome, Italy.

Background: Understanding the signalling pathways involved in angiogenesis, and developing anti-angiogenic drugs are one of the major focuses on cancer research. Herein, we assessed the effect of CPTH6, a lysine acetyltransferase inhibitor and anti-tumoral compound, on angiogenesis-related properties of both endothelial and cancer cells.

Methods: The in vitro effect of CPTH6 on protein acetylation and anti-angiogenic properties on endothelial and lung cancer cells was evaluated via wound healing, trans-well invasion and migration, tube formation, immunoblotting and immunofluorescence. Matrigel plug assay, zebrafish embryo and mouse xenograft models were used to evaluate in vivo anti-angiogenic effect of CPTH6.

Results: CPTH6 impaired in vitro endothelial angiogenesis-related functions, and decreased the in vivo vascularization both in mice xenografts and zebrafish embryos. Mechanistically, CPTH6 reduced α-tubulin acetylation and induced accumulation of acetylated microtubules in the perinuclear region of endothelial cells. Interestingly, CPTH6 also affected the angiogenesis-related properties of lung cancer cells, and conditioned media derived from CPTH6-treated lung cancer cells impaired endothelial cells morphogenesis. CPTH6 also modulated the VEGF/VEGFR2 pathway, and reshaped cytoskeletal organization of lung cancer cells. Finally, anti-migratory effect of CPTH6, dependent on α-tubulin acetylation, was also demonstrated by genetic approaches in lung cancer cells.

Conclusion: Overall, this study indicates that α-tubulin acetylation could play a role in the anti-angiogenic effect of CPTH6 and, more in general, it adds information to the role of histone acetyltransferases in tumor angiogenesis, and proposes the inhibition of these enzymes as an antiangiogenic therapy of cancer.
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http://dx.doi.org/10.1186/s13046-020-01604-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273677PMC
June 2020

Chemical Constituents and Biologic Activities of Sage Species: A Comparison between L., L. and .

Antioxidants (Basel) 2020 Jun 2;9(6). Epub 2020 Jun 2.

Faculty of Pharmacy, "Iuliu Hațieganu" University of Medicine and Pharmacy, 8 Victor Babeș Street, 400012 Cluj-Napoca, Romania.

Even though genus is one of the most known and studied taxa of Lamiaceae family, the knowledge regarding the chemical composition and health-related benefits of some locally used species (mostly endemic) is still scarce. In this regard, the present work aims to evaluate the chemical profile and potential bioactivities of 70% () ethanolic extracts obtained from the less-studied and in comparison with . HPLC-PDA analysis revealed the presence of rutin and catechin as the main compounds in the extracts of the three studied species (using the employed HPLC method), whereas the presence of naringenin was highlighted only in extract. Chlorogenic acid, rutin and quercetin were identified and quantified for the first time in extracts. The in vitro antioxidant capacity of each extract was tested through complementary methods (phosphomolybdenum assay, DPPH, ABTS, CUPRAC and FRAP assays), and correlated with the presence of phenolics (especially flavonoids) in high amounts. The neuroprotective and antidiabetic abilities of (the most active as AChE, BChE and α-glucosidase inhibitor), (the most active as α-amylase inhibitor) and were also studied. For each extract it was determined the antimicrobial, antifungal and cytotoxic effects using in vitro assays. The obtained results confirm the potential of and as promising sources of bioactive compounds and as a starting point for further analyses.
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http://dx.doi.org/10.3390/antiox9060480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346212PMC
June 2020

Azidothymidine "Clicked" into 1,2,3-Triazoles: First Report on Carbonic Anhydrase-Telomerase Dual-Hybrid Inhibitors.

J Med Chem 2020 07 10;63(13):7392-7409. Epub 2020 Jun 10.

NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy.

Cancer cells rely on the enzyme telomerase (EC 2.7.7.49) to promote cellular immortality. Telomerase inhibitors (i.e., azidothymidine) can represent promising antitumor agents, although showing high toxicity when administered alone. Better outcomes were observed within a multipharmacological approach instead. In this context, we exploited the validated antitumor targets carbonic anhydrases (CAs; EC 4.2.1.1) IX and XII to attain the first proof of concept on CA-telomerase dual-hybrid inhibitors. Compounds , , , and showed good in vitro inhibition potency against the CAs IX and XII, with values in the low nanomolar range, and strong antitelomerase activity in PC-3 and HT-29 cells (IC values ranging from 5.2 to 9.1 μM). High-resolution X-ray crystallography on selected derivatives in the adduct with hCA II as a model study allowed to determine their binding modes and thus to set the structural determinants necessary for further development of compounds selectively targeting the tumoral cells.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00636DOI Listing
July 2020

Water Extract from Inflorescences of Industrial Hemp Futura 75 Variety as a Source of Anti-Inflammatory, Anti-Proliferative and Antimycotic Agents: Results from In Silico, In Vitro and Ex Vivo Studies.

Antioxidants (Basel) 2020 May 17;9(5). Epub 2020 May 17.

Department of Pharmacy, University "G. d'Annunzio" of Chieti-Pescara, 66100 Chieti, Italy.

Industrial hemp () is traditionally cultivated as a valuable source of fibers and nutrients. Multiple studies also demonstrated antimicrobial, anti-proliferative, phytotoxic and insecticide effects of the essential oil from hemp female inflorescences. On the other side, only a few studies explored the potential pharmacological application of polar extracts from inflorescences. In the present study, we investigated the water extract from inflorescences of industrial hemp Futura 75 variety, from phytochemical and pharmacological point of view. The water extract was assayed for phenolic compound content, radical scavenger/reducing, chelating and anti-tyrosinase effects. Through an ex vivo model of toxicity induced by lipopolysaccharide (LPS) on isolated rat colon and liver, we explored the extract effects on serotonin, dopamine and kynurenine pathways and the production of prostaglandin (PG)E. Anti-proliferative effects were also evaluated against human colon cancer HCT116 cell line. Additionally, antimycotic effects were investigated against Finally, in silico studies, including bioinformatics, network pharmacology and docking approaches were conducted in order to predict the putative targets underlying the observed pharmacological and microbiological effects. Futura 75 water extract was able to blunt LPS-induced reduction of serotonin and increase of dopamine and kynurenine turnover, in rat colon. Additionally, the reduction of PGE levels was observed in both colon and liver specimens, as well. The extract inhibited the HCT116 cell viability, the growth of and and the activity of tyrosinase, in vitro, whereas in silico studies highlighting the inhibitions of cyclooxygenase-1 (induced by carvacrol), carbonic anhydrase IX (induced by chlorogenic acid and gallic acid) and lanosterol 14-α-demethylase (induced by rutin) further support the observed pharmacological and antimycotic effects. The present findings suggest female inflorescences from industrial hemp as high quality by-products, thus representing promising sources of nutraceuticals and cosmeceuticals against inflammatory and infectious diseases.
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http://dx.doi.org/10.3390/antiox9050437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278775PMC
May 2020

Phytocomplex Characterization and Biological Evaluation of Powdered Fruits and Leaves from .

Molecules 2020 Apr 26;25(9). Epub 2020 Apr 26.

Department of Drug Chemistry and Technologies, "Sapienza" University of Rome, 00185 Rome, Italy.

Fully ripe fruits and mature leaves of were harvested and analyzed by means of analytical and biological tests to better comprehend the chemical composition and therapeutic/nutraceutical potential of this plant. Fruits and leaves were dried and the obtained powders were analyzed to study their color character and (via headspace gas chromatography) describe the chemical profile. Subsequently, they were submitted to a chloroform-methanol extraction, to a hydroalcoholic extraction procedure assisted or not by microwaves, and to an extraction with supercritical CO, assisted or not by ethanol as the co-solvent, to detect the polyphenolic and the volatile content. The resulting extracts were evaluated in terms of chlorophyll and carotenoid content, polyphenolic content, volatile fraction, total phenolic content, total flavonoid content, antioxidant activity, radical scavenging activity, and enzymatic inhibition activity. The results confirmed the correlation between the chemical composition and the high antioxidant potential of leaf extracts compared to the fruit extracts in terms of the phenolic and pigment content. A promising effect against tyrosinase emerged for all the extracts, suggesting a therapeutic/nutraceutical use for this plant. Conversely, the volatile content from both natural matrices was similar.
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http://dx.doi.org/10.3390/molecules25092021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248930PMC
April 2020

Development of Thiazolidinones as Fungal Carbonic Anhydrase Inhibitors.

Int J Mol Sci 2020 Apr 22;21(8). Epub 2020 Apr 22.

Bezmialem Vakif University, Computer-aided drug discovery laboratory, Department of Pharmacology, Faculty of Pharmacy, 34093 Istanbul, Turkey.

In our efforts to find new and selective thiazolidinone-based anti- agents, we synthesized and tested 26 thiazolidinones against several spp. and Gram-positive and Gram-negative bacteria. The compounds showed selective antifungal activity with potency similar to fluconazole and clotrimazole, while lacking strong antibacterial activity. Molecular docking and molecular dynamics studies were performed on CYP51a1 and carbonic anhydrase (CA) enzymes to further suggest putative targets that could mediate the antifungal effects of these compounds. Finally, the compounds were tested in enzyme inhibition assays to assess their putative mechanism of action and showed promising values in the 0.1-10 µM range against the β-CA enzyme CgNce103.
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http://dx.doi.org/10.3390/ijms21082960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215574PMC
April 2020