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Fabrizio Carta

Università degli Studi di Firenze (University of Florence), Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino, Faculty Member

Università degli Studi di Firenze (University of Florence), Dipartimento di Chimica, Post-Doc

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Fabrizio Carta obtained his Master’sDegree from the University of Sassari (Italy) and his PhD in Chemistry fromthe University of Bristol (UK). He then carried out postdoctoral research at the Massachusetts Institute of Technology (USA) at the University of Florence (Italy). He is currently TenureTrack Assistant Professor in Medicinal Chemistry at the University of Florence (Italy).His main interests include metallo/organic and inorganicchemistry with emphasis on mechanistic pathways, medicinal chemistry, biochemistry, and X-ray crystallography

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Temple University

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The University of Newcastle

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Papers by Fabrizio Carta

The Integrase: An Overview of a Key Player Enzyme in the Antiviral Scenario

International Journal of Molecular Sciences

Integration of a desossiribonucleic acid (DNA) copy of the viral ribonucleic acid (RNA) into host... more Integration of a desossiribonucleic acid (DNA) copy of the viral ribonucleic acid (RNA) into host genomes is a fundamental step in the replication cycle of all retroviruses. The highly conserved virus-encoded Integrase enzyme (IN; EC 2.7.7.49) catalyzes such a process by means of two consecutive reactions named 3′-processing (3-P) and strand transfer (ST). The Authors report and discuss the major discoveries and advances which mainly contributed to the development of Human Immunodeficiency Virus (HIV) -IN targeted inhibitors for therapeutic applications. All the knowledge accumulated over the years continues to serve as a valuable resource for the design and development of effective antiretroviral drugs.

Uncovering Novel Capsaicin Inhibitory Activity towards Human Carbonic Anhydrase Isoforms IX and XII by Combining In Silico and In Vitro Studies

Antioxidants

Hot pepper (Capsicum annuum) represents one of the most widespread functional foods of the Medite... more Hot pepper (Capsicum annuum) represents one of the most widespread functional foods of the Mediterranean diet, and is associated with a reduced risk of developing cardiovascular disease, cancer, and mental disorders. In particular, its bioactive spicy molecules, named Capsaicinoids, exhibit polypharmacological properties. Among them, Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is the most studied and reported in variegated scientific contributions for its beneficial effects, often linked to mechanisms of action unrelated to the activation of Transient Receptor Potential Vanilloid 1 (TRPV1). In this study, we present the application of in silico methods to Capsaicin for evaluating its inhibitory activity against the tumor-associated human (h) expressed CA IX and XII. In vitro assays confirmed Capsaicin inhibitory activity towards the most relevant tumor-related hCA isoforms. In particular, the hCAs IX and XII showed an experimental KI value of 0.28 μM and 0.064 μM, respectivel...

Intramolecular oxidative deselenization of acylselenoureas: a facile synthesis of benzoxazole amides and carbonic anhydrase inhibitors

Organic & Biomolecular Chemistry, 2016

A mild, efficient and one pot procedure to access benzoxazoles using easily accessible acylseleno... more

New Insights into Conformationally Restricted Carbonic Anhydrase Inhibitors

Molecules

This paper reports an investigation into the impact of pyridyl functional groups in conjunction w... more This paper reports an investigation into the impact of pyridyl functional groups in conjunction with hydroxide-substituted benzenesulfonamides on the inhibition of human carbonic anhydrase (CA; EC 4.2.1.1) enzymes. These compounds were tested in vitro of CA II and CA IX, two physiologically important CA isoforms. The most potent inhibitory molecules against CA IX, 3g, 3h, and 3k, were studied to understand their binding modes via X-ray crystallography in adduct with CA II and CA IX-mimic. This research further adds to the field of CA inhibitors to better understand ligand selectivity between isoforms found in humans.

Inhibitory Effects of Sulfonamide Derivatives on the β-Carbonic Anhydrase (MpaCA) from Malassezia pachydermatis, a Commensal, Pathogenic Fungus Present in Domestic Animals

International Journal of Molecular Sciences

Fungi are exposed to various environmental variables during their life cycle, including changes i... more Fungi are exposed to various environmental variables during their life cycle, including changes in CO2 concentration. CO2 has the potential to act as an activator of several cell signaling pathways. In fungi, the sensing of CO2 triggers cell differentiation and the biosynthesis of proteins involved in the metabolism and pathogenicity of these microorganisms. The molecular machineries involved in CO2 sensing constitute a promising target for the development of antifungals. Carbonic anhydrases (CAs, EC 4.2.1.1) are crucial enzymes in the CO2 sensing systems of fungi, because they catalyze the reversible hydration of CO2 to proton and HCO3-. Bicarbonate in turn boots a cascade of reactions triggering fungal pathogenicity and metabolism. Accordingly, CAs affect microorganism proliferation and may represent a potential therapeutic target against fungal infection. Here, the inhibition of the unique β-CA (MpaCA) encoded in the genome of Malassezia pachydermatis, a fungus with substantial r...

Discovery of 4-Hydroxy-3-(3-(phenylureido)benzenesulfonamides As SLC-0111 Analogues For the Treatment of Hypoxic Tumors Overexpressing Carbonic Anhydrase IX

Journal of medicinal chemistry, Jan 2, 2018

Herein we report the 2-aminophenol-4-sulfonamide 1 and its ureido derivatives 2-23 as inhibitors ... more Herein we report the 2-aminophenol-4-sulfonamide 1 and its ureido derivatives 2-23 as inhibitors of the carbonic anhydrase (CA, EC 4.2.1.1) enzymes as analogs of the hypoxic tumor phase II entering drug SLC-0111. This scaffold may determine preferential rotational isomers to selectively interact within the tumor-associated CAs. Most compounds indeed showed in vitro selective inhibitory activities on the tumor associated CA isoforms IX and XII. The most potent derivative within the series was 11 (KIs of 2.59 and 7.64 nM on hCA IX and XII respectively) which shares the 4-fluorophenylureido tail with the clinical candidate. We investigated by means of X-ray crystallographic studies the binding modes of 3 selected compounds of this series to CA I. The evaluation of therapeutic efficacy of compound 11 in an orthotopic, syngeneic model of CA IX-positive breast cancer in vivo showed close matching antitumoral effects and tolerance with SLC-0111.

Thiosemicarbazide-Substituted Coumarins as Selective Inhibitors of the Tumor Associated Human Carbonic Anhydrases IX and XII

Molecules

A novel series of thiosemicarbazide-substituted coumarins was synthesized and the inhibitory effe... more A novel series of thiosemicarbazide-substituted coumarins was synthesized and the inhibitory effects against four physiologically relevant carbonic anhydrase isoforms I, II, IX and XII showed selective activities on the tumor-associated IX and XII isozymes. Molecular modeling studies on selected compounds 14a and 22a were performed. The binding modes of such compounds were determined assuming their enzymatically active structures (i.e., cinnamic acid) in the thermodynamically favored, and not previously explored, E geometry. Molecular modelling suggests multiple interactions within the enzymatic cavity and may explain the high potency and selectivity reported for the hCAs IX and XII.

Pain Relieving Effect of-NSAIDs-CAIs Hybrid Molecules: Systemic and Intra-Articular Treatments against Rheumatoid Arthritis

International Journal of Molecular Sciences, 2019

To study new target-oriented molecules that are active against rheumatoid arthritis-dependent pai... more To study new target-oriented molecules that are active against rheumatoid arthritis-dependent pain, new dual inhibitors incorporating both a carbonic anhydrase (CA)-binding moiety and a cyclooxygenase inhibitor (NSAID) were tested in a rat model of rheumatoid arthritis induced by CFA intra-articular (i.a.) injection. A comparison between a repeated per os treatment and a single i.a. injection was performed. CFA (50 µL) was injected in the tibiotarsal joint, and the effect of per os repeated treatment (1 mg kg −1) or single i.a injection (1 mg mL −1 , 50 µL) with NSAIDs-CAIs hybrid molecules, named 4 and 5, was evaluated. The molecules 4 and 5, which were administered daily for 14 days, significantly prevented CFA-induced hypersensitivity to mechanical noxious (Paw pressure test) and non-noxious stimuli (von Frey test), the postural unbalance related to spontaneous pain (Incapacitance test) and motor alterations (Beam balance test). Moreover, to study a possible localized activity, 4 and 5 were formulated in liposomes (lipo 4 and lipo 5, both 1 mg mL −1) and directly administered by a single i.a. injection seven days after CFA injection. Lipo 5 decreased the mechanical hypersensitivity to noxious and non-noxious stimuli and improved motor coordination. Oral and i.a. treatments did not rescue the joint, as shown by the histological analysis. This new class of potent molecules, which is able to inhibit at the same time CA and cyclooxygenase, shows high activity in a preclinical condition of rheumatoid arthritis, strongly suggesting a novel attractive pharmacodynamic profile.

Discovery of β-Adrenergic Receptors Blocker-Carbonic Anhydrase Inhibitor Hybrids for Multitargeted Antiglaucoma Therapy

Journal of medicinal chemistry, Jan 13, 2018

The combination of a β-adrenergic receptors (AR) blocker and a carbonic anhydrase (CA, EC 4.2.1.1... more The combination of a β-adrenergic receptors (AR) blocker and a carbonic anhydrase (CA, EC 4.2.1.1) inhibitor in eye drops formulations is one of the most clinically used treatment for glaucoma. A novel approach consisting of single-molecule, multitargeted compounds for the treatment of glaucoma is proposed here by designing compounds which concomitantly interact with the β-adrenergic and CA targets. Most derivatives of the two series of benzenesulfonamides incorporating 2-hydroxypropylamine moieties reported here exhibited striking efficacy against the target hCA II and XII, whereas a subset of compounds also showed significant modulation of β- and β-ARs. X-ray crystallography studies provided rationale for the observed hCA inhibition. The best dual-agents decreased IOP more effectively than clinically used dorzolamide, timolol, and the combination of them in an animal model of glaucoma. The reported evidence supports the proof-of-concept of β-ARs blocker-CAI hybrids for antiglaucom...

Chalcogenides-incorporating carbonic anhydrase inhibitors concomitantly reverted oxaliplatin-induced neuropathy and enhanced antiproliferative action

European Journal of Medicinal Chemistry, 2021

Platinum-based chemotherapy is widely used for the treatment of different tumors but is associate... more Platinum-based chemotherapy is widely used for the treatment of different tumors but is associated with serious side effects, among which neuropathic pain. Carbonic anhydrase (CA, EC 4.2.1.1) inhibitors have recently been validated as therapeutic agents in neuropathic pain and as antitumor agents. We report the synthesis of new organochalcogenides bearing the benzensulfonamide moiety acting as potent inhibitors of several human CA isoforms and, in particular, against hCA II and VII endowed with potent neuropathic pain attenuating effects. Moreover, in combination with cisplatin or doxorubicin, some of the new CA inhibitors enhanced the effects of the anticancer drugs capability in counteracting breast cancer MCF7 cell viability. The concomitant anti-neuropathic pain and antiproliferative effects of the new chalcogenide-based CA inhibitors represent an innovative approach for the counteraction and management of side effects associated with clinically platinum drugs as antitumor agents.

Crystal structure of human carbonic anhydrase II in complex with the inhibitor 4-Pyridin-3-yl-benzenesulfonamide

New Biological Targets for the Treatment of Leishmaniasis

Membrane permeable but not impermeable carbonic anhydrase inhibitors dilate precontracted porcine retinal arteries

Отчет о прошедшей 11-12 апреля 2018 г. на филологическом факультете Международной конференции сту... more Отчет о прошедшей 11-12 апреля 2018 г. на филологическом факультете Международной конференции студентов, аспирантов и молодых ученых «Ломоносов» (День науки) содержит сведения о количестве и составе участников, структуре и тематике подсекций, лучших докладчиках и наградах. Ключевые слова: конференция Ломоносов; День науки; молодежный форум. This report is dedicated to the philological section of the International conference "Lomonosov" which took place on April 11-12, 2018 at the Faculty of Philology. Approximately 1050 young scientists and scholars had applied and 600 were approved to participate. Guests from all over Russia as well as from Australia,

Pain Relieving Eect of-NSAIDs-CAIs HybridMolecules: Systemic and Intra-Articular Treatmentsagainst Rheumatoid Arthritis

Taurultams incorporating arylsulfonamide: First in vitro inhibition studies of α-, β- and γ-class Carbonic Anhydrases from Vibrio cholerae and Burkholderia pseudomallei

European Journal of Medicinal Chemistry, 2021

A new series of taurultambenzenesulfonamides 1-17 were prepared and considered for their inhibito... more A new series of taurultambenzenesulfonamides 1-17 were prepared and considered for their inhibitory activity in vitro against the Carbonic Anhydrases from Vibrio cholerae (VchCA-α, VchCA-β and VchCA-γ) and Burkholderia pseudomallei (BpsCA-β and BpsCA-γ). Among the compounds tested, derivatives 4, 5, 7, 10, 12, and 16 resulted in highly effective VchCAα inhibitors (KI values spanning within the 6.1-9.6 nM range) and endowed with excellent Selectivity Indexes (SIs; KI VchCA-α/KI hCA II) all comprised between 0.04 and 0.09. Potent in vitro inhibitors for the BpsCA-γ were also identified (KIs of 18.9-19.5 nM). The results here reported may represent the blueprint for the future development of a new generation of CA-based antibiotics integrated with free of resistance mechanisms of action adopted from known drugs.

Multitargeting application of proline-derived peptidomimetics addressing cancer-related human matrix metalloproteinase 9 and carbonic anhydrase II

European Journal of Medicinal Chemistry, 2021

A series of d-proline peptidomimetics were evaluated as dual inhibitors of both human carbonic an... more A series of d-proline peptidomimetics were evaluated as dual inhibitors of both human carbonic anhydrases (hCAs) and human gelatinases (MMP2 and MMP9), as these enzymes are both involved in the carcinogenesis and tumor invasion processes. The synthesis and enzyme inhibition kinetics of d-proline derivatives containing a biphenyl sulfonamido moiety revealed an interesting inhibition profile of compound XIV towards MMP9 and CAII. The SAR analysis and docking studies revealed a stringent requirement of a trans geometry for the two arylsulfonyl moieties, which are both necessary for inhibition of MMP9 and CAII. As MMP9 and CAII enzymes are both overexpressed in gastrointestinal stromal tumor cells, this molecule may represent an interesting chemical probe for a multitargeting approach on gastric and colorectal cancer.

Benzylaminoethyureido-Tailed Benzenesulfonamides: Design, Synthesis, Kinetic and X-ray Investigations on Human Carbonic Anhydrases

International Journal of Molecular Sciences, 2020

A drug design strategy of carbonic anhydrase inhibitors (CAIs) belonging to sulfonamides incorpor... more A drug design strategy of carbonic anhydrase inhibitors (CAIs) belonging to sulfonamides incorporating ureidoethylaminobenzyl tails is presented. A variety of substitution patterns on the ring and the tails, located on para- or meta- positions with respect to the sulfonamide warheads were incorporated in the new compounds. Inhibition of human carbonic anhydrases (hCA) isoforms I, II, IX and XII, involving various pathologies, was assessed with the new compounds. Selective inhibitory profile towards hCA II was observed, the most active compounds being low nM inhibitors (KIs of 2.8–9.2 nM, respectively). Extensive X-ray crystallographic analysis of several sulfonamides in an adduct with hCA I allowed an in-depth understanding of their binding mode and to lay a detailed structure-activity relationship.

Synthesis and carbonic anhydrase I, II, VII, and IX inhibition studies with a series of benzo[d]thiazole-5- and 6-sulfonamides

Journal of Enzyme Inhibition and Medicinal Chemistry, 2017

A series of benzo[d]thiazole-5-and 6-sulfonamides has been synthesized and investigated for the i... more A series of benzo[d]thiazole-5-and 6-sulfonamides has been synthesized and investigated for the inhibition of several human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoforms, using ethoxzolamide (EZA) as lead molecule. 2-Amino-substituted, 2-acylamino-and halogenated (bromo-and iodo-derivatives at the heterocyclic ring) compounds led to several interesting inhibitors against the cytosolic hCA I, II and VII, as well as the transmembrane, tumor-associated hCA IX isoforms. Several subnanomolar/low nanomolar, isoform-selective sulfonamide inhibitors targeting hCA II, VII and IX were detected. The sharp structure-activity relationship for CA inhibition with this small series of derivatives, with important changes of activity observed even after minor changes in the scaffold or at the 2-amino moiety, make this class of scarcely investigated sulfonamides of particular interest for further investigations.

Carbonic anhydrases and their functional differences in human and mouse sperm physiology

Biochemical and Biophysical Research Communications, 2015

Fertilization is a key reproductive event in which sperm and egg fuse to generate a new individua... more Fertilization is a key reproductive event in which sperm and egg fuse to generate a new individual. Proper regulation of certain parameters (such as intracellular pH) is crucial for this process. Carbonic anhydrases (CAs) are among the molecular entities that control intracellular pH dynamics in most cells. Unfortunately, little is known about the function of CAs in mammalian sperm physiology. For this reason, we re-explored the expression of CAI, II, IV and XIII in human and mouse sperm. We also measured the level of CA activity, determined by mass spectrometry, and found that it is similar in non-capacitated and capacitated mouse sperm. Importantly, we found that CAII activity accounts for half of the total CA activity in capacitated mouse sperm. Using the general CA inhibitor ethoxyzolamide, we studied how CAs participate in fundamental sperm physiological processes such as motility and acrosome reaction in both species. We found that capacitated human sperm depend strongly on CA activity to support normal motility, while capacitated mouse sperm do not. Finally, we found that CA inhibition increases the acrosome reaction in capacitated human sperm, but not in capacitated mouse sperm.

Inhibition studies of bacterial, fungal and protozoan β-class carbonic anhydrases with Schiff bases incorporating sulfonamide moieties

Bioorganic & Medicinal Chemistry, 2015

A series of new Schiff bases derived from sulfanilamide, 3-fluorosulfanilamide or 4-(2-aminoethyl... more A series of new Schiff bases derived from sulfanilamide, 3-fluorosulfanilamide or 4-(2-aminoethyl)-benzenesulfonamide containing either a hydrophobic or a hydrophilic tail, have been investigated as inhibitors of three b-carbonic anhydrases (CA, EC 4.2.1.1) from three different microorganisms. Their antifungal, antibacterial and antiprotozoan activities have been determined against the pathogenic fungus Cryptococcus neoformans, the bacterial pathogen Brucella suis and the protozoan parasite Leishmania donovani chagasi, responsible for Leishmaniasis. The results of these inhibition studies show that all three enzymes were efficiently inhibited by the Schiff base sulfonamides with K I values in the nanomolar or submicromolar range, depending on the nature of the tail, coming from the aryl/heteroaryl moiety present in the starting aldehyde employed in the synthesis. Furthermore, the compounds hereby investigated revealed high b-CAs selectivity over the ubiquitous, physiologically relevant and off-target human isoforms (CA I and II) and to be more potent as antifungal and antibacterial than as antiprotozoan potential drugs.

The Integrase: An Overview of a Key Player Enzyme in the Antiviral Scenario

International Journal of Molecular Sciences

Integration of a desossiribonucleic acid (DNA) copy of the viral ribonucleic acid (RNA) into host... more Integration of a desossiribonucleic acid (DNA) copy of the viral ribonucleic acid (RNA) into host genomes is a fundamental step in the replication cycle of all retroviruses. The highly conserved virus-encoded Integrase enzyme (IN; EC 2.7.7.49) catalyzes such a process by means of two consecutive reactions named 3′-processing (3-P) and strand transfer (ST). The Authors report and discuss the major discoveries and advances which mainly contributed to the development of Human Immunodeficiency Virus (HIV) -IN targeted inhibitors for therapeutic applications. All the knowledge accumulated over the years continues to serve as a valuable resource for the design and development of effective antiretroviral drugs.

Uncovering Novel Capsaicin Inhibitory Activity towards Human Carbonic Anhydrase Isoforms IX and XII by Combining In Silico and In Vitro Studies

Antioxidants

Hot pepper (Capsicum annuum) represents one of the most widespread functional foods of the Medite... more Hot pepper (Capsicum annuum) represents one of the most widespread functional foods of the Mediterranean diet, and is associated with a reduced risk of developing cardiovascular disease, cancer, and mental disorders. In particular, its bioactive spicy molecules, named Capsaicinoids, exhibit polypharmacological properties. Among them, Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is the most studied and reported in variegated scientific contributions for its beneficial effects, often linked to mechanisms of action unrelated to the activation of Transient Receptor Potential Vanilloid 1 (TRPV1). In this study, we present the application of in silico methods to Capsaicin for evaluating its inhibitory activity against the tumor-associated human (h) expressed CA IX and XII. In vitro assays confirmed Capsaicin inhibitory activity towards the most relevant tumor-related hCA isoforms. In particular, the hCAs IX and XII showed an experimental KI value of 0.28 μM and 0.064 μM, respectivel...

Intramolecular oxidative deselenization of acylselenoureas: a facile synthesis of benzoxazole amides and carbonic anhydrase inhibitors

Organic & Biomolecular Chemistry, 2016

A mild, efficient and one pot procedure to access benzoxazoles using easily accessible acylseleno... more

New Insights into Conformationally Restricted Carbonic Anhydrase Inhibitors

Molecules

This paper reports an investigation into the impact of pyridyl functional groups in conjunction w... more This paper reports an investigation into the impact of pyridyl functional groups in conjunction with hydroxide-substituted benzenesulfonamides on the inhibition of human carbonic anhydrase (CA; EC 4.2.1.1) enzymes. These compounds were tested in vitro of CA II and CA IX, two physiologically important CA isoforms. The most potent inhibitory molecules against CA IX, 3g, 3h, and 3k, were studied to understand their binding modes via X-ray crystallography in adduct with CA II and CA IX-mimic. This research further adds to the field of CA inhibitors to better understand ligand selectivity between isoforms found in humans.

Inhibitory Effects of Sulfonamide Derivatives on the β-Carbonic Anhydrase (MpaCA) from Malassezia pachydermatis, a Commensal, Pathogenic Fungus Present in Domestic Animals

International Journal of Molecular Sciences

Fungi are exposed to various environmental variables during their life cycle, including changes i... more Fungi are exposed to various environmental variables during their life cycle, including changes in CO2 concentration. CO2 has the potential to act as an activator of several cell signaling pathways. In fungi, the sensing of CO2 triggers cell differentiation and the biosynthesis of proteins involved in the metabolism and pathogenicity of these microorganisms. The molecular machineries involved in CO2 sensing constitute a promising target for the development of antifungals. Carbonic anhydrases (CAs, EC 4.2.1.1) are crucial enzymes in the CO2 sensing systems of fungi, because they catalyze the reversible hydration of CO2 to proton and HCO3-. Bicarbonate in turn boots a cascade of reactions triggering fungal pathogenicity and metabolism. Accordingly, CAs affect microorganism proliferation and may represent a potential therapeutic target against fungal infection. Here, the inhibition of the unique β-CA (MpaCA) encoded in the genome of Malassezia pachydermatis, a fungus with substantial r...

Discovery of 4-Hydroxy-3-(3-(phenylureido)benzenesulfonamides As SLC-0111 Analogues For the Treatment of Hypoxic Tumors Overexpressing Carbonic Anhydrase IX

Journal of medicinal chemistry, Jan 2, 2018

Herein we report the 2-aminophenol-4-sulfonamide 1 and its ureido derivatives 2-23 as inhibitors ... more Herein we report the 2-aminophenol-4-sulfonamide 1 and its ureido derivatives 2-23 as inhibitors of the carbonic anhydrase (CA, EC 4.2.1.1) enzymes as analogs of the hypoxic tumor phase II entering drug SLC-0111. This scaffold may determine preferential rotational isomers to selectively interact within the tumor-associated CAs. Most compounds indeed showed in vitro selective inhibitory activities on the tumor associated CA isoforms IX and XII. The most potent derivative within the series was 11 (KIs of 2.59 and 7.64 nM on hCA IX and XII respectively) which shares the 4-fluorophenylureido tail with the clinical candidate. We investigated by means of X-ray crystallographic studies the binding modes of 3 selected compounds of this series to CA I. The evaluation of therapeutic efficacy of compound 11 in an orthotopic, syngeneic model of CA IX-positive breast cancer in vivo showed close matching antitumoral effects and tolerance with SLC-0111.

Thiosemicarbazide-Substituted Coumarins as Selective Inhibitors of the Tumor Associated Human Carbonic Anhydrases IX and XII

Molecules

A novel series of thiosemicarbazide-substituted coumarins was synthesized and the inhibitory effe... more A novel series of thiosemicarbazide-substituted coumarins was synthesized and the inhibitory effects against four physiologically relevant carbonic anhydrase isoforms I, II, IX and XII showed selective activities on the tumor-associated IX and XII isozymes. Molecular modeling studies on selected compounds 14a and 22a were performed. The binding modes of such compounds were determined assuming their enzymatically active structures (i.e., cinnamic acid) in the thermodynamically favored, and not previously explored, E geometry. Molecular modelling suggests multiple interactions within the enzymatic cavity and may explain the high potency and selectivity reported for the hCAs IX and XII.

Pain Relieving Effect of-NSAIDs-CAIs Hybrid Molecules: Systemic and Intra-Articular Treatments against Rheumatoid Arthritis

International Journal of Molecular Sciences, 2019

To study new target-oriented molecules that are active against rheumatoid arthritis-dependent pai... more To study new target-oriented molecules that are active against rheumatoid arthritis-dependent pain, new dual inhibitors incorporating both a carbonic anhydrase (CA)-binding moiety and a cyclooxygenase inhibitor (NSAID) were tested in a rat model of rheumatoid arthritis induced by CFA intra-articular (i.a.) injection. A comparison between a repeated per os treatment and a single i.a. injection was performed. CFA (50 µL) was injected in the tibiotarsal joint, and the effect of per os repeated treatment (1 mg kg −1) or single i.a injection (1 mg mL −1 , 50 µL) with NSAIDs-CAIs hybrid molecules, named 4 and 5, was evaluated. The molecules 4 and 5, which were administered daily for 14 days, significantly prevented CFA-induced hypersensitivity to mechanical noxious (Paw pressure test) and non-noxious stimuli (von Frey test), the postural unbalance related to spontaneous pain (Incapacitance test) and motor alterations (Beam balance test). Moreover, to study a possible localized activity, 4 and 5 were formulated in liposomes (lipo 4 and lipo 5, both 1 mg mL −1) and directly administered by a single i.a. injection seven days after CFA injection. Lipo 5 decreased the mechanical hypersensitivity to noxious and non-noxious stimuli and improved motor coordination. Oral and i.a. treatments did not rescue the joint, as shown by the histological analysis. This new class of potent molecules, which is able to inhibit at the same time CA and cyclooxygenase, shows high activity in a preclinical condition of rheumatoid arthritis, strongly suggesting a novel attractive pharmacodynamic profile.

Discovery of β-Adrenergic Receptors Blocker-Carbonic Anhydrase Inhibitor Hybrids for Multitargeted Antiglaucoma Therapy

Journal of medicinal chemistry, Jan 13, 2018

The combination of a β-adrenergic receptors (AR) blocker and a carbonic anhydrase (CA, EC 4.2.1.1... more The combination of a β-adrenergic receptors (AR) blocker and a carbonic anhydrase (CA, EC 4.2.1.1) inhibitor in eye drops formulations is one of the most clinically used treatment for glaucoma. A novel approach consisting of single-molecule, multitargeted compounds for the treatment of glaucoma is proposed here by designing compounds which concomitantly interact with the β-adrenergic and CA targets. Most derivatives of the two series of benzenesulfonamides incorporating 2-hydroxypropylamine moieties reported here exhibited striking efficacy against the target hCA II and XII, whereas a subset of compounds also showed significant modulation of β- and β-ARs. X-ray crystallography studies provided rationale for the observed hCA inhibition. The best dual-agents decreased IOP more effectively than clinically used dorzolamide, timolol, and the combination of them in an animal model of glaucoma. The reported evidence supports the proof-of-concept of β-ARs blocker-CAI hybrids for antiglaucom...

Chalcogenides-incorporating carbonic anhydrase inhibitors concomitantly reverted oxaliplatin-induced neuropathy and enhanced antiproliferative action

European Journal of Medicinal Chemistry, 2021

Platinum-based chemotherapy is widely used for the treatment of different tumors but is associate... more Platinum-based chemotherapy is widely used for the treatment of different tumors but is associated with serious side effects, among which neuropathic pain. Carbonic anhydrase (CA, EC 4.2.1.1) inhibitors have recently been validated as therapeutic agents in neuropathic pain and as antitumor agents. We report the synthesis of new organochalcogenides bearing the benzensulfonamide moiety acting as potent inhibitors of several human CA isoforms and, in particular, against hCA II and VII endowed with potent neuropathic pain attenuating effects. Moreover, in combination with cisplatin or doxorubicin, some of the new CA inhibitors enhanced the effects of the anticancer drugs capability in counteracting breast cancer MCF7 cell viability. The concomitant anti-neuropathic pain and antiproliferative effects of the new chalcogenide-based CA inhibitors represent an innovative approach for the counteraction and management of side effects associated with clinically platinum drugs as antitumor agents.

Crystal structure of human carbonic anhydrase II in complex with the inhibitor 4-Pyridin-3-yl-benzenesulfonamide

New Biological Targets for the Treatment of Leishmaniasis

Membrane permeable but not impermeable carbonic anhydrase inhibitors dilate precontracted porcine retinal arteries

Отчет о прошедшей 11-12 апреля 2018 г. на филологическом факультете Международной конференции сту... more Отчет о прошедшей 11-12 апреля 2018 г. на филологическом факультете Международной конференции студентов, аспирантов и молодых ученых «Ломоносов» (День науки) содержит сведения о количестве и составе участников, структуре и тематике подсекций, лучших докладчиках и наградах. Ключевые слова: конференция Ломоносов; День науки; молодежный форум. This report is dedicated to the philological section of the International conference "Lomonosov" which took place on April 11-12, 2018 at the Faculty of Philology. Approximately 1050 young scientists and scholars had applied and 600 were approved to participate. Guests from all over Russia as well as from Australia,

Pain Relieving Eect of-NSAIDs-CAIs HybridMolecules: Systemic and Intra-Articular Treatmentsagainst Rheumatoid Arthritis

Taurultams incorporating arylsulfonamide: First in vitro inhibition studies of α-, β- and γ-class Carbonic Anhydrases from Vibrio cholerae and Burkholderia pseudomallei

European Journal of Medicinal Chemistry, 2021

A new series of taurultambenzenesulfonamides 1-17 were prepared and considered for their inhibito... more A new series of taurultambenzenesulfonamides 1-17 were prepared and considered for their inhibitory activity in vitro against the Carbonic Anhydrases from Vibrio cholerae (VchCA-α, VchCA-β and VchCA-γ) and Burkholderia pseudomallei (BpsCA-β and BpsCA-γ). Among the compounds tested, derivatives 4, 5, 7, 10, 12, and 16 resulted in highly effective VchCAα inhibitors (KI values spanning within the 6.1-9.6 nM range) and endowed with excellent Selectivity Indexes (SIs; KI VchCA-α/KI hCA II) all comprised between 0.04 and 0.09. Potent in vitro inhibitors for the BpsCA-γ were also identified (KIs of 18.9-19.5 nM). The results here reported may represent the blueprint for the future development of a new generation of CA-based antibiotics integrated with free of resistance mechanisms of action adopted from known drugs.

Multitargeting application of proline-derived peptidomimetics addressing cancer-related human matrix metalloproteinase 9 and carbonic anhydrase II

European Journal of Medicinal Chemistry, 2021

A series of d-proline peptidomimetics were evaluated as dual inhibitors of both human carbonic an... more A series of d-proline peptidomimetics were evaluated as dual inhibitors of both human carbonic anhydrases (hCAs) and human gelatinases (MMP2 and MMP9), as these enzymes are both involved in the carcinogenesis and tumor invasion processes. The synthesis and enzyme inhibition kinetics of d-proline derivatives containing a biphenyl sulfonamido moiety revealed an interesting inhibition profile of compound XIV towards MMP9 and CAII. The SAR analysis and docking studies revealed a stringent requirement of a trans geometry for the two arylsulfonyl moieties, which are both necessary for inhibition of MMP9 and CAII. As MMP9 and CAII enzymes are both overexpressed in gastrointestinal stromal tumor cells, this molecule may represent an interesting chemical probe for a multitargeting approach on gastric and colorectal cancer.

Benzylaminoethyureido-Tailed Benzenesulfonamides: Design, Synthesis, Kinetic and X-ray Investigations on Human Carbonic Anhydrases

International Journal of Molecular Sciences, 2020

A drug design strategy of carbonic anhydrase inhibitors (CAIs) belonging to sulfonamides incorpor... more A drug design strategy of carbonic anhydrase inhibitors (CAIs) belonging to sulfonamides incorporating ureidoethylaminobenzyl tails is presented. A variety of substitution patterns on the ring and the tails, located on para- or meta- positions with respect to the sulfonamide warheads were incorporated in the new compounds. Inhibition of human carbonic anhydrases (hCA) isoforms I, II, IX and XII, involving various pathologies, was assessed with the new compounds. Selective inhibitory profile towards hCA II was observed, the most active compounds being low nM inhibitors (KIs of 2.8–9.2 nM, respectively). Extensive X-ray crystallographic analysis of several sulfonamides in an adduct with hCA I allowed an in-depth understanding of their binding mode and to lay a detailed structure-activity relationship.

Synthesis and carbonic anhydrase I, II, VII, and IX inhibition studies with a series of benzo[d]thiazole-5- and 6-sulfonamides

Journal of Enzyme Inhibition and Medicinal Chemistry, 2017

A series of benzo[d]thiazole-5-and 6-sulfonamides has been synthesized and investigated for the i... more A series of benzo[d]thiazole-5-and 6-sulfonamides has been synthesized and investigated for the inhibition of several human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoforms, using ethoxzolamide (EZA) as lead molecule. 2-Amino-substituted, 2-acylamino-and halogenated (bromo-and iodo-derivatives at the heterocyclic ring) compounds led to several interesting inhibitors against the cytosolic hCA I, II and VII, as well as the transmembrane, tumor-associated hCA IX isoforms. Several subnanomolar/low nanomolar, isoform-selective sulfonamide inhibitors targeting hCA II, VII and IX were detected. The sharp structure-activity relationship for CA inhibition with this small series of derivatives, with important changes of activity observed even after minor changes in the scaffold or at the 2-amino moiety, make this class of scarcely investigated sulfonamides of particular interest for further investigations.

Carbonic anhydrases and their functional differences in human and mouse sperm physiology

Biochemical and Biophysical Research Communications, 2015

Fertilization is a key reproductive event in which sperm and egg fuse to generate a new individua... more Fertilization is a key reproductive event in which sperm and egg fuse to generate a new individual. Proper regulation of certain parameters (such as intracellular pH) is crucial for this process. Carbonic anhydrases (CAs) are among the molecular entities that control intracellular pH dynamics in most cells. Unfortunately, little is known about the function of CAs in mammalian sperm physiology. For this reason, we re-explored the expression of CAI, II, IV and XIII in human and mouse sperm. We also measured the level of CA activity, determined by mass spectrometry, and found that it is similar in non-capacitated and capacitated mouse sperm. Importantly, we found that CAII activity accounts for half of the total CA activity in capacitated mouse sperm. Using the general CA inhibitor ethoxyzolamide, we studied how CAs participate in fundamental sperm physiological processes such as motility and acrosome reaction in both species. We found that capacitated human sperm depend strongly on CA activity to support normal motility, while capacitated mouse sperm do not. Finally, we found that CA inhibition increases the acrosome reaction in capacitated human sperm, but not in capacitated mouse sperm.

Inhibition studies of bacterial, fungal and protozoan β-class carbonic anhydrases with Schiff bases incorporating sulfonamide moieties

Bioorganic & Medicinal Chemistry, 2015

A series of new Schiff bases derived from sulfanilamide, 3-fluorosulfanilamide or 4-(2-aminoethyl... more A series of new Schiff bases derived from sulfanilamide, 3-fluorosulfanilamide or 4-(2-aminoethyl)-benzenesulfonamide containing either a hydrophobic or a hydrophilic tail, have been investigated as inhibitors of three b-carbonic anhydrases (CA, EC 4.2.1.1) from three different microorganisms. Their antifungal, antibacterial and antiprotozoan activities have been determined against the pathogenic fungus Cryptococcus neoformans, the bacterial pathogen Brucella suis and the protozoan parasite Leishmania donovani chagasi, responsible for Leishmaniasis. The results of these inhibition studies show that all three enzymes were efficiently inhibited by the Schiff base sulfonamides with K I values in the nanomolar or submicromolar range, depending on the nature of the tail, coming from the aryl/heteroaryl moiety present in the starting aldehyde employed in the synthesis. Furthermore, the compounds hereby investigated revealed high b-CAs selectivity over the ubiquitous, physiologically relevant and off-target human isoforms (CA I and II) and to be more potent as antifungal and antibacterial than as antiprotozoan potential drugs.