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1.
J Enzyme Inhib Med Chem ; 35(1): 21-30, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-31619095

RESUMO

Trypanosoma cruzi carbonic anhydrase (TcCA) has recently emerged as an interesting target for the design of new compounds to treat Chagas disease. In this study we report the results of a structure-based virtual screening campaign to identify novel and selective TcCA inhibitors. The combination of properly validated computational methodologies such as comparative modelling, molecular dynamics and docking simulations allowed us to find high potency hits, with KI values in the nanomolar range. The compounds also showed trypanocidal effects against T. cruzi epimastigotes and trypomastigotes. All the candidates are selective for inhibiting TcCA over the human isoform CA II, which is encouraging in terms of possible therapeutic safety and efficacy.

2.
Arch Microbiol ; 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31650197

RESUMO

Metabolic changes occurring in white lupine grain were investigated in response to Plant Growth Promoting Rhizobacteria (PGPR) root inoculation under field condition. We precisely targeted lipids and phenolics changes occurring in white lupine grain in response to Pseudomonas brenneri LJ215 and/or Paenibacillus glycanilyticus LJ121 inoculation. Lipids and phenolic composition were analyzed using an Ultra High-Performance Liquid Chromatography/Tandem Mass Spectrometry Methods. As compared to grain of un-inoculated control plant, Paenibacillus glycaniliticus inoculation highly increased the total lipids content (from 232.55 in seeds of un-inoculated control plant to 944.95 mg/kg) and the relative percentage of several fatty acid such as oleic acid (+20.95%) and linoleic acid (+14.28%) and decreased the relative percentage of glycerophospholipids (- 13.11%), sterol (- 0.2% and - 0.34% for stigmasterol and campesterol, respectively) and prenol (- 17.45%) class. Paenibacillus glycaniliticus inoculation did not affect total phenolic content, while it modulated content of individual phenolic compounds and induced the accumulation of "new" phenolics compounds such as kaempferol. Paenibacillus glycanilyticus LJ121 can be a useful bio-fertilizer to enhance nutritional quality of white lupine grain.

3.
Eur J Med Chem ; 182: 111642, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31476557

RESUMO

By exploiting the power of multicomponent chemistry, a relatively small, diverse set of primary sulfonamides was synthesized and screened against a panel of human carbonic anhydrases to reveal a low-nanomolar, albeit non-selective hCA IV lead inhibitor. Investigation of the docking poses of this compound identified a hydrophilic pocket unique to hCA IV and conveniently positioned near the carboxylate functionality of the initial lead. Various residues capable of forming hydrogen bonds as well as salt bridges were placed in this pocket via a carboxamides linkage, which led to drastic improvement of potency and selectivity towards hCA IV. This improvement of the desired inhibitory profile was rationalized by the new contacts as had been envisioned. These new tool compounds were shown to possess selective, dose-dependent cytotoxicity against human glioma T98G cell line. The latter showed a substantially increased hCA IV mRNA expression under hypoxic conditions.

4.
Bioorg Med Chem ; 27(21): 115090, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31515058

RESUMO

Novel series of 2-morpholino-4-phenylthiazol-5-yl acrylamide derivatives (8a-s) have been synthesized and explored as a non-sulfonamide class of carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The newly synthesized molecules were evaluated for their CA inhibitory potency against four isoforms: the cytosolic isozyme hCA I, II as well as trans-membrane tumor associated isoform hCA IX and hCA XII taking acetazolamide (AAZ) as standard drug. The results revealed that most of the compounds showed good activity against hCA II, IX, and XII whereas none of them were active against hCA I (Ki >100 µM). It is observed that the physiologically most important cytosolic isoform hCA II was inhibited by these molecules in the range of Ki 9.3-77.7 µM. It is also found the both the transmembrane isoforms hCA IX and XII were also inhibited with Kis ranging between 54.7-96.7 µM and 4.6-8.8 µM, respectively. The binding modes of the active compounds within the catalytic pockets of hCA II, IX and XII were evaluated by docking studies. This new non-sulfonamide class of selective inhibitors of hCA II, IX and XII over the hCA I isoform may be used for further understanding the physiological roles of some of these isoforms in various pathologies.

5.
Bioorg Chem ; 92: 103210, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31473472

RESUMO

A novel series of 4-oxo-spirochromane bearing primary sulfonamide group were synthetized as Carbonic Anhydrase inhibitors (CAIs) and tested for their management of neuropathic pain. Indeed, CAs have been recently validated as novel therapeutic targets in neuropathic pain. All compounds, here reported, showed strong activity against hCA II and hCA VII with KI values in the low or sub-nanomolar range. Two compounds (6d and 6l) showed good neuropathic pain attenuating effects and longer duration than drug reference acetazolamide in an animal model of oxaliplatin induced neuropathy.

6.
Bioorg Chem ; 92: 103222, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31499260

RESUMO

Inhibition of carbonic anhydrases (CAs, EC 4.2.1.1) has clinical importance for the treatment of several diseases. They participate in crucial regulatory mechanisms for balancing intracellular and extracellular pH of the cells. Among CA isoforms, selective inhibition of hCA IX has been linked to decreasing of cell growth for both primary tumors and metastases. The discovery of novel CA inhibitors as anticancer drug candidates is a current topic in medicinal chemistry. 1,3,5-Trisubstituted pyrazoles carrying benzenesulfonamide were evaluated against physiologically abundant cytosolic hCA I and hCA II and trans-membrane, tumor-associated hCA IX isoforms by a stopped-flow CO2 hydrase method. Their in vitro cytotoxicities were screened against human oral squamous cell carcinoma (OSCC) cell lines (HSC-2) and human mesenchymal normal oral cells (HGF) via 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) test. Compounds 6, 8, 9, 11, and 12 showed low nanomolar hCA II inhibitory potency with Ki < 10 nM, whereas compounds 9 and 12 displayed Ki < 10 nM against hCA IX isoenzyme when compared with reference Acetazolamide (AZA). Compound 9, 4-(3-(hydrazinecarbonyl)-5-(4-nitrophenyl)-1H-pyrazol-1-yl)benzenesulfonamide, can be considered as the most selective hCA IX inhibitor over off-target cytosolic isoenzymes hCA I and hCA II with the lowest Ki value of 2.3 nM and selectivity ratios of 3217 (hCA I/hCA IX) and 3.9 (hCA II/hCA IX). Isoform selectivity profiles were also discussed using in silico modelling. Cytotoxicity results pointed out that compounds 5 (CC50 = 37.7 µM) and 11 (CC50 = 58.1 µM) can be considered as lead cytotoxic compounds since they were more cytotoxic than 5-Fluorouracil (5-FU) and Methotrexate (MTX).

7.
Eur J Med Chem ; 183: 111702, 2019 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-31542715

RESUMO

Carbonic anhydrases isoforms CA IX, and XII are known to be highly expressed in various human tissues and malignancies. CA IX is a prominent target for especially colorectal cancers, because it is overexpressed in colorectal cancer and this overexpression leads poor prognosis. Inhibition of CA IX activity by small molecule CA inhibitors like sulfonamides, sulfonamide derivative or coumarins leads to inhibition of tumorigenesis. Novel twenty-seven compounds in three series (sulfonamide-based imines (6a-6i), coumarin-based aldehydes (7a-7i), and coumarin-sulfonamide-based target molecules (8a-8i)) were synthesized and characterized by means of IR, NMR, and mass spectra. All compounds were tested for their ability to inhibit CA I, CA II, CA IX, and CA XII isoforms. 4-((((2-((1-(3-((2-oxo-2H-chromen-7-yl)oxy)propyl)-1H-1,2,3-triazol-4-yl)methoxy)naphthalen-1-yl)-methylene)amino)methyl)benzenesulfonamide (8i) exhibited the highest hCA IX inhibition with the Ki of 45.5 nM. In addition, 8i was found to be potent in inhibiting cancer cell proliferation as selective (IC50 = 17.01 ±â€¯1.35 µM for HT-29, IC50 = 118.73 ±â€¯1.19 µM for HEK293T). This novel compound inhibited the CA IX and CA XII protein expression in HT-29 cells. These findings indicate that 8i can inhibit cellular proliferation in human colon cancer cells by specifically targeting the CA IX and CA XII expression.

8.
Eur J Med Chem ; 182: 111600, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31419777

RESUMO

Carbonic anhydrase inhibitors (CAIs) of the sulfonamide, sulfamate and coumarin classes bearing the phenylureido tail found in the clinically used drug Sorafenib, a multikinase inhibitor actually used for the management of hepatocellular carcinomas, are reported. All compounds were assayed on human (h) CA isoforms I, II, VII and IX, involved in various pathologies. Among the sulfonamides, several compounds were selective for inhibiting hCA IX, with KI values in the low nanomolar ranges (i.e. 0.7-30.2 nM). We explored the binding modes of such compounds by means of X-ray crystallographic studies on isoform hCA I in adduct with one sulfonamide and a sulfamate inhibitor. Antiproliferative properties of some sulfamates on breast tumor cell lines were also investigated.

9.
Eur J Med Chem ; 181: 111586, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31401537

RESUMO

We have synthetized a novel series of ß-hydroxy tellurides bearing the benzenesulfonamide group as potent inhibitors of carbonic anhydrase enzymes. In a one pot procedure, we discovered both the ring opening reaction of the three-membered ring and the cleavage of the sulfonamide protecting moiety at the same time. Moreover, the first X-ray co-crystallographic structure of a ß-hydroxy telluride derivative with hCA II is reported. The potent effects of these compounds against the tumor-associated hCA IX with low nanomolar constant inhibition values give the possibility to evaluate their activity in vitro using a breast cancer cell line (MDA-MB-231). Compounds 7e and 7g induced significant toxic effects against tumor cells after 48 h incubation in normoxic conditions killing over 50% of tumor cells at 3 µM, but their efficacy decreased in hypoxic conditions reaching the 50% of the tumor cell viability only at 30 µM. These unusual features make them interesting lead compounds to act as antitumor agents, not only as Carbonic Anhydrase IX inhibitors, but reasonably in different pathways, where hCA IX is not overexpressed.

10.
Bioorg Chem ; 91: 103130, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31374520

RESUMO

Starting from the molecular simplification of (R) 4-(3,4-dibenzylpiperazine-1-carbonyl)benzenesulfonamide 9a, a compound endowed with selectivity for human Carbonic Anhydrase (hCA) IV, a series of piperazines and 4-aminopiperidines carrying a 4-sulfamoylbenzamide moiety as Zn-binding group have been designed and tested on human isoforms hCA I, II, IV and IX, using a stopped flow CO2 hydrase assay. The aim of the work was to derive structure-activity relationships useful for designing isoform selective compounds. These structural modifications changed the selectivity profile of the analogues from hCA IV to hCA I and II, and improved potency. Several of the new compounds showed subnanomolar activity on hCA II. X-ray crystallography of ligand-hCAII complexes was used to compare the binding modes of the new piperazines and the previously synthesized 2-benzyl-piperazine analogues, explaining the inhibition profiles.

11.
J Enzyme Inhib Med Chem ; 34(1): 1400-1413, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31401897

RESUMO

A large library of derivatives based on the scaffold of 2-(benzylsulfinyl)benzoic acid were synthesised and tested as atypical inhibitors against four different isoforms of human carbonic anhydrase (hCA I, II, IX and XII, EC 4.2.1.1). The exploration of the chemical space around the main functional groups led to the discovery of selective hCA IX inhibitors in the micromolar/nanomolar range, thus establishing robust structure-activity relationships within this versatile scaffold. HPLC separation of some selected chiral compounds and biological evaluation of the corresponding enantiomers was performed along with molecular modelling studies on the most active derivatives.


Assuntos
Ácido Benzoico/química , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/efeitos dos fármacos , Desenho de Drogas , Isoenzimas/efeitos dos fármacos , Inibidores da Anidrase Carbônica/síntese química , Domínio Catalítico , Cromatografia Líquida de Alta Pressão , Humanos , Simulação de Acoplamento Molecular , Estereoisomerismo , Relação Estrutura-Atividade
12.
J Enzyme Inhib Med Chem ; 34(1): 1526-1533, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31431095

RESUMO

A library of 4-[(3-methyl-4-aryl-2,3-dihydro-1,3-thiazol-2-ylidene)amino]benzene-1-sulphonamides (EMAC8002a-m) was designed and synthesised to evaluate the effect of substituents in the positions 3 and 4 of the dihydrothiazole ring on the inhibitory potency and selectivity toward human carbonic anhydrase isoforms I, II, IX, and XII. Most of the new compounds preferentially inhibit the isoforms II and XII. Both electronic and steric features on the aryl substituent in the position 4 of the dihydrothiazole ring concur to determine the overall biological activity of these new derivatives.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
13.
Expert Opin Ther Pat ; 29(10): 793-803, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31462124

RESUMO

Introduction: Elevated intraocular pressure (IOP) is the most prevalent risk factor for glaucoma. Prostaglandin analogs are a first-line therapy for glaucoma due to their ability to reduce IOP, once-daily dosing, efficacy, and minimal side-effect profile. Many compounds targeting different PG receptors have been developed in the last years, some of them being in clinical use. Latanoprost, Bimatoprost, Travoprost, and Tafluprost are clinically used as antiglaucoma drugs and act as agonists of the PGF2α receptor. The inability to fully understand the mechanism of action of clinically used PGF2α analogs is thus a strong driver for additional research into the mechanism of action of ocular hypotensive drugs belonging to this class of pharmacological agents. Areas covered: This review explores the last 5 years (2013-2018), where many patents describing new compounds acting on different prostaglandin receptors, and mainly targeting EP1-4 and FP receptors, were released. Expert opinion: To date, there has been a growing awareness over recent years of the therapeutic use of novel derivatives as new antiglaucoma pharmaceutical products. Patents involved in discovering new approaches and new molecules for the treatment of glaucoma diseases encouraged the scientific community to increase the variety of drugs available for the treatment of ocular diseases.

14.
Bioorg Chem ; 91: 103110, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31310883

RESUMO

The present work describe the synthesis of a novel series of celecoxib derivatives (6a-m) and they were evaluated as Carbonic Anhydrase (CA, EC 4.2.1.1) inhibitors against the human (h) isoforms hCA I, II, IV and IX which are involved in a variety of diseases such as glaucoma, retinitis pigmentosa, epilepsy and tumors etc. These compounds showed interesting inhibitory activity for these isoforms, with several low nanomolar derivatives identified against all these enzymes. The in-vivo anti-inflammatory activity of the synthesized compounds were evaluated using Celecoxib as reference standard by paw Oedema model on albino Wistar. Most of the compounds showed higher in-vivo anti-inflammatory activity compared to Celecoxib.

15.
J Enzyme Inhib Med Chem ; 34(1): 1178-1185, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31282230

RESUMO

The activation of the ß-class carbonic anhydrases (CAs, EC 4.2.1.1) from the bacteria Brucella suis and Francisella tularensis with amine and amino acids was investigated. BsuCA 1 was sensitive to activation with amino acids and amines, whereas FtuCA was not. The most effective BsuCA 1 activators were L-adrenaline and D-Tyr (KAs of 0.70-0.95 µM). L-His, L-/D-Phe, L-/D-DOPA, L-Trp, L-Tyr, 4-amino-L-Phe, dopamine, 2-pyridyl-methylamine, D-Glu and L-Gln showed activation constants in the range of 0.70-3.21 µM. FtuCA was sensitive to activation with L-Glu (KA of 9.13 µM). Most of the investigated compounds showed a weak activating effect against FtuCA (KAs of 30.5-78.3 µM). Many of the investigated amino acid and amines are present in high concentrations in many tissues in vertebrates, and their role in the pathogenicity of the two bacteria is poorly understood. Our study may bring insights in processes connected with invasion and pathogenic effects of intracellular bacteria.


Assuntos
Aminas/farmacologia , Aminoácidos/farmacologia , Brucella suis/enzimologia , Anidrases Carbônicas/metabolismo , Ativação Enzimática/efeitos dos fármacos , Francisella tularensis/enzimologia , Aminas/química , Aminoácidos/química , Anidrases Carbônicas/genética , Relação Estrutura-Atividade
16.
J Med Chem ; 62(15): 7233-7249, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31287314

RESUMO

Carbon monoxide (CO) is a gas endogenously produced in humans, reported to exhibit anti-inflammatory and cytoprotective effects at low concentration. In this context, CO releasing molecules (CORMs) are attracting enormous interest. Herein, we report a series of small-molecule hybrids consisting of a carbonic anhydrase (CA; EC 4.2.1.1) inhibitor linked to a CORM tail section (CAI-CORMs). All compounds were screened in vitro for their inhibition activity against the human (h) CA I, II, IV, IX, and XII isoforms. On selected CAI-CORM hybrids, the CO releasing properties were evaluated, along with their pain-relieving effect, in a model of rheumatoid arthritis. One CAI-CORM hybrid (5b) induced a higher pain-relieving effect compared to the one exerted by the single administration of CAI (5a) and CORM (15b) fragments, shedding light on the possibility to enhance the pain relief effect of CA inhibitors inserting a CO releasing moiety on the same molecular scaffold.

17.
J Enzyme Inhib Med Chem ; 34(1): 1199-1209, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31237458

RESUMO

The synthesis of a novel series of 3-functionalised benzenesulfonamides incorporating phenyl-1,2,3-triazole with an amide linker was achieved by using the "click-tail" approach. The new compounds, including the intermediates, were assayed as inhibitors of human carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I and II (cytosolic isoforms) and also for hCA IV and IX (transmembrane isoforms) taking acetazolamide as standard drug. Most of these compounds exhibited excellent activity against all these isoforms. hCA I was inhibited with Kis in the range of 50.8-966.8 nM, while the glaucoma associated hCA II was inhibited with Kis in the range of 6.5-760.0 nM. Isoform hCA IV was inhibited with Kis in the range of 65.3-957.5 nM, whereas the tumor associated hypoxia induced hCA IX was inhibited with Kis in the range of 30.8-815.9 nM. The structure activity relationship study for the 3-functionalised-1-phenyl-1,2,3-triazole sulfamoylbenzamides against these isoforms was also inferred from the results.


Assuntos
Inibidores da Anidrase Carbônica/síntese química , Isoenzimas/antagonistas & inibidores , Sulfonamidas/farmacologia , Triazóis/química , Triazóis/farmacologia , Inibidores da Anidrase Carbônica/química , Humanos , Isoenzimas/química , Relação Estrutura-Atividade , Sulfonamidas/química
18.
J Enzyme Inhib Med Chem ; 34(1): 1172-1177, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31218888

RESUMO

A series of novel 8-substituted-N-(4-sulfamoylphenyl)quinoline-2-carboxamides was synthesised by the reaction of 8-hydroxy-N-(4-sulfamoylphenyl) quinoline-2-carboxamide with alkyl and benzyl halides. The compounds were assayed for carbonic anhydrase (CA) inhibitory activity against four hCA isoforms, hCA I, hCA II, hCA IV, and hCA IX. Barring hCA IX, all the isoforms were inhibited from low to high nanomolar range. hCA I was inhibited in the range of 61.9-8126 nM, with compound 5h having an inhibition constant of KI = 61.9 nM. hCA II was inhibited in the range of 33.0-8759 nM, with compound 5h having an inhibition constant of 33.0 nM and compounds 5a and 5b having inhibition constants of 88.4 and 85.7 nM, respectively. hCA IV was inhibited in the range of 657.2-6757 nM. Hence, compound 5h, possessing low nanomolar hCA I and II inhibition, can be selected as a lead for the design of novel CA I and II inhibitors.


Assuntos
Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/química , Relação Dose-Resposta a Droga , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Estrutura Molecular , Relação Estrutura-Atividade
19.
Bioorg Chem ; 89: 103033, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31212085

RESUMO

Herein we report for the first time an efficient synthetic procedure for the preparation of N-aryl-N'-ureido-O-sulfamates (AUSs) as a new class of Carbonic Anhydrase Inhibitors (CAIs). The compounds were tested for the inhibition of several human (h) Carbonic Anhydrase (CA; EC 4.2.1.1) isoforms. Interesting inhibition activity and high selectivity against CA VII and XII versus CA I and II, with KIs in the low nanomolar range, were observed. Molecular modeling studies allowed us to decipher the structural features underpinning the selective inhibitory profile of AUSs towards isoforms CAs VII and XII. A selection of sulfamates showed promising neuropathic pain modulating effects in an in vivo animal model of oxaliplatin induced pain.

20.
Food Chem ; 296: 150-159, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31202299

RESUMO

Sea fennel is an herbaceous aromatic and edible halophyte, naturally occurring in coastal areas of the Mediterranean basin. Besides its scientific interest as a salt-tolerant species it exhibits considerable nutritional value and economical potential. As sea fennel is distributed in maritime areas, where natural iodine is available in high concentrations, the aim of this study was to evaluate whether sea fennel has the potential to accumulate elevated iodine concentrations under cultivation. A biofortification experiment in a hydroponic system applying two forms of iodine, KI and KIO3 in different concentrations was set up and monitored using sophisticated targeted elementary and metabolite analysis. The biofortification potential and possible effects on nutritional value were investigated. This study revealed that both iodine forms increased the iodine content of sea fennel tissues. Nutritional and health promoting components, biomass production but also antioxidant potential were stable or even improved under the iodine treatments.


Assuntos
Apiaceae/metabolismo , Hidroponia/métodos , Iodo/química , Valor Nutritivo , Apiaceae/crescimento & desenvolvimento , Biofortificação , Biomassa , Carotenoides/análise , Carotenoides/isolamento & purificação , Cromatografia Líquida de Alta Pressão , Cromatografia Gasosa-Espectrometria de Massas , Extratos Vegetais/análise , Plântula/metabolismo , Compostos Orgânicos Voláteis/análise
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