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19 pages, 9657 KiB

Open AccessArticle

Azole-Based Compounds That Are Active against Candida Biofilm: In Vitro, In Vivo and In Silico Studies

by Simone Carradori, Alessandra Ammazzalorso, Barbara De Filippis, Ahmet Fatih Şahin, Atilla Akdemir, Anastasia Orekhova, Graziana Bonincontro and Giovanna Simonetti

Antibiotics 2022, 11(10), 1375; https://doi.org/10.3390/antibiotics11101375 - 8 Oct 2022

Cited by 11 | Viewed by 3210

Abstract

Fungal pathogens, including Candida spp., Aspergillus spp. and dermatophytes, cause more than a billion human infections every year. A large library of imidazole- and triazole-based compounds were in vitro screened for their antifungal activity against C. albicans, C. glabrata, C. krusei, A. fumigatus and dermatophytes, such as Microsporum gypseum, Trichophyton rubrum and Trichophyton mentagrophytes. The imidazole carbamate 12 emerged as the most active compound, showing a valuable antifungal activity against C. glabrata (MIC 1–16 μg/mL) and C. krusei (MIC 4–24 μg/mL). No activity against A. fumigatus or the dermatophytes was observed among all the tested compounds. The compound 12 inhibited the formation of C. albicans, C. glabrata and C. krusei biofilms and reduced the mature Candida biofilm. In the Galleria mellonella larvae, 12 showed a significant reduction in the Candida infection, together with a lack of toxicity at the concentration used to activate its antifungal activity. Moreover, the in silico prediction of the putative targets revealed that the concurrent presence of the imidazole core, the carbamate and the p-chlorophenyl is important for providing a strong affinity for lanosterol 14α-demethylase (CgCYP51a1) and the fungal carbonic anhydrase (CgNce103), the S-enantiomer being more productive in these interactions. Full article

(This article belongs to the Special Issue Design and Synthesis of Novel Antimicrobial Agents)

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14 pages, 2484 KiB

Open AccessArticle

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

by Arzu Gumus, Murat Bozdag, Atilla Akdemir, Andrea Angeli, Silvia Selleri, Fabrizio Carta and Claudiu T. Supuran

Molecules 2022, 27(14), 4610; https://doi.org/10.3390/molecules27144610 - 19 Jul 2022

Cited by 9 | Viewed by 2203

Abstract

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. Full article

(This article belongs to the Special Issue Enzyme Inhibitors: Design, Synthesis and Biological Evaluation)

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21 pages, 2378 KiB

Open AccessEditor’s ChoiceReview

Carbonic Anhydrase Inhibitors Targeting Metabolism and Tumor Microenvironment

by Andrea Angeli, Fabrizio Carta, Alessio Nocentini, Jean-Yves Winum, Raivis Zalubovskis, Atilla Akdemir, Valentina Onnis, Wagdy M. Eldehna, Clemente Capasso, Giuseppina De Simone, Simona Maria Monti, Simone Carradori, William A. Donald, Shoukat Dedhar and Claudiu T. Supuran

Metabolites 2020, 10(10), 412; https://doi.org/10.3390/metabo10100412 - 14 Oct 2020

Cited by 142 | Viewed by 8051

Abstract

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. Full article

(This article belongs to the Special Issue Metabolism in the Tumor Microenvironment)

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12 pages, 3434 KiB

Open AccessArticle

Novel Indole-Based Hydrazones as Potent Inhibitors of the α-class Carbonic Anhydrase from Pathogenic Bacterium Vibrio cholerae

by Kübra Demir-Yazıcı, Özlen Güzel-Akdemir, Andrea Angeli, Claudiu T. Supuran and Atilla Akdemir

Int. J. Mol. Sci. 2020, 21(9), 3131; https://doi.org/10.3390/ijms21093131 - 29 Apr 2020

Cited by 8 | Viewed by 2959

Abstract

Due to the increasing resistance of currently used antimicrobial drugs, there is an urgent problem for the treatment of cholera disease, selective inhibition of the α-class carbonic anhydrases (CA, EC 4.2.1.1) from the pathogenic bacterium Vibrio cholerae (VcCA) presents an alternative therapeutic target. In this study, a series of hydrazone derivatives, carrying the 2-(hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide scaffold, have been evaluated as inhibitors of the VcCA with molecular modeling studies. The results suggest that these compounds may bind to the active site of VcCA. To verify this, VcCA enzyme inhibition studies were performed and as predicted most of the tested compounds displayed potent inhibitory activities against VcCA with three compounds showing K_I values lower than 30 nM. In addition, all these compounds showed selectivity for VcCA and the off-targets hCA I and II. Full article

(This article belongs to the Special Issue Carbonic Anhydrases: A Superfamily of Ubiquitous Enzymes)

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17 pages, 4258 KiB

Open AccessArticle

Development of Thiazolidinones as Fungal Carbonic Anhydrase Inhibitors

by Özlen Güzel-Akdemir, Simone Carradori, Rossella Grande, Kübra Demir-Yazıcı, Andrea Angeli, Claudiu T. Supuran and Atilla Akdemir

Int. J. Mol. Sci. 2020, 21(8), 2960; https://doi.org/10.3390/ijms21082960 - 22 Apr 2020

Cited by 22 | Viewed by 3621

Abstract

In our efforts to find new and selective thiazolidinone-based anti-Candida agents, we synthesized and tested 26 thiazolidinones against several Candida 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 Candida 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 K_I values in the 0.1–10 µM range against the Candida glabrata β-CA enzyme CgNce103. Full article

(This article belongs to the Special Issue Carbonic Anhydrases: A Superfamily of Ubiquitous Enzymes)

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14 pages, 1707 KiB

Open AccessArticle

Indole-Based Hydrazones Containing A Sulfonamide Moiety as Selective Inhibitors of Tumor-Associated Human Carbonic Anhydrase Isoforms IX and XII

by Kübra Demir-Yazıcı, Silvia Bua, Nurgül Mutlu Akgüneş, Atilla Akdemir, Claudiu T. Supuran and Özlen Güzel-Akdemir

Int. J. Mol. Sci. 2019, 20(9), 2354; https://doi.org/10.3390/ijms20092354 - 12 May 2019

Cited by 24 | Viewed by 4563

Abstract

Novel sulfonamidoindole-based hydrazones with a 2-(hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide scaffold were synthesized and tested in enzyme inhibition assays against the tumor-associated carbonic anhydrase isoforms, hCA IX and XII, and the off-targets, hCA I and II. The compounds showed selectivity against hCA IX and XII over hCA I and II. Six compounds showed K_I values lower than 10 nM against hCA IX or XII. Molecular modeling studies were performed to suggest binding interactions between the ligand and the hCA active sites. Full article

(This article belongs to the Special Issue Protease and Carbonic Anhydrase Inhibitors, II)

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13 pages, 3093 KiB

Open AccessArticle

Five- and Six-Membered Nitrogen-Containing Compounds as Selective Carbonic Anhydrase Activators

by Adriano Mollica, Giorgia Macedonio, Azzurra Stefanucci, Simone Carradori, Atilla Akdemir, Andrea Angeli and Claudiu T. Supuran

Molecules 2017, 22(12), 2178; https://doi.org/10.3390/molecules22122178 - 9 Dec 2017

Cited by 18 | Viewed by 5383

Abstract

It has been proven that specific isoforms of human carbonic anhydrase (hCA) are able to fine-tune physiological pathways connected to signal processing, and that decreased CAs expression negatively influences cognition, leading to mental retardation, Alzheimer’s disease, and aging-related cognitive dysfunctions. For this reason, a small library of natural and synthetic nitrogen containing cyclic derivatives was assayed as activators of four human isoforms of carbonic anhydrase (hCA I, II, IV and VII). Most of the compounds activated hCA I, IV and VII in the micromolar range, with K_As ranging between 3.46 and 80.5 μM, whereas they were not active towards hCA II (K_As > 100 μM). Two natural compounds, namely l-(+)-ergothioneine (1) and melatonin (2), displayed K_As towards hCA VII in the nanomolar range after evaluation by a CO₂ hydration method in vitro, showing a rather efficient and selective activation profile with respect to histamine, used as a reference compound. Corroborated with the above in vitro findings, a molecular modelling in silico approach has been performed to correlate these biological data, and to elucidate the binding interaction of these activators within the enzyme active site. Full article

(This article belongs to the Special Issue Metalloenzyme Inhibitors and Activators)

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