RESUMEN

In the search of new cymantrenyl- and ferrocenyl-sulfonamides as potencial inhibitors of human carbonic anhydrases (hCAs), four compounds based on N-ethyl or N-methyl benzenesulfonamide units have been obtained. These cymantrenyl (1a-b) and ferrocenyl (2a-b) derivatives were prepared by the reaction between aminobenzene sulfonamides ([NH2-(CH2)n-(C6H4)-SO2-NH2)], where n = 1, 2) with cymantrenyl sulfonyl chloride (P1) or ferrocenyl sulfonyl chloride (P2), respectively. All compounds were characterized by conventional spectroscopic techniques and cyclic voltammetry. In the solid state, the molecular structures of compounds 1a, 1b, and 2b were determined by single-crystal X-ray diffraction. Biological evaluation as carbonic anhydrases inhibitors were carried out and showed derivatives 1b y 2b present a higher inhibition than the drug control for the Human Carbonic Anhydrase (hCA) II and IX isoforms (KI = 7.3 nM and 5.8 nM, respectively) and behave as selective inhibition for hCA II isoform. Finally, the docking studies confirmed they share the same binding site and interactions as the known inhibitors acetazolamide (AAZ) and agree with biological studies.

Asunto(s)

Inhibidores de Anhidrasa Carbónica , Anhidrasas Carbónicas , Simulación del Acoplamiento Molecular , Sulfonamidas , Humanos , Inhibidores de Anhidrasa Carbónica/química , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/farmacología , Sulfonamidas/química , Sulfonamidas/farmacología , Sulfonamidas/síntesis química , Anhidrasas Carbónicas/metabolismo , Anhidrasas Carbónicas/química , Anhidrasa Carbónica II/antagonistas & inhibidores , Anhidrasa Carbónica II/metabolismo , Anhidrasa Carbónica II/química , Anhidrasa Carbónica IX/antagonistas & inhibidores , Anhidrasa Carbónica IX/metabolismo , Antígenos de Neoplasias/metabolismo , Antígenos de Neoplasias/química , Anhidrasa Carbónica I/antagonistas & inhibidores , Anhidrasa Carbónica I/metabolismo , Bencenosulfonamidas , Compuestos Organometálicos/química , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/farmacología , Cristalografía por Rayos X

RESUMEN

Exploring therapeutic options is crucial in the ongoing COVID-19 pandemic caused by SARS-CoV-2. Nirmatrelvir, which is a potent inhibitor that targets the SARS-CoV-2 Mpro, shows promise as an antiviral treatment. Additionally, Ivermectin, which is a broad-spectrum antiparasitic drug, has demonstrated effectiveness against the virus in laboratory settings. However, its clinical implications are still debated. Using computational methods, such as molecular docking and 100 ns molecular dynamics simulations, we investigated how Nirmatrelvir and Ivermectin interacted with SARS-CoV-2 Mpro(A). Calculations using density functional theory were instrumental in elucidating the behavior of isolated molecules, primarily by analyzing the frontier molecular orbitals. Our analysis revealed distinct binding patterns: Nirmatrelvir formed strong interactions with amino acids, like MET49, MET165, HIS41, HIS163, HIS164, PHE140, CYS145, GLU166, and ASN142, showing stable binding, with a root-mean-square deviation (RMSD) of around 2.0 Å. On the other hand, Ivermectin interacted with THR237, THR239, LEU271, LEU272, and LEU287, displaying an RMSD of 1.87 Å, indicating enduring interactions. Both ligands stabilized Mpro(A), with Ivermectin showing stability and persistent interactions despite forming fewer hydrogen bonds. These findings offer detailed insights into how Nirmatrelvir and Ivermectin bind to the SARS-CoV-2 main protease, providing valuable information for potential therapeutic strategies against COVID-19.

Asunto(s)

Antivirales , Tratamiento Farmacológico de COVID-19 , Proteasas 3C de Coronavirus , Ivermectina , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , SARS-CoV-2 , Ivermectina/química , Ivermectina/farmacología , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/enzimología , Proteasas 3C de Coronavirus/química , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Proteasas 3C de Coronavirus/metabolismo , Humanos , Antivirales/química , Antivirales/farmacología , Unión Proteica , Sulfonamidas/química , Sulfonamidas/farmacología , Sitios de Unión , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Lactamas , Leucina , Nitrilos , Prolina

RESUMEN

In the present study, the effect of sulfonamide-chalcone 185 (SSC185) was investigated against B16-F10 metastatic melanoma cells aggressive actions, besides migration and adhesion processes, by in silico and in vitro assays. In silico studies were used to characterize the pharmacokinetic profile and possible targets of SSC185, using the pkCSM web server, and docking simulations with AutoDock Tools. Furthermore, the antimetastatic effect of SSC185 was investigated by in vitro experiments using MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide), colony, scratch, and cell adhesion assays, and atomic force microscopy (AFM). The molecular docking results show better affinity of SSC185 with the metalloproteinases-2 (MMP-2) and α5ß1 integrin. SSC185 effectively restricts the formation of colonies, migration, and adhesion of B16-F10 metastatic melanoma cells. Through the AFM images changes in cells morphology was identified, with a decrease in the filopodia and increase in the average cellular roughness. The results obtained demonstrate the potential of this molecule in inhibit the primordial steps for metastasis, which is responsible for a worse prognosis of late stage cancer, being the main cause of morbidity among cancer patients.

Asunto(s)

Adhesión Celular , Movimiento Celular , Chalcona , Simulación del Acoplamiento Molecular , Sulfonamidas , Movimiento Celular/efectos de los fármacos , Adhesión Celular/efectos de los fármacos , Sulfonamidas/farmacología , Sulfonamidas/química , Ratones , Animales , Línea Celular Tumoral , Chalcona/farmacología , Chalcona/química , Chalcona/análogos & derivados , Metaloproteinasa 2 de la Matriz/metabolismo , Melanoma Experimental/patología , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/metabolismo , Microscopía de Fuerza Atómica , Antineoplásicos/farmacología , Antineoplásicos/química , Chalconas/farmacología , Chalconas/química , Humanos

RESUMEN

Human carbonic anhydrase VII (hCA VII) constitutes a promising molecular target for the treatment of epileptic seizures and other central nervous system disorders due to its almost exclusive expression in neurons. Achieving isoform selectivity is one of the main challenges for the discovery of new hCA inhibitors, since nonspecific inhibition may lead to tolerance and side effects. In the present work, we report the development of a molecular docking protocol based on AutoDock4Zn for the search of new hCA VII inhibitors by virtual screening. The docking protocol was applied to the screening of two sets of compounds: a ZINC15 subset of sulfur-containing structures and an in-house library consisting of synthetic and commercial candidates (including approved drugs). Five compounds were selected from the first screening campaign and three from the second one, and they were tested in vitro against the enzyme. Among the eight selected structures, four showed Ki values in the low nanomolar range. These confirmed hits include three approved drugs: meloxicam, piroxicam, and nitrofurantoin, which also showed good selectivity for hCA VII versus hCA II.

Asunto(s)

Inhibidores de Anhidrasa Carbónica , Anhidrasas Carbónicas , Inhibidores de Anhidrasa Carbónica/farmacología , Anhidrasas Carbónicas/química , Humanos , Meloxicam , Simulación del Acoplamiento Molecular , Estructura Molecular , Nitrofurantoína , Piroxicam , Isoformas de Proteínas/metabolismo , Relación Estructura-Actividad , Sulfonamidas/química , Azufre

RESUMEN

Sulphonamides are a group of synthetic antibiotics used specially in veterinary medicine. Among the procedures employed in the sample preparation for sulphonamide determination are liquid-liquid extraction (LLE) and solid-phase extraction (SPE) that use large volumes of organic solvents. Hence, a clean procedure was developed based on preconcentration and cloud point extraction (CPE) without using organic solvents to quantify total sulphonamides in bovine milk. The procedure was optimized as follows: 2 mL of pre-cleaned milk sample, 2 mL of reagent solution and 1 mL of Triton X-114 7% (m/v) were added to a tube, heated in a water bath at 40 °C for 10 minutes and centrifuged at 2950 rcf for 20 minutes. Digital image acquisition was employed directly at the tube without removing the supernatant/aqueous phase. The linear response was observed between 10 and 400 µg L-1 of total sulphonamides and described by the following equation: S = 2.50 + 0.0514C (µg L-1) and R = 0.999. The LOD and the CV (n = 11) were estimated to be 10 µg L-1 and 1.3%, respectively. The main interferents present at their usual concentrations in the sample did not interfere with the results. Spike and recovery tests of total sulphonamides were carried out in UHT and pasteurized milk with recovery values between 73 and 106% and the results obtained for this kind of sample were in agreement with those achieved by a high performance liquid chromatography (HPLC) procedure at the 95% confidence level. The analytical procedure presents an adequate sensitivity to determine total sulphonamides in bovine milk and does not require organic solvents, being aligned to the principles of green chemistry.

Asunto(s)

Leche , Teléfono Inteligente , Animales , Cromatografía Líquida de Alta Presión/métodos , Leche/química , Solventes , Sulfonamidas/análisis , Sulfonamidas/química

RESUMEN

Herein we describe results for the synthesis and synthetic application of 4-amino-3-(arylselenyl)benzenesulfonamides, and preliminary evaluation of antioxidant, anti-edematogenic and antinociceptive properties. This class of compounds was synthesized in good yields by a reaction of commercially available sulfanilamide and diorganyl diselenides in the presence of 10 mol% of I2 . Furthermore, the synthesized compound 4-amino-3-(phenylselenyl)benzenesulfonamide (3 a) was evaluated on complete Freund's adjuvant (CFA)-induced acute inflammatory pain. Dose- and time-response curves of antinociceptive effect of compound 3 a were performed using this experimental model. Also, the effect of compound 3 a was monitored in a hot-plate test to evaluate the acute non-inflammatory antinociception. The open-field test was performed to evaluate the locomotor and exploratory behaviors of mice. Oxidative stress markers, such as glutathione peroxidase activity; reactive species, non-protein thiols, and lipid peroxidation levels were performed to investigate the antioxidant action of compound 3 a. Our findings suggest that the antioxidant effect of compound 3 a may contribute to reducing the nociception and suppress the signaling pathways of inflammation on the local injury induced by CFA. Thus, compound 3 a reduced the paw edema as well as the hyperalgesic behavior in mice, being a promising therapeutic agent for the treatment of painful conditions.

Asunto(s)

Analgésicos Opioides/farmacología , Antiinflamatorios no Esteroideos/farmacología , Compuestos Organometálicos/farmacología , Dolor/tratamiento farmacológico , Compuestos de Selenio/farmacología , Sulfonamidas/farmacología , Analgésicos Opioides/síntesis química , Analgésicos Opioides/química , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Antioxidantes , Conducta Animal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Edema/tratamiento farmacológico , Adyuvante de Freund , Inflamación/tratamiento farmacológico , Peroxidación de Lípido/efectos de los fármacos , Locomoción/efectos de los fármacos , Ratones , Estructura Molecular , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Estrés Oxidativo/efectos de los fármacos , Compuestos de Selenio/química , Relación Estructura-Actividad , Sulfonamidas/química , Bencenosulfonamidas

RESUMEN

Chagas disease is a neglected illness caused by Trypanosoma cruzi and its treatment is done only with two drugs, nifurtimox and benznidazole. However, both drugs are ineffective in the chronic phase, in addition to causing serious side effects. This context of therapeutic limitation justifies the continuous research for alternative drugs. Here, we study the in vitro trypanocidal effects of the non-steroidal anti-inflammatory drug nimesulide, a molecule that has in its chemical structure a toxicophoric nitroaromatic group (NO2). The set of results obtained in this work highlights the potential for repurposing nimesulide in the treatment of this disease that affects millions of people around the world.

Asunto(s)

Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/parasitología , Reposicionamiento de Medicamentos , Sulfonamidas/uso terapéutico , Trypanosoma cruzi/fisiología , Animales , Muerte Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Estadios del Ciclo de Vida/efectos de los fármacos , Ratones Endogámicos BALB C , Parásitos/efectos de los fármacos , Sulfonamidas/química , Sulfonamidas/farmacología , Trypanosoma cruzi/efectos de los fármacos , Trypanosoma cruzi/crecimiento & desarrollo , Trypanosoma cruzi/ultraestructura

RESUMEN

We review progress in the application of fragment-based drug discovery (FBDD) to epigenetic drug discovery (EPIDD) targeted at epigenetic writer and eraser enzymes as well as reader domains over the last 15 years. The greatest successes to date are in prospecting for bromodomain binding ligands. From a diverse array of fragment hits, multiple potent and selective compounds ensued, including the oncology clinical candidates mivebresib, ABBV-744, pelabresib, and PLX51107.

Asunto(s)

Descubrimiento de Drogas , Oxazoles/química , Piridinas/química , Piridonas/química , Pirroles/química , Sulfonamidas/química , Humanos , Ligandos , Estructura Molecular

RESUMEN

We present a novel nitroxyl (HNO) generation method, which avoids the need of using a liquid system or extreme experimental conditions. This method consists of the reaction between a gaseous base and an HNO donor (Piloty's acid) in the solid phase, allowing the formation of gaseous HNO in a fast and economical way. Detection of HNO was carried out indirectly, measuring the nitrous oxide (N2O) byproduct of HNO dimerization using infrared spectroscopy, and directly, using mass spectrometry techniques and an electrochemical HNO sensor.

Asunto(s)

Óxidos de Nitrógeno/síntesis química , Amoníaco/química , Gases/química , Ácidos Hidroxámicos/química , Sulfonamidas/química

RESUMEN

To increase milk production, antibiotics are administered to animals to provide weight gain and to prevent or treat diseases. The inappropriate use of these substances can lead to antibiotic resistance and allergic reactions and toxic effects to milk consumers. We describe the development of a simple, fast, portable, and low-cost microfluidic paper-based analytical device (µPAD) to quantify sulfonamides in milk using the inhibition of the colorimetric reaction between carbonic anhydrase (CA) and 4-nitrophenyl acetate. The main advantages presented by the µPAD include reproducible batch production, simple application, and precise analysis without previous treatment. The µPAD displayed good linearity (R2 ≥ 0.986) in a wide range of sulfonamides in milk (2.5 to 40.0 µmol L-1), being selective for the drugs even in a highly complex matrix. We expect that this device allows in situ monitoring of milk quality, reducing the prejudicial conditions associated with high concentrations of sulfonamides in milk.

Asunto(s)

Anhidrasas Carbónicas/química , Colorimetría/métodos , Leche/química , Papel , Sulfonamidas/química , Animales , Anhidrasas Carbónicas/metabolismo , Bovinos , Colorimetría/instrumentación , Concentración de Iones de Hidrógeno , Técnicas Analíticas Microfluídicas , Leche/metabolismo , Nitrofenoles/química , Nitrofenoles/metabolismo , Sulfonamidas/metabolismo

RESUMEN

Using molecular hybridization, specific sulfonamide derivatives of eugenol were synthesized with subtle modifications in the allylic chain of the eugenol subunit (and also in the nature of the substituent group in the sulfonamide aromatic ring) which allowed us to study the influence of structural changes on the antimicrobial potential of the hybrids. Antimicrobial test results showed that most of the synthesized hybrid compounds showed good activity with better results than the parent compounds. Molecular docking studies of the hybrids with the essential bacterial enzyme DHPS showed complexes with low binding energies, suggesting that DHPS could be a possible target for the antibacterial sulfonamide-eugenol hybrids. Furthermore, most of the final compounds presented similar docking poses to that of the crystallographic ligand sulfamethoxazole. The results obtained allow us to conclude that these are promising compounds for use as new leads in the search for new antibacterial sulfonamides.

Asunto(s)

Antibacterianos/farmacología , Diseño de Fármacos , Eugenol/farmacología , Bacterias Gramnegativas/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Sulfonamidas/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Relación Dosis-Respuesta a Droga , Eugenol/química , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad , Sulfonamidas/química

RESUMEN

AIM: The purpose of this study was to evaluate the antifungal activity and toxicological parameters of 8-hydroxyquinoline derivatives PH151 and PH153 using alternative animal models, to understand their behaviour when subjected to in vivo experiments. METHODS AND RESULTS: We used Toll-deficient Drosophila melanogaster to test the protective effect of compounds against Candida albicans infection. Toxicological parameters were investigated in chicken and zebrafish embryos. PH151 and PH153 showed low toxicity and the treated flies with these compounds had a significantly higher survival rate than untreated flies after 7 days of infection. The compounds did not cause interruption of chicken embryogenesis. Zebrafish embryos exposed to compounds showed dose-dependent toxicity. CONCLUSIONS: The data supported the potential of PH151 and PH153 for the treatment of systemic candidiasis and demonstrated to be appropriate drug candidates for further studies using mammalian models. SIGNIFICANCE AND IMPACT OF THE STUDY: The increased incidence of Candida infections resistant to antifungals currently available requires acceleration of the discovery of new agents with properties of inhibiting this fungal pathogen. In this study, we have described the antifungal potential and toxicity of two 8-hydroxyquinoline derivatives using in vivo alternative models, and the results confirm their potential to be developed as new drug candidates.

Asunto(s)

Antifúngicos/uso terapéutico , Candidiasis/tratamiento farmacológico , Modelos Animales de Enfermedad , Oxiquinolina/uso terapéutico , Sulfonamidas/uso terapéutico , Animales , Antifúngicos/química , Candida albicans/efectos de los fármacos , Candidiasis/microbiología , Embrión de Pollo , Drosophila melanogaster , Oxiquinolina/química , Sulfonamidas/química , Pez Cebra

RESUMEN

Sulfonamides have been in clinical use for many years, and the development of bioactive substances containing the sulfonamide subunit has grown steadily in view of their important biological properties such as antibacterial, antifungal, antiparasitic, antioxidant, and antitumour properties. This review addresses the medicinal chemistry aspects of sulfonamides; covering their discovery, the structure- activity relationship and the mechanism of action of the antibacterial sulfonamide class, as well as the physico-chemical and pharmacological properties associated with this class. It also provides an overview of the various biological activities inherent to sulfonamides, reporting research that emphasises the importance of this group in the planning and development of bioactive substances, with a special focus on potential antitumour properties. The synthesis of sulfonamides is considered to be simple and provides a diversity of derivatives from a wide variety of amines and sulfonyl chlorides. The sulfonamide group is a non-classical bioisostere of carboxyl groups, phenolic hydroxyl groups and amide groups. This review highlights that most of the bioactive substances have the sulfonamide group, or a related group such as sulfonylurea, in an orientation towards other functional groups. This structural characteristic was observed in molecules with distinct antibacterial activities, demonstrating a clear structure-activity relationship of sulfonamides. This short review sought to contextualise the discovery of classic antibacterial sulfonamides and their physico-chemical and pharmacological properties. The importance of the sulfonamide subunit in Medicinal Chemistry has been highlighted and emphasised, in order to promote its inclusion in the planning and synthesis of future drugs.

Asunto(s)

Antibacterianos/química , Antineoplásicos/química , Sulfonamidas/química , Actinobacillus/efectos de los fármacos , Antibacterianos/metabolismo , Antibacterianos/farmacología , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Supervivencia Celular/efectos de los fármacos , Humanos , Relación Estructura-Actividad , Sulfonamidas/metabolismo , Sulfonamidas/farmacología , Tetrahidrofolato Deshidrogenasa/química , Tetrahidrofolato Deshidrogenasa/metabolismo

RESUMEN

Fosamprenavir calcium is an amprenavir prodrug of the protease inhibitors class used in the treatment of patients with acquired immunodeficiency syndrome (AIDS). Different solid forms of this drug are described in patents, in this sense studies on the physico-chemical characterization and stability are relevant for the selection of a solid form with adequate features for pharmaceutical purposes. In the present work form I (commercial) and amorphous of fosamprenavir calcium were characterized by the techniques of Differential Scanning Calorimetry (DSC), Thermogravimetry (TGA), Powder X-ray Diffraction (PXRD), Fourier-Transform Infrared Spectroscopy (FTIR) and Scanning Electron Microscopy (SEM). Furthermore, the chemical and polymorphic stability of the commercial form were evaluated by DSC, PXRD, FTIR and High-Performance Liquid Chromatography (HPLC). In the studies of characterization, thermal analyses allied to spectroscopic methods (PXRD and FTIR) demonstrated that the presence of water in the crystalline structure of Form I is fundamental for maintaining its crystallinity. In studies of accelerated stability the techniques of DSC, PXRD and FTIR showed that Form I does not suffer phase change when submitted to controlled conditions of temperature and humidity. Moreover, HPLC and FTIR proved the chemical stability of this solid form of fosamprenavir, thus demonstrating its suitability for pharmaceutical purposes.

Asunto(s)

Carbamatos/química , Organofosfatos/química , Preparaciones Farmacéuticas/análisis , Sulfonamidas/química , Tecnología Farmacéutica/métodos , Furanos , Humedad , Microscopía Electrónica de Rastreo , Análisis Espectral/métodos , Temperatura , Termodinámica

RESUMEN

A series of bio-organometallic-hydrazones of the general formula [{(η5-C5H4)-C(R)=N-N(H)-C6H4-4-SO2NH2}]MLn(MLn = Re(CO)3, Mn(CO)3, FeCp; R=H, CH3) were prepared by reaction of formyl/acetyl organometallic precursors with 4-hydrazino-benzenesulphonamide. All compounds were characterized by conventional spectroscopic techniques (infra-red, 1H and 13C NMR, mass spectrometry and elemental analysis). Biological evaluation as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors agents was carried out using four human/h) isoforms, hCA I, II, IX and XII. The cytosolic isoforms hCA I and II were effectively inhibited by almost all derivatives with inhibition constants of 1.7-22.4 nM. Similar effects were observed for the tumour-associated transmembrane isoform hCA XII (KIs of 1.9-24.4 nM). hCA IX was less sensitive to inhibition with these compounds. The presence of bio-organometallic or metallo-carbonyl moieties in the molecules of these CAIs makes them amenable for interesting pharmacologic applications, for example for compounds with CO donating properties.

Asunto(s)

Inhibidores de Anhidrasa Carbónica/farmacología , Anhidrasas Carbónicas/metabolismo , Hidrazinas/farmacología , Compuestos Organometálicos/farmacología , Sulfonamidas/farmacología , Dióxido de Carbono/antagonistas & inhibidores , Dióxido de Carbono/química , Dióxido de Carbono/metabolismo , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Relación Dosis-Respuesta a Droga , Humanos , Hidrazinas/química , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Estructura Molecular , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Relación Estructura-Actividad , Sulfonamidas/química , Bencenosulfonamidas

RESUMEN

Phialophora verrucosa causes several fungal human diseases, mainly chromoblastomycosis, which is extremely difficult to treat. Several studies have shown that human immunodeficiency virus peptidase inhibitors (HIV-PIs) are attractive candidates for antifungal therapies. This work focused on studying the action of HIV-PIs on peptidase activity secreted by P. verrucosa and their effects on fungal proliferation and macrophage interaction. We detected a peptidase activity from P. verrucosa able to cleave albumin, sensitive to pepstatin A and HIV-PIs, especially lopinavir, ritonavir and amprenavir, showing for the first time that this fungus secretes aspartic-type peptidase. Furthermore, lopinavir, ritonavir and nelfinavir reduced the fungal growth, causing remarkable ultrastructural alterations. Lopinavir and ritonavir also affected the conidia-macrophage adhesion and macrophage killing. Interestingly, P. verrucosa had its growth inhibited by ritonavir combined with either itraconazole or ketoconazole. Collectively, our results support the antifungal action of HIV-PIs and their relevance as a possible alternative therapy for fungal infections.

Asunto(s)

Antifúngicos/farmacología , Proteasas de Ácido Aspártico/antagonistas & inhibidores , Inhibidores de la Proteasa del VIH/farmacología , Macrófagos/efectos de los fármacos , Phialophora/efectos de los fármacos , Antifúngicos/síntesis química , Antifúngicos/química , Proteasas de Ácido Aspártico/metabolismo , Carbamatos/síntesis química , Carbamatos/química , Carbamatos/farmacología , Relación Dosis-Respuesta a Droga , Furanos , Inhibidores de la Proteasa del VIH/síntesis química , Inhibidores de la Proteasa del VIH/química , Humanos , Lopinavir/síntesis química , Lopinavir/química , Lopinavir/farmacología , Macrófagos/metabolismo , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Phialophora/enzimología , Phialophora/crecimiento & desarrollo , Ritonavir/síntesis química , Ritonavir/química , Ritonavir/farmacología , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfonamidas/farmacología

RESUMEN

More than 10 million people around the world are afflicted by Neglected Tropical Diseases, such as Chagas Disease, Human African Trypanosomiasis, and Leishmania. These diseases mostly occur in undeveloped countries that suffer from a lack of economic incentive, research, and policy for new compound development. Sulfonamide moieties are effective scaffolds present in several compounds that are determinants to treat various diseases, principally neglected tropical diseases. This review article examines the contribution of these scaffolds in medicinal chemistry in the last five years, focusing on three trypanosomatid parasites: Trypanosoma cruzi, Trypanosoma brucei, and Leishmania ssp. We also present perspectives for their use in drug designs in an effort to contribute to new drug development. In addition, we consider the physicochemical parameters, whose molecules all presented according to Lipinski's rule. The correlation between the selective index and LogP was evaluated, showing that sulfonamide derivatives can act differently against each trypanosomatid parasite. Moreover, the approaches of novel drugs and technologies are very important for the eventual drug discovery against trypanosomatid diseases.

Asunto(s)

Antiprotozoarios/farmacología , Leishmania/efectos de los fármacos , Sulfonamidas/farmacología , Trypanosoma brucei brucei/efectos de los fármacos , Trypanosoma cruzi/efectos de los fármacos , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Relación Dosis-Respuesta a Droga , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química

RESUMEN

Biophysical, theoretical and biological in vitro studies were carried out to evaluate the interaction of the main allergen protein of egg white (ovalbumin, OVA) with sulphonamides (SA): sulphathiazole (S1), sulfaquinoxaline (S2), sulfadimethoxine (S3) and sulfamethazine (S4). The binding constants for the OVA-SA supramolecular complexes ranged from 1.20 to 30.66 × 105 M-1, observing the following order of affinity: S1 > S2 > S4 > S3. The preferential forces in the stabilization of the OVA complexes with S2 and S3 were hydrogen bonds and Van der Waals forces, whereas for OVA-S1 and OVAS4, were electrostatic interactions. Interaction process led to a change in the native structure of the protein, which may potentiate its natural allergenicity. Cations Ca(II), Mg(II) and Fe(III) favor the interaction of OVA with S1 and S2. The theoretical studies performed were consistent with the spectroscopic data. Finally, it was found that the interaction process for sulfonamides evaluated with OVA change the inhibition activity profile these antibiotics against strains of Escherichia coli ATCC 25922 and Bacillus megaterium APFSG3isox, but not the minimal inhibitory concentration values.

Asunto(s)

Alérgenos/metabolismo , Antibacterianos/metabolismo , Ovalbúmina/metabolismo , Sulfonamidas/metabolismo , Alérgenos/química , Animales , Antibacterianos/química , Pollos , Hipersensibilidad al Huevo/etiología , Hipersensibilidad al Huevo/metabolismo , Clara de Huevo/química , Humanos , Simulación del Acoplamiento Molecular , Ovalbúmina/química , Unión Proteica , Sulfonamidas/química

RESUMEN

AIM: The purpose of this study was to uncover insights into the mechanism of action of the 8-hydroxyquinoline derivatives PH151 and PH153. In addition, with the future perspective of developing a topical drug for the treatment of candidiasis and dermatophytosis, the antifungal activity of a nanoemulsion formulation containing the most active compound (PH151) is also presented here. METHODS AND RESULTS: Sorbitol protection assay and scanning electron microscopy indicate that the 8-hydroxyquinoline derivatives act on the cell wall of Candida sp. and dermatophytes and they inhibit the pseudohyphae formation of C. albicans. These findings demonstrate a strong effect of these compounds on C. albicans morphogenesis, which can be considered a potential mode of action for this molecule. Besides, the nanoemulsion formulation MIC values ranged from 0·5 to 4 µg ml-1 demonstrating the significant antifungal activity when incorporated into a pharmaceutical formulation. CONCLUSIONS: Taken together, the results support the potential of these molecules as promising antifungal candidates for the treatment of candidiasis and dermatophytosis. SIGNIFICANCE AND IMPACT OF THE STUDY: There is an emerging need to fill the pipeline with new antifungal drugs due to the limitations presented by the currently used drugs. In this study, we have described a novel formulation with a 8-hydroxyquinoline-5-sulfonamide derivative which has presented a great potency in providing a finished product. Furthermore, the derivative has shown a selective mechanism of action confirming its potential to be developed into a new drug candidate.

Asunto(s)

Antifúngicos/farmacología , Arthrodermataceae/efectos de los fármacos , Dermatomicosis/microbiología , Oxiquinolina/farmacología , Sulfonamidas/farmacología , Antifúngicos/química , Arthrodermataceae/crecimiento & desarrollo , Candida albicans/efectos de los fármacos , Candida albicans/crecimiento & desarrollo , Candidiasis/tratamiento farmacológico , Candidiasis/microbiología , Pared Celular/efectos de los fármacos , Dermatomicosis/tratamiento farmacológico , Hifa/efectos de los fármacos , Hifa/crecimiento & desarrollo , Pruebas de Sensibilidad Microbiana , Oxiquinolina/química , Sulfonamidas/química

RESUMEN

BACKGROUND: Bacterial resistance to antibiotics is a growing problem in all countries and has been discussed worldwide. In this sense, the development of new drugs with antibiotic properties is highly desirable in the context of medicinal chemistry. METHODOLOGY: In this paper we investigate the antioxidant and antibacterial potential of sulfonamides derived from carvacrol, a small molecule with drug-like properties. Most sulfonamides had antioxidant and antibacterial potential, especially compound S-6, derived from beta-naphthylamine. RESULTS: To understand the possible mechanisms of action involved in biological activity, the experimental results were compared with molecular docking data. CONCLUSION: This research allows appropriate discussion on the identified structure activity relationships.

Asunto(s)

Antibacterianos/farmacología , Antioxidantes/farmacología , Cimenos/farmacología , Molibdeno/química , Sulfonamidas/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Antioxidantes/síntesis química , Antioxidantes/química , Cimenos/química , Relación Dosis-Respuesta a Droga , Escherichia coli/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Oxidación-Reducción , Staphylococcus aureus/efectos de los fármacos , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química