RESUMEN

Cruzipain (CZP), the major cysteine protease present in T. cruzi, the ethiological agent of Chagas disease, has attracted particular attention as a therapeutic target for the development of targeted covalent inhibitors (TCI). The vast chemical space associated with the enormous molecular diversity feasible to explore by means of modern synthetic approaches allows the design of CZP inhibitors capable of exhibiting not only an efficient enzyme inhibition but also an adequate translation to anti-T. cruzi activity. In this work, a computer-aided design strategy was developed to combinatorially construct and screen large libraries of 1,4-disubstituted 1,2,3-triazole analogues, further identifying a selected set of candidates for advancement towards synthetic and biological activity evaluation stages. In this way, a virtual molecular library comprising more than 75 thousand diverse and synthetically feasible analogues was studied by means of molecular docking and molecular dynamic simulations in the search of potential TCI of CZP, guiding the synthetic efforts towards a subset of 48 candidates. These were synthesized by applying a Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) centered synthetic scheme, resulting in moderate to good yields and leading to the identification of 12 hits selectively inhibiting CZP activity with IC50 in the low micromolar range. Furthermore, four triazole derivatives showed good anti-T. cruzi inhibition when studied at 50 µM; and Ald-6 excelled for its high antitrypanocidal activity and low cytotoxicity, exhibiting complete in vitro biological activity translation from CZP to T. cruzi. Overall, not only Ald-6 merits further advancement to preclinical in vivo studies, but these findings also shed light on a valuable chemical space where molecular diversity might be explored in the search for efficient triazole-based antichagasic agents.

Asunto(s)

Cisteína Endopeptidasas , Simulación del Acoplamiento Molecular , Proteínas Protozoarias , Triazoles , Trypanosoma cruzi , Triazoles/química , Triazoles/farmacología , Triazoles/síntesis química , Cisteína Endopeptidasas/química , Proteínas Protozoarias/antagonistas & inhibidores , Proteínas Protozoarias/química , Trypanosoma cruzi/efectos de los fármacos , Trypanosoma cruzi/enzimología , Inhibidores de Cisteína Proteinasa/química , Inhibidores de Cisteína Proteinasa/farmacología , Inhibidores de Cisteína Proteinasa/síntesis química , Simulación de Dinámica Molecular , Relación Estructura-Actividad , Diseño Asistido por Computadora , Diseño de Fármacos , Humanos , Estructura Molecular , Tripanocidas/farmacología , Tripanocidas/química , Tripanocidas/síntesis química , Enfermedad de Chagas/tratamiento farmacológico

RESUMEN

BACKGROUND: This study investigates the potential of eleven 1H-1,2,3-triazol-1,4-naphthoquinone conjugates as virulence factor inhibitors (like Pyocyanin) and their affinity for PhzM, a crucial enzyme for Pyocyanin biosynthesis in Pseudomonas aeruginosa infections. METHODS: A straightforward synthetic pathway enabled the production of these compounds, which were characterized and structurally confirmed through spectroscopic analyses. Evaluation of their impact on PhzM thermal stability identified promising candidates for PhzM binders. RESULTS: Concentration-response behavior elucidated their binding affinity, revealing them as the first reported micromolar affinity ligands for PhzM. Structure-activity relationship analysis emphasized the role of specific molecular moieties in binding affinity modulation, paving the way for future advanced inhibitors' development. CONCLUSION: These findings highlight the potential of naphthoquinone-triazole derivatives as leads for novel therapeutics against P. aeruginosa infections.

Asunto(s)

Antibacterianos , Pruebas de Sensibilidad Microbiana , Naftoquinonas , Pseudomonas aeruginosa , Piocianina , Triazoles , Naftoquinonas/farmacología , Naftoquinonas/química , Naftoquinonas/síntesis química , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/metabolismo , Piocianina/antagonistas & inhibidores , Piocianina/biosíntesis , Piocianina/metabolismo , Relación Estructura-Actividad , Triazoles/química , Triazoles/farmacología , Triazoles/metabolismo , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/síntesis química , Estructura Molecular , Infecciones por Pseudomonas/tratamiento farmacológico , Infecciones por Pseudomonas/microbiología , Humanos , Relación Dosis-Respuesta a Droga

RESUMEN

Aim: The design, synthesis, docking studies and evaluation of the in vitro antifungal and cytotoxic properties of eugenol (EUG) containing 1,2,3-triazole derivatives are reported. Most of the derivatives have not been reported.Materials & methods: The EUG derivatives were synthesized, molecular docked and tested for their antifungal activity.Results: The compounds showed potent antifungal activity against Trichophyton rubrum, associated with dermatophytosis. Compounds 2a and 2i exhibited promising results, with 2a being four-times more potent than EUG. The binding mode prediction was similar to itraconazole in the lanosterol-14-α-demethylase wild-type and G73E mutant binding sites. Additionally, the pharmacokinetic profile prediction suggests good gastrointestinal absorption and potential oral administration.Conclusion: Compound 2a is a promising antifungal agent against dermatophytosis caused by T. rubrum.

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[Box: see text].

Asunto(s)

Antifúngicos , Diseño de Fármacos , Eugenol , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Triazoles , Eugenol/farmacología , Eugenol/química , Eugenol/síntesis química , Eugenol/análogos & derivados , Triazoles/química , Triazoles/farmacología , Triazoles/síntesis química , Antifúngicos/farmacología , Antifúngicos/síntesis química , Antifúngicos/química , Humanos , Trichophyton/efectos de los fármacos , Relación Estructura-Actividad , Estructura Molecular

RESUMEN

A series of new hybrid compounds was prepared combining tetrahydropyran rings with different aromatic systems by means of a 1,2,3-triazole, using a building block strategy. The design of these structures was guided by Lead-Likeness and Molecular Analysis (LLAMA) software, adding modifications to our most potent scaffold (the tetrahydropyran ring) to generate promising "lead-like" candidates, which were subsequently compared against reported anticancer compounds. Our synthesized compounds demonstrated significant antiproliferative activity when compared with the standards cisplatin and 5-fluorouracil, across a panel of six different tumor cell lines. Moreover, compared with our group's previous hybrid compounds, these new structures exhibit similar activity while offering simpler synthesis and greater potential for structural diversification, a fact that was previously an issue. Further investigations on the most active compounds included assessments of reproductive cell survival, inhibition of cell migration, and effects on nuclear morphology, indicating potential diverse mechanisms of action for these compounds. Pharmacokinetic properties were also calculated for the whole series of compounds using the pkCSM online software.

Asunto(s)

Antineoplásicos , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Piranos , Triazoles , Humanos , Triazoles/farmacología , Triazoles/química , Triazoles/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Piranos/farmacología , Piranos/síntesis química , Piranos/química , Línea Celular Tumoral , Estructura Molecular , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga

RESUMEN

BACKGROUND: The current treatments for Chagas disease (CD) include benznidazole and nifurtimox, which have limited efficacy and cause numerous side effects. Triazoles are candidates for new CD treatments due to their ability to eliminate T. cruzi parasites by inhibiting ergosterol synthesis, thereby damaging the cell membranes of the parasite. METHODS: Eleven synthetic analogs of the kinase inhibitor SRPIN340 containing a triazole core (compounds 6A-6K) were screened in vitro against the Tulahuen strain transfected with ß-galactosidase, and their IC50, CC50, and selectivity indexes (SI) were calculated. Compounds with an SI > 50 were further evaluated in mice infected with the T. cruzi Y strain by rapid testing. RESULTS: Eight compounds were active in vitro with IC50 values ranging from 0.5-10.5 µg/mL. The most active compounds, 6E and 6H, had SI values of 125.2 and 69.6, respectively. These compounds also showed in vivo activity, leading to a reduction in parasitemia at doses of 10, 50, and 250 mg/kg/day. At doses of 50 and 250 mg/kg/day, parasitemia was significantly reduced compared to infected untreated animals, with no significant differences between the effects of 6E and 6H. CONCLUSIONS: This study identified two new promising compounds for CD chemotherapy and confirmed their activity against T. cruzi.

Asunto(s)

Enfermedad de Chagas , Triazoles , Tripanocidas , Trypanosoma cruzi , Trypanosoma cruzi/efectos de los fármacos , Animales , Triazoles/farmacología , Enfermedad de Chagas/tratamiento farmacológico , Tripanocidas/farmacología , Ratones , Concentración 50 Inhibidora , Pruebas de Sensibilidad Parasitaria , Tiazoles

RESUMEN

Sterol 14-demethylase (CYP51) inhibitors, encompassing new chemical entities and repurposed drugs, have emerged as promising candidates for Chagas disease treatment, based on preclinical studies reporting anti-Trypanosoma cruzi activity. Triazoles like ravuconazole (RAV) and posaconazole (POS) progressed to clinical trials. Unexpectedly, their efficacy was transient in chronic Chagas disease patients, and their activity was not superior to benznidazole (BZ) treatment. This paper aims to summarize evidence on the global activity of CYP51 inhibitors against T. cruzi by applying systematic review strategies, risk of bias assessment, and meta-analysis from in vivo studies. PubMed and Embase databases were searched for original articles, obtaining fifty-six relevant papers meeting inclusion criteria. Characteristics of animal models, parasite strain, treatment schemes, and cure rates were extracted. Primary outcomes such as maximum parasitaemia values, survival, and parasitological cure were recorded for meta-analysis, when possible. The risk of bias was uncertain in most studies. Animals treated with itraconazole, RAV, or POS survived significantly longer than the infected non-treated groups (RR = 4.85 [3.62, 6.49], P < 0.00001), and they showed no differences with animals treated with positive control drugs (RR = 1.01 [0.98, 1.04], P = 0.54). Furthermore, the overall analysis showed that RAV or POS was not likely to achieve parasitological cure when compared with BZ or NFX treatment (OD = 0.49 [0.31, 0.77], P = 0.002). This systematic review contributes to understanding why the azoles had failed in clinical trials and, more importantly, how to improve the animal models of T. cruzi infection by filling the gaps between basic, translational, and clinical research.

Asunto(s)

Inhibidores de 14 alfa Desmetilasa , Enfermedad de Chagas , Modelos Animales de Enfermedad , Trypanosoma cruzi , Animales , Humanos , Inhibidores de 14 alfa Desmetilasa/farmacología , Inhibidores de 14 alfa Desmetilasa/uso terapéutico , Enfermedad de Chagas/tratamiento farmacológico , Enfermedad de Chagas/parasitología , Esterol 14-Desmetilasa/metabolismo , Tiazoles , Resultado del Tratamiento , Triazoles/uso terapéutico , Triazoles/farmacología , Tripanocidas/farmacología , Tripanocidas/uso terapéutico , Trypanosoma cruzi/efectos de los fármacos

RESUMEN

Alpha-glucosidase inhibitors play an important role in Diabetes Mellitus (DM) treatment since they prevent postprandial hyperglycemia. The Glycoside Hydrolase family 13 (GH13) is the major family of enzymes acting on substrates containing α-glucoside linkages, such as maltose and amylose/amylopectin chains in starch. Previously, our group identified glycoconjugate 1H-1,2,3-triazoles (GCTs) inhibiting two GH13 α-glycosidases: yeast maltase (MAL12) and porcine pancreatic amylase (PPA). Here, we combined kinetic studies and computational methods on nine GCTs to characterize their inhibitory mechanism. They all behaved as reversible inhibitors, and kinetic models encompassed noncompetitive and various mechanisms of mixed-type inhibition for both enzymes. Most potent inhibitors displayed Ki values of 30 µM for MAL12 (GPESB16) and 37 µM for PPA (GPESB15). Molecular dynamics and docking simulations indicated that on MAL12, GPESB15 and GPESB16 bind in a cavity adjacent to the active site, while on the PPA, GPESB15 was predicted to bind at the entrance of the catalytic site. Notably, despite its putative location within the active site, the binding of GPESB15 does not obstruct the substrate's access to the cleavage site. Our study contributes to paving the way for developing novel therapeutic strategies for managing DM-2 through GH13 α-glycosidases inhibition.

Asunto(s)

Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Cinética , Ligandos , Porcinos , Inhibidores de Glicósido Hidrolasas/farmacología , Inhibidores de Glicósido Hidrolasas/química , Animales , Dominio Catalítico , alfa-Glucosidasas/metabolismo , alfa-Glucosidasas/química , Glicósido Hidrolasas/química , Glicósido Hidrolasas/metabolismo , Glicósido Hidrolasas/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/química , Triazoles/química , Triazoles/farmacología , Modelos Moleculares

RESUMEN

A series of 19 novel eugenol derivatives containing a 1,2,3-triazole moiety was synthesized via a two-step process, with the key step being a copper(I)-catalyzed azide-alkyne cycloaddition reaction. The compounds were assessed for their antifungal activities against Colletotrichum gloeosporioides, the causative agent of papaya anthracnose. Triazoles 2k, 2m, 2l, and 2n, at 100 ppm, were the most effective, reducing mycelial growth by 88.3, 85.5, 82.4, and 81.4%, respectively. Molecular docking calculations allowed us to elucidate the binding mode of these derivatives in the catalytic pocket of C. gloeosporioides CYP51. The best-docked compounds bind closely to the heme cofactor and within the channel access of the lanosterol (LAN) substrate, with crucial interactions involving residues Tyr102, Ile355, Met485, and Phe486. From such studies, the antifungal activity is likely attributed to the prevention of substrate LAN entry by the 1,2,3-triazole derivatives. The triazoles derived from natural eugenol represent a novel lead in the search for environmentally safe agents for controlling C. gloeosporioides.

Asunto(s)

Carica , Colletotrichum , Eugenol , Fungicidas Industriales , Simulación del Acoplamiento Molecular , Enfermedades de las Plantas , Triazoles , Colletotrichum/efectos de los fármacos , Eugenol/farmacología , Eugenol/química , Carica/química , Fungicidas Industriales/farmacología , Fungicidas Industriales/química , Fungicidas Industriales/síntesis química , Triazoles/química , Triazoles/farmacología , Triazoles/síntesis química , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/prevención & control , Relación Estructura-Actividad , Diseño de Fármacos , Proteínas Fúngicas/química , Estructura Molecular

RESUMEN

Organic-inorganic hybrid materials have a range of applications due to their unique properties. Their application in agriculture brings alternatives for the controlled release of nutrients in the soil, the seed coating, the transport of herbicides, and the treatment of plant diseases. The present study aimed to investigate the use of fungicides incorporated into hybrid membranes formed by synthetic hectorite (LAPONITE®) and polymers in the pre-treatment of garlic bulbils exposed to the pathogen Stromatinia cepivora, which causes white rot. The coatings were selected by a germination test, based on the bulbil sprouting index, and by a mycelial growth inhibition test, based on the percentage of mycelial growth inhibition. The chosen membranes were used to coat the bulbils for bioassays conducted in a biochemical oxygen demand incubator at 17 °C. The coated bulbils were planted in soil samples containing three different densities of Stromatinia cepivora: 0.1 g, 1.0 g, and 10 g of sclerotium per L of soil. Membranes containing 2% carboxymethyl cellulose and 2% LAPONITE® incorporated with (i) the fungicide tebuconazole (36 mg L-1) and (ii) the combination of the actives tebuconazole (36 mg L-1) and triadimenol (62 mg L-1) showed the total rate of sprouting and null indices of incidence of symptoms and mortality in its repetitions. The hybrid membranes were characterized employing several techniques, including X-ray diffraction, infrared and Raman spectroscopy, thermogravimetric analysis and differential scanning calorimetry coupled to mass spectrometry, and optical microscopy. Characterization data confirmed the presence of fungicides incorporated into the membranes. Some concentrations of fungicides were low enough not to be detected in all analyses performed, although they guaranteed a protective character to the bulbils about the fungus S. cepivora present in the soil, with a possibility of antifungal pre-treatment with a potential reduction in the concentration used.

Asunto(s)

Fungicidas Industriales , Ajo , Enfermedades de las Plantas , Ajo/química , Fungicidas Industriales/farmacología , Fungicidas Industriales/química , Enfermedades de las Plantas/prevención & control , Enfermedades de las Plantas/microbiología , Membranas Artificiales , Triazoles/química , Triazoles/farmacología , Ascomicetos/efectos de los fármacos

RESUMEN

The search for novel anticancer drugs is essential to expand treatment options, overcome drug resistance, reduce toxicity, promote innovation, and tackle the economic impact. The importance of these studies lies in their contribution to advancing cancer research and enhancing patient outcomes in the battle against cancer. Here, we developed new asymmetric hybrids containing two different naphthoquinones linked by a 1,2,3-1H-triazole nucleus, which are potential new drugs for cancer treatment. The antitumor activity of the novel compounds was tested using the breast cancer cell lines MCF-7 and MDA-MB-231, using the non-cancer cell line MCF10A as control. Our results showed that two out of twenty-two substances tested presented potential antitumor activity against the breast cancer cell lines. These potential drugs, named here 12g and 12h were effective in reducing cell viability and promoting cell death of the tumor cell lines, exhibiting minimal effects on the control cell line. The mechanism of action of the novel drugs was assessed revealing that both drugs increased reactive oxygen species production with consequent activation of the AMPK pathway. Therefore, we concluded that 12g and 12h are novel AMPK activators presenting selective antitumor effects.

Asunto(s)

Antineoplásicos , Neoplasias de la Mama , Naftoquinonas , Humanos , Femenino , Células MCF-7 , Especies Reactivas de Oxígeno/metabolismo , Triazoles/farmacología , Naftoquinonas/farmacología , Proteínas Quinasas Activadas por AMP , Proliferación Celular , Apoptosis , Línea Celular Tumoral , Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Ensayos de Selección de Medicamentos Antitumorales

RESUMEN

Fungal infections have emerged worldwide, and azole antifungals are widely used to control these infections. However, the emergence of antifungal resistance has been compromising the effectiveness of these drugs. Therefore, the objective of this study was to evaluate the antifungal and cytotoxic activities of the nine new 1,2,3 triazole compounds derived from thymol that were synthesized through Click chemistry. The binding mode prediction was carried out by docking studies using the crystallographic structure of Lanosterol 14α-demethylase G73E mutant from Saccharomyces cerevisiae. The new compounds showed potent antifungal activity against Trichophyton rubrum but did not show relevant action against Aspergillus fumigatus and Candida albicans. For T. rubrum, molecules nº 5 and 8 showed promising results, emphasizing nº 8, whose fungicidal and fungistatic effects were similar to fluconazole. In addition, molecule nº 8 showed low toxicity for keratinocytes and fibroblasts, concluding that this compound demonstrates promising characteristics for developing a new drug for dermatophytosis caused by T. rubrum, or serves as a structural basis for further research.

Asunto(s)

Antifúngicos , Arthrodermataceae , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Timol , Triazoles , Antifúngicos/farmacología , Antifúngicos/química , Triazoles/farmacología , Triazoles/química , Humanos , Timol/farmacología , Timol/química , Arthrodermataceae/efectos de los fármacos , Arthrodermataceae/genética , Candida albicans/efectos de los fármacos , Candida albicans/genética , Aspergillus fumigatus/efectos de los fármacos , Aspergillus fumigatus/genética , Saccharomyces cerevisiae/efectos de los fármacos , Saccharomyces cerevisiae/genética , Queratinocitos/efectos de los fármacos , Trichophyton/efectos de los fármacos , Trichophyton/genética

RESUMEN

OBJECTIVE: To evaluate the efficacy of sublingually administered human chorionic gonadotropin (HCG) in combination with clomiphene citrate (CC) or letrozole (LTZ) for ovulation induction. METHODS: In this prospective, double-blind, randomized study, the patients were divided into two placebo groups and two intervention groups using CC, LTZ, and HCG. RESULTS: There were no statistically significant differences in ovulation induction between the groups. We compared endometrial thickness at the beginning of the cycle and during the pre-ovulatory period, and detected a moderately positive correlation when CC was administered with HCG. CONCLUSIONS: Sublingual HCG with CC caused a moderately positive correlation with endometrial thickening when compared with that at the beginning of the cycle and during the pre-ovulatory period. There was no significant change in the number of pre-ovulatory follicles.

Asunto(s)

Infertilidad Femenina , Femenino , Humanos , Gonadotropina Coriónica/uso terapéutico , Clomifeno/uso terapéutico , Clomifeno/farmacología , Fármacos para la Fertilidad Femenina/uso terapéutico , Infertilidad Femenina/etiología , Letrozol , Nitrilos/farmacología , Nitrilos/uso terapéutico , Inducción de la Ovulación/efectos adversos , Estudios Prospectivos , Triazoles/farmacología , Triazoles/uso terapéutico , Método Doble Ciego

RESUMEN

Aim: The assessment of the antileishmanial potential of 22 vanillin-containing 1,2,3-triazole derivatives against Leishmania braziliensis is reported. Materials & methods: Initial screening was performed against the parasite promastigote form. The most active compound, 4b, targeted parasites within amastigotes (IC50 = 4.2 ± 1.0 µmol l-1), presenting low cytotoxicity and a selective index value of 39. 4D quantitative structure-activity relationship and molecular docking studies provided insights into structure-activity and biological effects. Conclusion: A vanillin derivative with significant antileishmanial activity was identified. Enhanced activity was linked to increased electrostatic and Van der Waals interactions near the benzyl ring of the derivatives. Molecular docking indicated the inhibition of the Leishmania amazonensis sterol 14α-demethylase, using Leishmania infantum sterol 14α-demethylase as a model, without affecting the human isoform. Inhibition was active site competition with lanosterol.

Asunto(s)

Antiprotozoarios , Benzaldehídos , Relación Estructura-Actividad Cuantitativa , Humanos , Simulación del Acoplamiento Molecular , Antiprotozoarios/farmacología , Antiprotozoarios/química , Triazoles/farmacología , Esteroles , Relación Estructura-Actividad

RESUMEN

In cystic fibrosis (CF) patients, fungal colonization of the respiratory tract is frequently found. Aspergillus fumigatus, Scedosporium genus, and Exophiala dermatitidis are the most commonly isolated moulds from the respiratory tract secretions of CF patients. The aim of this 5-year surveillance study was to identify trends in species distribution and susceptibility patterns of 212 mould strains identified as Aspergillus spp., Scedosporium spp., and Exophiala spp., isolated from sputum of 63 CF patients who received long-term therapy with itraconazole (ITR) and/or voriconazole (VRC). The Aspergillus isolates were identified as members of the sections Fumigati (n = 130), Flavi (n = 22), Terrei (n = 20), Nigri (n = 8), Nidulantes (n = 1), and Usti (n = 1). Among the 16 species of the genus Scedosporium, 9 were S. apiospermum, 3 S. aurantiacum, and 4 S. boydii. Among the 14 Exophiala species, all were molecularly identified as E. dermatitidis. Overall, 94% (15/16) of Scedosporium spp., 50% (7/14) of E. dermatitidis, and 7.7% (14/182) of Aspergillus spp. strains showed high MIC values (≥8 µg/ml) for at least one antifungal. Particularly, 8.9% (19/212) of isolates showed high MIC values for amphotericin B, 11.7% (25/212) for ITR, 4.2% (9/212) for VRC, and 3.3% (7/212) for posaconazole. In some cases, such as some A. fumigatus and E. dermatitidis isolates recovered from the same patient, susceptibility to antifungal azoles decreased over time. We show that the use of azoles for a long time in CF patients causes the selection/isolation of mould strains with higher MIC values.

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The use of azoles for a long time in cystic fibrosis patients causes the selection/isolation of Aspergillus, Scedosporium, and Exophiala species with higher MIC values.

Asunto(s)

Fibrosis Quística , Exophiala , Scedosporium , Animales , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Anfotericina B/farmacología , Anfotericina B/uso terapéutico , Fibrosis Quística/complicaciones , Fibrosis Quística/veterinaria , Exophiala/genética , Triazoles/farmacología , Triazoles/uso terapéutico , Itraconazol , Voriconazol/farmacología , Voriconazol/uso terapéutico , Aspergillus , Azoles

RESUMEN

Objective: To evaluate the antifungal activity of hydralazine hydrochloride alone and in synergy with azoles against Candida spp. and the action mechanism. Methods: We used broth microdilution assays to determine the MIC, checkerboard assays to investigate synergism, and flow cytometry and molecular docking tests to ascertain action mechanism. Results: Hydralazine alone had antifungal activity in the range of 16-128 µg/ml and synergistic effect with itraconazole versus 100% of the fungal isolates, while there was synergy with fluconazole against 11.11% of the isolates. There was molecular interaction with the receptors exo-B(1,3)-glucanase and CYP51, causing reduced cell viability and DNA damage. Conclusion: Hydralazine is synergistic with itraconazole and triggers cell death of Candida spp. at low concentrations, demonstrating antifungal potential.

Asunto(s)

Antifúngicos , Triazoles , Antifúngicos/farmacología , Triazoles/farmacología , Candida , Itraconazol/farmacología , Plancton , Simulación del Acoplamiento Molecular , Fluconazol/farmacología , Hidralazina/farmacología , Pruebas de Sensibilidad Microbiana , Farmacorresistencia Fúngica

RESUMEN

Cryptococcosis is an infectious fungal disease widely studied for its epidemiological importance in the context of public health, given the high morbidity and mortality associated with this invasive fungal infection. Many cases of the disease present clinical resistance and progress to death, even in the presence of antifungal therapy. The prolonged use of triazole drugs to maintain the treatment of cryptococcosis in AIDS patients, can lead to selective pressure from mutant strains, among other resistance mechanisms, justifying the poor clinical evolution of some cases. In this study, a narrative review of the literature on the occurrence of antifungal resistance in cryptococcosis agents was performed. Publications from 2010 to 2022 that address this topic were selected using Google Scholars and Scopus website. Data from the studies were analyzed for the values of minimum inhibitory concentration (MIC) of drugs used in the management of cryptococcosis. The review showed that the highest MIC values occurred for voriconazole, especially against C. neoformans. It is concluded that there is a lack of studies with statistical analysis of the data obtained, in order to provide a better dimensioning of the resistance rates of cryptococcosis agents to different antifungal agents, both in geographical and temporal context.

Asunto(s)

Criptococosis , Cryptococcus neoformans , Humanos , Antifúngicos/farmacología , Antifúngicos/uso terapéutico , Criptococosis/tratamiento farmacológico , Criptococosis/epidemiología , Criptococosis/microbiología , Voriconazol/farmacología , Triazoles/farmacología , Pruebas de Sensibilidad Microbiana , Farmacorresistencia Fúngica

RESUMEN

Previous studies from our laboratory have shown that the pressor response to intracerebroventricular (icv) administered ANG II in normotensive rats or spontaneously hypertensive rats (SHRs) is attenuated by increased central H2O2 concentration, produced either by direct H2O2 icv injection or by increased endogenous H2O2 centrally in response to local catalase inhibition with 3-amino-1,2,4-triazole (ATZ). In the present study, we evaluated the effects of ATZ administered peripherally on arterial pressure and sympathetic and angiotensinergic activity in SHRs. Male SHRs weighing 280-330 g were used. Mean arterial pressure (MAP) and heart rate (HR) were recorded in conscious freely moving SHRs. Acute intravenous injection of ATZ (300 mg/kg of body weight) did not modify MAP and HR during the next 4 h, however, the treatment with ATZ (300 mg/kg of body weight twice per day) for 3 days reduced MAP (144 ± 6, vs. saline, 183 ± 13 mmHg), without changing HR. Intravenous hexamethonium (ganglionic blocker) produced a smaller decrease in MAP 4 h after ATZ (-25 ± 3, vs saline -38 ± 4 mmHg). Losartan (angiotensinergic AT1 receptor blocker) produced a significant depressor response 4 h after ATZ (-22 ± 4, vs. saline: -2 ± 4 mmHg) and in 3-day ATZ treated SHRs (-25 ± 5, vs. saline: -9 ± 4 mmHg). The results suggest that the treatment with ATZ reduces sympathetic activity in SHRs and simultaneously increases angiotensinergic activity.

Asunto(s)

Hipertensión , Triazoles , Ratas , Masculino , Animales , Ratas Endogámicas SHR , Amitrol (Herbicida)/farmacología , Triazoles/farmacología , Peróxido de Hidrógeno/farmacología , Presión Sanguínea , Frecuencia Cardíaca , Peso Corporal , Hipertensión/tratamiento farmacológico

RESUMEN

Chagas disease (CD) is a neglected tropical disease endemic in 21 countries and affects about 8 million people around the world. The pharmacotherapy for this disease is limited to two drugs (Benznidazole and Nifurtimox) and both are associated with important limitations, as low cure rate in the chronic phase of the disease, high toxicity and increasing resistance by Trypanosoma cruzi. Recently, we reported a bioactive 1,2,3-triazole (compound 35) active in vitro (IC50 42.8 µM) and in vivo (100 mg/kg) against T. cruzi Y strains and preliminary in silico studies suggested the cysteine protease cruzain as a possible target. Considering these initial findings, we describe here the design and synthesis of new 1,2,3-triazoles derivatives of our hit compound (35). The triazoles were initially evaluated against healthy cells derived from neonatal rat cardiomyoblasts (H9c2 cells) to determine their cytotoxicity and against epimastigotes forms of T. cruzi Y strain. The most active triazoles were compounds 26 (IC50 19.7 µM) and 27 (IC50 7.3 µM), while benznidazole was active at 21.6 µM. Derivative 27 showed an interesting selectivity index considering healthy H9c2 cells (>77). Promising activities against trypomastigotes forms of the parasite were also observed for triazoles 26 (IC50 20.74 µM) and 27 (IC50 8.41 µM), mainly 27 which showed activity once again higher than that observed for benznidazole (IC50 12.72 µM). While docking results suggested cruzain as a potential target for these compounds, no significant enzyme inhibition was observed in vitro, indicating that their trypanocidal activity is related to another mode of action. Considering the promising in vitro results of triazoles 26 and 27, the in vivo toxicity was initially verified based on the evaluation of behavioral and physiological parameters, mortality, effect in body weight gain, and through the measurement of AST/ALT enzymes, which are markers of liver toxicity. All these evaluations pointed to a good tolerability of the animals, especially considering triazole 27. A reduction in parasitemia was observed among animals treated with triazole 27, but not among those treated with derivative 26. Regarding the dosage, derivative 27 (100 mg/kg) was the most active sample against T. cruzi infection, showing a 99.4% reduction in parasitemia peak. Triazole 27 at a dosage of 100 mg/kg influenced the humoral immune response and reduced myocarditis in the animals, bringing antibody levels closer to those observed among healthy mice. Altogether, our results indicate compound 27 as a new lead for the development of drug candidates to treat Chagas disease.

Asunto(s)

Enfermedad de Chagas , Tripanocidas , Trypanosoma cruzi , Ratones , Ratas , Animales , Eugenol/farmacología , Triazoles/farmacología , Triazoles/uso terapéutico , Parasitemia/tratamiento farmacológico , Tripanocidas/toxicidad , Enfermedad de Chagas/tratamiento farmacológico

RESUMEN

Malaria can be caused by several Plasmodium species and the development of an effective vaccine is challenging. Currently, the most effective tool to control the disease is the administration of specific chemotherapy; however, resistance to the frontline antimalarials is one of the major problems in malaria control and thus the development of new drugs becomes urgent. The study presented here sought to evaluate the antimalarial activities of compounds derived from 2-amino-1,4-naphthoquinones containing 1,2,3-triazole using in vivo and in vitro models. 1H-1,2,3-Triazole 2-amino-1,4-naphthoquinone derivatives were synthesized and evaluated for antimalarial activity in vitro, using P. falciparum W2 chloroquine (CQ) resistant strain and in vivo using the murine-P. berghei ANKA strain. Acute toxicity was determined as established by the OECD (2001). Cytotoxicity was evaluated against HepG2 and Vero mammalian cell lines. Transmission electron microscopy of the Plasmodium falciparum trophozoite (early and late stages) was used to evaluate the action of compounds derived at ultra-structural level. The compounds displayed low cytotoxicity CC50 > 100 µM, neither did they cause hemolysis at the tested doses and nor the signs of toxicity in the in vivo acute toxicity test. Among the five compounds tested, one showed IC50 values in submicromolar range of 0.8 µM. Compounds 7, 8 and 11 showed IC50 values < 5 µM, and selectivity index (SI) ranging from 6.8 to 343 for HepG2, and from 13.7 to 494.8 for Vero cells. Compounds 8 and 11 were partially active against P. berghei induced parasitemia in vivo. Analysis of the ultrastructural changes associated with the treatment of these two compounds, showed trophozoites with completely degraded cytoplasm, loss of membrane integrity, organelles in the decomposition stage and possible food vacuole deterioration. Our results indicated that compounds 8 and 11 may be considered hit molecules for antimalarial drug discovery platform and deserve further optimization studies.

Asunto(s)

Antimaláricos , Malaria Falciparum , Malaria , Naftoquinonas , Chlorocebus aethiops , Humanos , Animales , Ratones , Antimaláricos/farmacología , Antimaláricos/química , Naftoquinonas/química , Células Vero , Triazoles/farmacología , Triazoles/uso terapéutico , Malaria/tratamiento farmacológico , Malaria Falciparum/tratamiento farmacológico , Plasmodium falciparum , Plasmodium berghei , Mamíferos

RESUMEN

Vanillin is the main component of natural vanilla extract and is responsible for its flavoring properties. Besides its well-known applications as an additive in food and cosmetics, it has also been reported that vanillin can inhibit fungi of clinical interest, such as Candida spp., Cryptococcus spp., Aspergillus spp., as well as dermatophytes. Thus, the present work approaches the synthesis of a series of vanillin derivatives with 1,2,3-triazole fragments and the evaluation of their antifungal activities against Candida albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans, Cryptococcus gattii, Trichophyton rubrum, and Trichophyton interdigitale strains. Twenty-two vanillin derivatives were obtained, with yields in the range of 60%-91%, from copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) click reaction between two terminal alkynes prepared from vanillin and different benzyl azides. In general, the evaluated compounds showed moderate activity against the microorganisms tested, with minimum inhibitory concentration (MIC) values ranging from 32 to >512 µg mL-1 . Except for compound 3b against the C. gattii R265 strain, all vanillin derivatives showed fungicidal activity for the yeasts tested. The predicted physicochemical and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties for the compounds indicated favorable profiles for drug development. In addition, a four-dimensional structure-activity relationship (4D-SAR) analysis was carried out and provided useful insights concerning the structures of the compounds and their biological profile. Finally, molecular docking calculations showed that all compounds bind favorably at the lanosterol 14α-demethylase enzyme active site with binding energies ranging from -9.1 to -12.2 kcal/mol.

Asunto(s)

Fungicidas Industriales , Fungicidas Industriales/farmacología , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , Antifúngicos/química , Triazoles/farmacología , Pruebas de Sensibilidad Microbiana