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1.
Chem Biodivers ; : e202402100, 2024 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-39327235

RESUMEN

Microorganisms can induce diseases with significant clinical implications for human health. Multidrug-resistant microorganisms have been on the rise worldwide over the past few decades, and no new antibiotics have been introduced to the market in a considerable amount of time. Such situation highlights the urgency of discovering new antimicrobial drugs to address this pressing issue. Therefore, the objective of this study was to identify bioactive compounds against 15 species of bacteria and 5 species of fungi of clinical relevance through in vitro screening of 58 synthetic compounds from four chemical classes of our internal library of synthetic compounds. Our findings highlight arylpiperazines 18, 20, 26, 27, and 29, and the aminothiazole 50, as potent broad-spectrum antimicrobials (MICs = 12.5 - 15.6 mg.mL-1) against clinically relevant bacteria and fungi. Additionally, these compounds displayed low cytotoxicity against various host cells and a favorable in vitro pharmacokinetic profile for oral administration. Indeed, all six showed adequate lipophilicity, high gastrointestinal permeability, metabolic stability in human and mouse liver microsomes, and satisfactory aqueous solubility. Thus, they emerge as promising starting points for hit-to-lead studies towards new antibacterial and antifungal agents, especially against Staphylococcus epidermidis, Staphylococcus aureus, Lactobacillus paracasei and Candida orthopsilosis.

2.
Eur J Med Chem ; 275: 116621, 2024 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-38944935

RESUMEN

An optimization of the pyridylpiperazine series against Plasmodium falciparum has been performed, exploring a structure-activity relationship carried out on the toluyl fragment of hit 1, a compound with low micromolar activity against Plasmodium falciparum discovered by high-throughput screening. After confirming the crucial role played by this aryl fragment in the antiplasmodial activity, the replacement of the ortho-methyl substituent of 1 by halogenated ones led to an improvement for four analogs, either in terms of potency, expected pharmacokinetics profile, or both. Further introduction of endocyclic nitrogens in this fragment identified two more optimized compounds, 20 and 23, which are expected to be much more metabolically stable than 1. Additional assessment of the cytotoxicity, Ligand Lipophilic Efficiency, potency against the chloroquine-resistant Dd2 strain and in silico ADMET predictions revealed a satisfactory profile for most compounds, ultimately identifying the four optimized compounds 7, 9, 20 and 23 as promising compounds for further lead optimization of this series against Plasmodium falciparum.


Asunto(s)
Antimaláricos , Diseño de Fármacos , Pruebas de Sensibilidad Parasitaria , Piperazinas , Plasmodium falciparum , Antimaláricos/farmacología , Antimaláricos/síntesis química , Antimaláricos/química , Plasmodium falciparum/efectos de los fármacos , Relación Estructura-Actividad , Piperazinas/química , Piperazinas/farmacología , Piperazinas/síntesis química , Humanos , Estructura Molecular , Relación Dosis-Respuesta a Droga , Animales
3.
Life (Basel) ; 14(6)2024 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-38929667

RESUMEN

Plakortinic acids C (1) and D (2), an unseparable pair of endoperoxide polyketides isolated and purified from the symbiotic association of Caribbean Sea sponges Plakortis symbiotica-Xestospongia deweerdtae, underwent in vitro evaluation for antiplasmodial activity against the malaria parasite Plasmodium berghei using a drug luminescence assay. Initial screening at 10 µM revealed 50% in vitro parasite growth inhibition. The title compounds displayed antiplasmodial activity with an EC50 of 5.3 µM toward P. berghei parasites. The lytic activity against erythrocytes was assessed through an erythrocyte cell lysis assay, which showed non-lytic activity at lower concentrations ranging from 1.95 to 3.91 µM. The antiplasmodial activity and the absence of hemolytic activity support the potential of plakortinic acids C (1) and D (2) as promising lead compounds. Moreover, drug-likeness (ADMET) properties assessed through the pkCSM server predicted high intestinal absorption, hepatic metabolism, and volume of distribution, indicating favorable pharmacokinetic profiles for oral administration. These findings suggest the potential suitability of these metabolites for further investigations of antiplasmodial activity in multiple parasitic stages in the mosquito and Plasmodium falciparum. Notably, this study represents the first report of a marine natural product exhibiting the unique 7,8-dioxatricyclo[4.2.2.02,5]dec-9-ene motif being evaluated against malaria.

4.
Naunyn Schmiedebergs Arch Pharmacol ; 397(10): 7797-7818, 2024 10.
Artículo en Inglés | MEDLINE | ID: mdl-38722342

RESUMEN

This study aims to evaluate the antitrypanosomiasis activity of a synthetic dichloro-substituted aminochalcone via in vitro assays against infected cell cultures, as well as a theoretical characterization of pharmacokinetics and pharmacodynamics against the protein targets of the evolutionary cycle of T. cruzi. The in vitro evaluation of parasite proliferation inhibition was performed via cytotoxicity analysis on mammalian host cells, effect on epimastigote and trypomastigote forms, and cell death analysis, while computer simulations characterized the electronic structure of (2E)-1-(4-aminophenyl)-3-(2,4-dichlorophenyl)prop-2-en-1-one (DCl), the mechanism of action against the proteins of the evolutionary cycle of T. cruzi: Cruzain, Trypanothione reductase, TcGAPDH, and CYP51 by molecular docking and dynamics and predictive pharmacokinetics by MPO-based ADMET. The in vitro tests showed that the DCl LC50 in order of 178.9 ± 23.9 was similar to the BZN, evidencing the effectiveness of chalcone against Trypomastigotes. Molecular docking and dynamics simulations suggest that DCl acts on the active site of the CYP51 receptor, with hydrogen interactions that showed a high degree of occupation, establishing a stable complex with the target. MPO analysis and ADMET prediction tests suggest that the compound presents an alignment between permeability and hepatic clearance, although it presents low metabolic stability. Chalcone showed stable pharmacodynamics against the CYP51 target, but can form reactive metabolites from N-conjugation and C = C epoxidation, as an indication of controlled oral dose, although the estimated LD50 rate > 500 mg/kg is a indicative of low incidence of lethality by ingestion, constituting a promising therapeutic strategy.


Asunto(s)
Chalconas , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Tripanocidas , Trypanosoma cruzi , Tripanocidas/farmacología , Tripanocidas/química , Trypanosoma cruzi/efectos de los fármacos , Animales , Chalconas/farmacología , Chalconas/química , Proteínas Protozoarias/metabolismo , Humanos , NADH NADPH Oxidorreductasas/antagonistas & inhibidores , NADH NADPH Oxidorreductasas/metabolismo , Teoría Cuántica , Ratones , Enfermedad de Chagas/tratamiento farmacológico
5.
ACS Chem Neurosci ; 15(9): 1904-1914, 2024 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-38639539

RESUMEN

The compound N-(3-(phenylselanyl)prop-2-yn-1-yl)benzamide (SePB), which combines a selenium atom and a benzamide nucleus in an organic structure, has demonstrated a fast antidepressant-like effect in mice. This action is influenced by the serotonergic system and represents a promising development in the search for novel antidepressant drugs to treat major depressive disorder (MDD), which often resists conventional treatments. This study aimed to further explore the mechanism underlying the antidepressant-like effect of SePB by investigating the involvement of the dopaminergic and noradrenergic systems in the tail suspension test (TST) in mice and evaluating its pharmacokinetic profile in silico. Preadministration of the dopaminergic antagonists haloperidol (0.05 mg/kg, intraperitoneally (i.p.)), a nonselective antagonist of dopamine (DA) receptors, SCH23390 (0.01 mg/kg, subcutaneously (s.c.)), a D1 receptor antagonist, and sulpiride (50 mg/kg, i.p.), a D2/3 receptor antagonist, before SePB (10 mg/kg, intragastrically (i.g.)) prevented the anti-immobility effect of SePB in the TST, demonstrating that these receptors are involved in the antidepressant-like effect of SePB. Administration of the noradrenergic antagonists prazosin (1 mg/kg, i.p.), an α1-adrenergic antagonist, yohimbine (1 mg/kg, i.p.), an α2-adrenergic antagonist, and propranolol (2 mg/kg, i.p.), a ß-adrenergic antagonist, did not block the antidepressant-like effect of SePB on TST, indicating that noradrenergic receptors are not involved in this effect. Additionally, the coadministration of SePB and bupropion (a noradrenaline/dopamine reuptake inhibitor) at subeffective doses (0.1 and 3 mg/kg, respectively) produced antidepressant-like effects. SePB also demonstrated good oral bioavailability and low toxicity in computational absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses. These findings suggest that SePB has potential as a new antidepressant drug candidate with a particular focus on the dopaminergic system.


Asunto(s)
Antidepresivos , Benzamidas , Animales , Antidepresivos/farmacología , Antidepresivos/farmacocinética , Benzamidas/farmacología , Benzamidas/farmacocinética , Ratones , Masculino , Antagonistas de Dopamina/farmacología , Antagonistas de Dopamina/farmacocinética , Dopamina/metabolismo , Suspensión Trasera , Compuestos de Organoselenio/farmacología , Compuestos de Organoselenio/farmacocinética , Compuestos de Organoselenio/química
6.
Nat Prod Res ; : 1-6, 2024 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-38516734

RESUMEN

Pseudomonas aeruginosa is a well-known pathogen for its rapid development of multi-drug antibiotic resistance. This pathogen is responsible for numerous human diseases, particularly affecting immunocompromised and elderly patients. Hence, discovering novel therapeutics has become necessary in the fight against antimicrobial resistance. This study is focused on evaluating the potential inhibitory activity of eleven phytocompounds from Azadirachta indica against the nucleotide-binding site of the FtsZ protein of P. aeruginosa through a cheminformatics approach. FtsZ is an indispensable and highly conserved protein in prokaryotic cell division. Docking studies revealed favourable binding energies (ΔG= - 8.3 to - 5.4 kcal/mol) for all selected phytoconstituents. Finally, we selected Nimbiol (CID 11119228), as a lead compound, exhibiting a binding energy (ΔG= -7.8 kcal/mol) for the target. Based on our findings, Nimbiol shows potential as an anti-FtsZ compound, making it a promising candidate for further in vitro and in vivo investigations to assess its antimicrobial activity.

7.
Int J Mol Sci ; 25(4)2024 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-38396647

RESUMEN

Helicobacter pylori (Hp) infections pose a global health challenge demanding innovative therapeutic strategies by which to eradicate them. Urease, a key Hp virulence factor hydrolyzes urea, facilitating bacterial survival in the acidic gastric environment. In this study, a multi-methodological approach combining pharmacophore- and structure-based virtual screening, molecular dynamics simulations, and MM-GBSA calculations was employed to identify novel inhibitors for Hp urease (HpU). A refined dataset of 8,271,505 small molecules from the ZINC15 database underwent pharmacokinetic and physicochemical filtering, resulting in 16% of compounds for pharmacophore-based virtual screening. Molecular docking simulations were performed in successive stages, utilizing HTVS, SP, and XP algorithms. Subsequent energetic re-scoring with MM-GBSA identified promising candidates interacting with distinct urease variants. Lys219, a residue critical for urea catalysis at the urease binding site, can manifest in two forms, neutral (LYN) or carbamylated (KCX). Notably, the evaluated molecules demonstrated different interaction and energetic patterns in both protein variants. Further evaluation through ADMET predictions highlighted compounds with favorable pharmacological profiles, leading to the identification of 15 candidates. Molecular dynamics simulations revealed comparable structural stability to the control DJM, with candidates 5, 8 and 12 (CA5, CA8, and CA12, respectively) exhibiting the lowest binding free energies. These inhibitors suggest a chelating capacity that is crucial for urease inhibition. The analysis underscores the potential of CA5, CA8, and CA12 as novel HpU inhibitors. Finally, we compare our candidates with the chemical space of urease inhibitors finding physicochemical similarities with potent agents such as thiourea.


Asunto(s)
Helicobacter pylori , Helicobacter pylori/metabolismo , Ureasa/metabolismo , Simulación de Dinámica Molecular , Simulación del Acoplamiento Molecular , Urea/farmacología
8.
Fundam Clin Pharmacol ; 38(1): 84-98, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37649138

RESUMEN

BACKGROUND: Thiadiazines are heterocyclic compounds that contain two nitrogen atoms and one sulfur atom in their structure. These synthetic molecules have several relevant pharmacological activities, such as antifungal, antibacterial, and antiparasitic. OBJECTIVES: The present study aimed to evaluate the possible in vitro and in silico interactions of compounds derived from thiadiazines. METHODS: The compounds were initially synthesized, purified, and confirmed through HPLC methodology. Multi-drug resistant bacterial strains of Staphylococcus aureus 10 and Pseudomonas aeruginosa 24 were used to evaluate the direct and modifying antibiotic activity of thiadiazine derivatives. ADMET assays (absorption, distribution, metabolism, excretion, and toxicity) were conducted, which evaluated the influence of the compounds against thousands of macromolecules considered as bioactive targets. RESULTS: There were modifications in the chemical synthesis in carbon 4 or 3 in one of the aromatic rings of the structure where different ions were added, ensuring a variability of products. It was possible to observe results that indicate the possibility of these compounds acting through the cyclooxygenase 2 mechanism, which, in addition to being involved in inflammatory responses, also acts by helping sodium reabsorption. The amine group present in thiadiazine analogs confers hydrophilic characteristics to the substances, but this primary characteristic has been altered due to alterations and insertions of other ligands. The characteristics of the analogs generally allow easy intestinal absorption, reduce possible hepatic toxic effects, and enable possible neurological and anti-inflammatory action. The antibacterial activity tests showed a slight direct action, mainly of the IJ23 analog. Some compounds were able to modify the action of the antibiotics gentamicin and norfloxacin against multi-drug resistant strains, indicating a possible synergistic action. CONCLUSIONS: Among all the results obtained in the study, the relevance of thiadiazine analogs as possible coadjuvant drugs in the antibacterial, anti-inflammatory, and neurological action with low toxicity is clear. Need for further studies to verify these effects in living organisms is not ruled out.


Asunto(s)
Antiinfecciosos , Tiadiazinas , Antibacterianos/farmacología , Tiadiazinas/farmacología , Tiadiazinas/química , Norfloxacino/farmacología , Antiinflamatorios , Pruebas de Sensibilidad Microbiana
9.
J Biomol Struct Dyn ; 42(5): 2616-2631, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37166375

RESUMEN

The withanolides are naturally occurring steroidal lactones found mainly in plants of the Solanaceae family. The subtribe Withaninae includes species like Withania sominifera, which are a source of many bioactive withanolides. In this work, we selected and evaluate the ADMET-related properties of 91 withanolides found in species of the subtribe Withaninae computationally, to predict the relationship between their structures and their pharmacokinetic profiles. We also evaluated the interaction of these withanolides with known targets of Alzheimer's disease (AD) through molecular docking and molecular dynamics. Withanolides presented favorable pharmacokinetic properties, like high gastrointestinal absorption, lipophilicity (logP ≤ 5), good distribution and excretion parameters, and a favorable toxicity profile. The specie Withania aristata stood out as an interesting source of the promising withanolides classified as 5-ene with 16-ene or 17-ene. These withanolides presented a favourable pharmacokinetic profile and were also highlighted as the best candidates for inhibition of AD-related targets. Our results also suggest that withanolides are likely to act as cholinesterase inhibitors by interacting with the catalytic pocket in an energy favorable and stable way.Communicated by Ramaswamy H. Sarma.


Asunto(s)
Enfermedad de Alzheimer , Withania , Witanólidos , Witanólidos/farmacología , Simulación del Acoplamiento Molecular , Enfermedad de Alzheimer/tratamiento farmacológico , Simulación de Dinámica Molecular , Withania/química
10.
Pharmaceuticals (Basel) ; 16(12)2023 Dec 09.
Artículo en Inglés | MEDLINE | ID: mdl-38139835

RESUMEN

A series of heterocyclic chloroquine hybrids, containing a chain of two carbon atoms at position four of the quinolinic chain and acting as a link between quinoline and several benzoyl groups, is synthesized and screened in vitro as an inhibitor of ß-hematin formation and in vivo for its antimalarial activity against chloroquine-sensitive strains of Plasmodium berghei ANKA in this study. The compounds significantly reduced haeme crystallization, with IC50 values < 10 µM. The values were comparable to chloroquine's, with an IC50 of 1.50 ± 0.01 µM. The compounds 4c and 4e prolonged the average survival time of the infected mice to 16.7 ± 2.16 and 14.4 ± 1.20 days, respectively. We also studied the effect of the compounds 4b, 4c, and 4e on another important human parasite, Leishmania mexicana, which is responsible for cutaneous leishmaniasis, demonstrating a potential leishmanicidal effect against promasigotes, with an IC50 < 10 µM. Concerning the possible mechanism of action of these compounds on Lesihmania mexicana, we performed experiments demonstrating that these three compounds could induce the collapse of the parasite mitochondrial electrochemical membrane potential (Δφ). The in vitro cytotoxicity assays against mammalian cancerous and noncancerous human cell lines showed that the studied compounds exhibit low cytotoxic effects. The ADME/Tox analysis predicted moderate lipophilicity values, low unbound fraction values, and a poor distribution for these compounds. Therefore, moderate bioavailability was expected. We calculated other molecular descriptors, such as the topological polar surface area, according to Veber's rules, and except for 2 and 4i, the rest of the compounds violated this descriptor, demonstrating the low antimalarial activity of our compounds in vivo.

11.
J Biomol Struct Dyn ; : 1-19, 2023 Nov 03.
Artículo en Inglés | MEDLINE | ID: mdl-37921757

RESUMEN

To contribute to the development of products capable of complexing with the SARS-CoV-2 spike protein, and thus preventing the virus from entering the host cell, this work aimed at discovering binding sites in the whole protein structure, as well as selecting substances capable of binding efficiently to such sites. Initially, the three-dimensional structure of the protein, with all receptor binding domains in the closed state, underwent blind docking with 38 substances potentially capable of binding to this protein according to the literature. This allowed the identification of five binding sites. Then, those substances with more affinities for these sites underwent pharmacophoric search in the ZINC15 database. The 14,329 substances selected from ZINC15 were subjected to docking to the five selected sites of the spike protein. The ligands with more affinities for the protein sites, as well as the selected sites themselves, were used in the de novo design of new ligands that were also docked to the binding sites of the protein. The best ligands, regardless of their origins, were used to form complexes with the spike protein, which were subsequently used in molecular dynamics simulations and calculations of ligands affinities to the protein through the molecular mechanics/Poisson-Boltzmann surface area method (MMPBSA). Seven substances with good affinities to the spike protein (-12.9 to -20.6 kcal/mol), satisfactory druggability (Bioavailability score: 0.17 to 0.55), and low acute toxicity to mice (LD50: 751 to 1421 mg/kg) were selected as potentially useful for the future development of new products to manage COVID-19 infections.Communicated by Ramaswamy H. Sarma.

12.
Chem Biodivers ; 20(11): e202300905, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37798253

RESUMEN

Microbial contamination remains a significant economic challenge in the food industry, emphasizing the need for innovative antimicrobial solutions. In this study, we synthesized N-sulfonyl-1,2,3,4-tetrahydroisoquinolines (NSTHIQ) derivatives using an environmentally friendly Preyssler heteropolyacid catalyst, obtaining moderate to high yields (35-91 %) under mild conditions. Two derivatives (5 and 6) exhibited significant antifungal properties against various fungal species, including Aspergillus spp, Penicillium spp, and Botrytis cinerea. ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) analysis revealed the absence of hepatic toxicity in all compounds, making derivatives 2, 3, 4, and 5 potential candidates for further development. However, derivatives 6 and 7 exhibited immunotoxicity. In support of our experimental findings, reactivity indices were computed using Density Functional Theory principles, deriving valuable insights into the chemical properties of these derivatives. This study underscores the potential of NSTHIQ compounds as potent antifungal agents, coupled with the importance of employing environmentally friendly catalysts in drug discovery.


Asunto(s)
Antiinfecciosos , Tetrahidroisoquinolinas , Pruebas de Sensibilidad Microbiana , Antiinfecciosos/química , Antifúngicos/farmacología , Antifúngicos/química , Aspergillus , Tetrahidroisoquinolinas/farmacología , Relación Estructura-Actividad
13.
Mol Divers ; 2023 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-37670118

RESUMEN

The dopamine transporter (DAT), responsible for the regulation of dopaminergic neurotransmission, is implicated in the etiology of several neuropsychiatric disorders which, in turn, have contributed to high rates of disability and numerous deaths in recent years, significantly impacting the global health system. Although the research for new drugs for the treatment of neuropsychiatric disorders has evolved in recent years, the availability of DAT-selective drugs that do not generate the same psychostimulant effects observed in drugs of abuse remains scarce. Therefore, we performed a QSAR study based on a dataset of 36 methylamine derivatives described as DAT inhibitors. The model was obtained based only in descriptors derived from 2D structures, and it was validated and generated satisfactory results considering the metrics used for internal and external validation. Subsequently, a virtual screening step also based on 2D similarity was performed, where it was possible to identify a total of 1157 compounds. After a series of reductions of the set using toxicity filters, applicability domain evaluation, and pharmacokinetic properties in silico assessment, seven hit compounds were selected as the most promising to be used, in future studies, as new scaffolds for the development of new DAT inhibitors.

14.
Pharmaceuticals (Basel) ; 16(8)2023 Aug 04.
Artículo en Inglés | MEDLINE | ID: mdl-37631024

RESUMEN

Chickpea (Cicer arietinum L.) peptides can inhibit dipeptidyl peptidase IV (DPP-IV), an important type 2 diabetes mellitus therapeutic target. The molecular interactions between the inhibitory peptides and the active site of DPP-IV have not been thoroughly examined, nor have their pharmacokinetic properties. Therefore, the predictions of legumin- and provicilin-derived DPP-IV inhibitory peptides, their molecular interactions with the active site of DPP-IV, and their pharmacokinetic properties were carried out. Ninety-two unique DPP-IV inhibitory peptides were identified. Papain and trypsin were the enzymes with the highest AE (0.0927) and lowest BE (6.8625 × 10-7) values, respectively. Peptide binding energy values ranged from -5.2 to -7.9 kcal/mol. HIS-PHE was the most potent DPP-IV inhibitory peptide and interacts with residues of the active sites S1 (TYR662) and S2 (GLU205/ARG125 (hydrogen bonds: <3.0 Å)), S2 (GLU205/GLU206 (electrostatic interactions: <3.0 Å)), and S2' pocket (PHE357 (hydrophobic interaction: 4.36 Å)). Most peptides showed optimal absorption (76.09%), bioavailability (89.13%), and were non-toxic (97.8%) stable for gastrointestinal digestion (73.9%). Some peptides (60.86%) could also inhibit ACE-I. Chickpea is a source of non-toxic and bioavailable DPP-IV-inhibitory peptides with dual bioactivity. Studies addressing the potential of chickpea peptides as therapeutic or adjunct agents for treating type 2 diabetes are warranted.

15.
Acta Trop ; 245: 106965, 2023 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-37295486

RESUMEN

The present work aimed to carry out in vitro biological assays of thiazole compounds against adult worms of Schistosoma mansoni, as well as the in silico determination of pharmacokinetic parameters to predict the oral bioavailability of these compounds. In addition to presenting moderate to low cytotoxicity against mammalian cells, thiazole compounds are not considered hemolytic. All compounds were initially tested at concentrations ranging from 200 to 6.25 µM against adult worms of S. mansoni parasites. The results showed the best activity of PBT2 and PBT5 at a concentration of 200 µM, which caused 100% mortality after 3 h of incubation. While at 6 h of exposure, 100% mortality was observed at the concentration of 100 µM. Subsequent studies with these same compounds allowed classifying PBT5, PBT2, PBT6 and PBT3 compounds, which were considered active and PBT1 and PBT4 compounds, which were considered inactive. In the ultrastructural analysis the compounds PBT2 and PBT5 (200 µM) promoted integumentary changes with exposure of the muscles, formation of integumentary blisters, integuments with abnormal morphology and destruction of tubercles and spicules. Therefore, the compounds PBT2 and PBT5 are promising antiparasitics against S. mansoni.


Asunto(s)
Esquistosomiasis mansoni , Esquistosomicidas , Animales , Schistosoma mansoni/ultraestructura , Tiazoles/farmacología , Tiazoles/uso terapéutico , Esquistosomicidas/farmacología , Esquistosomicidas/uso terapéutico , Antiparasitarios/uso terapéutico , Esquistosomiasis mansoni/tratamiento farmacológico , Mamíferos
16.
Med Chem ; 19(10): 1002-1017, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37259926

RESUMEN

BACKGROUND: Dimeric acylphloroglucinols occurring in species from sections Brathys and Trigynobrathys of the genus Hypericum exhibit acylfilicinic acid and acylphloroglucinol moieties linked by a methylene bridge. However, this chemical feature differs from hyperforin, from H. perforatum (Hypericum section). Some dimeric acylphloroglucinols, such as uliginosin B, display similar pharmacological activities, namely antidepressant and antinociceptive. However, there is no knowledge about the pharmacokinetic profile and no toxicity studies of these compounds in intact mammals. OBJECTIVE: To perform an in silico evaluation of the similarity, pharmacokinetics and toxicity (ADMET) properties of dimeric acylphloroglucinols from species native to Central and South America. METHODS: ADMET prediction of eleven elected phloroglucinols followed by the chemical space evaluation of thirty-five dimeric acylphloroglucinols derivatives labeled according to their prenylation/ geranylation pattern through principal component analysis (PCA). The similarity analysis was performed using the Tanimoto similarity index. ADMET properties were predicted with the opensource software SwissADME and pkCSM-pharmacokinetics. RESULTS: Several compounds showed good human intestinal absorption. However, they may present difficulties in crossing the blood-brain barrier, probably due to the high tPSA values. The predicted toxicity parameters indicated that most compounds have low toxicity. Most non-prenylated phloroglucinols were disposed into Lipinski's rule limits. Uliginosin B, isouliginosin B and japonicin A seem to be druglike compounds. The PCA model explained 77.49% of the total variance, and molecular similarity analyses revealed some expected similarities between isomers and different compounds. CONCLUSION: Dimeric acylphloroglucinols may be promising drug candidates and deserve further pharmacological and medicinal chemistry studies.

17.
Pharmaceutics ; 15(5)2023 May 19.
Artículo en Inglés | MEDLINE | ID: mdl-37242777

RESUMEN

Chagas disease (CD) caused by the protozoan Trypanosoma cruzi affects more than six million people worldwide. Treatment is restricted to benznidazole (Bz) and nifurtimox (Nf) that display low activity in the later chronic stage besides triggering toxic events that result in treatment abandonment. Therefore, new therapeutic options are necessary. In this scenario, natural products emerge as promising alternatives to treat CD. In the family Plumbaginaceae, Plumbago sp. exhibits a broad spectrum of biological and pharmacological activities. Thus, our main objective was to evaluate, in vitro and in silico, the biological effect of crude extracts of root and of aerial parts of P. auriculata, as well as its naphthoquinone Plumbagin (Pb) against T. cruzi. The phenotypic assays revealed potent activity of the root extract against different forms (trypomastigote and intracellular forms) and strains (Y and Tulahuen), with a compound concentration that reduced 50% of the number of the parasite (EC50) values ranging from 1.9 to 3.9 µg/mL. In silico analysis showed that Pb is predicted to have good oral absorption and permeability in Caco2 cells, besides excellent probability of absorption by human intestinal cells, without toxic or mutagenic potential effects, not being predicted as a substrate or inhibitor of P-glycoprotein. Pb was as potent as Bz against intracellular forms and displayed a superior trypanosomicidal effect (about 10-fold) in bloodstream forms (EC50 = 0.8 µM) as compared to the reference drug (8.5 µM). The cellular targets of Pb on T. cruzi were evaluated using electron microscopy assays and the findings on bloodstream trypomastigotes showed several cellular insults related to the autophagic process. Regarding toxicity in mammalian cells, the root extracts and the naphthoquinone present a moderate toxic profile on fibroblasts and cardiac cell lines. Then, aiming to reduce host toxicity, the root extract and Pb were tested in combination with Bz, and the data showed additive profiles with the sum of the fractional inhibitory concentration indexes (ΣFICIs) being 1.45 and 0.87, respectively. Thus, our work reveals the promising antiparasitic activity of Plumbago auriculata crude extracts and its purified naphthoquinone Plumbagin against different forms and strains of Trypanosoma cruzi in vitro.

18.
J Toxicol Environ Health A ; 86(14): 479-490, 2023 07 18.
Artículo en Inglés | MEDLINE | ID: mdl-37246633

RESUMEN

The development of new drugs through studies of candidate molecules is a complex undertaking; however, computational or in silico approaches aimed at optimizing molecules with greater development potential are being utilized for predictions of pharmacokinetic properties such as absorption, distribution, metabolism and excretion (ADME) as well as toxicological parameters. The objective of this study was to examine in silico and in vivo pharmacokinetic and toxicological properties of the chemical constituents present in the essential oil of Croton heliotropiifolius Kunth leaves. The following Pubchem platform as well as Software SwissADME and PreADMET software were employed for in silico studies while micronucleus (MN) testing for in vivo determination of mutagenicity, using Swiss adult male Mus musculus mice. In silico findings demonstrated that all chemical constituents presented (1) high oral absorption (2) medium cellular permeability and (3) high blood brain permeability. As for toxicity, these chemical constituents exhibited low to medium risk of occurrence of cytotoxicity. Regarding in vivo evaluation, peripheral blood samples obtained from animals tested with the oil showed no significant differences in number of MN compared to negative controls. Data indicate that further investigations are necessary to corroborate the findings of this study. Our data suggest that essential oil extracted from Croton heliotropiifolius Kunth leaves may serve as a candidate for new drug development.


Asunto(s)
Croton , Aceites Volátiles , Masculino , Animales , Ratones , Aceites Volátiles/toxicidad , Croton/química , Encéfalo , Hojas de la Planta/toxicidad , Hojas de la Planta/química
19.
Eur J Med Chem ; 256: 115445, 2023 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-37156183

RESUMEN

An early hit-to-lead optimization of a novel pyrazinylpiperazine series against L. infantum and L. braziliensis has been performed after an extensive SAR focusing on the benzoyl fragment of hit (4). Deletion of the meta-Cl of (4) led to the obtention of the para-hydroxyl derivative (12), on which the design of most monosubstituted derivatives of the SAR was based. Further optimization of the series, involving disubstituted benzoyl fragments and the hydroxyl substituent of (12), allowed the obtention of a total of 15 compounds with increased antileishmanial potency (IC50 < 10 µM), nine of which displayed activity in the low micromolar range (IC50 < 5 µM). This optimization ultimately identified the ortho, meta-dihydroxyl derivative (46) as an early lead for this series (IC50 (L. infantum) = 2.8 µM, IC50 (L. braziliensis) = 0.2 µM). Additional assessment of some selected compounds against other trypanosomatid parasites revealed that this series is selective towards Leishmania parasites, and in silico ADMET predictions revealed satisfactory profiles for these compounds, allowing further lead optimization of the pyrazinylpiperazine class against Leishmania.


Asunto(s)
Antiprotozoarios , Leishmania braziliensis , Leishmania infantum , Antiprotozoarios/farmacología , Radical Hidroxilo
20.
Pharmaceutics ; 15(4)2023 Mar 29.
Artículo en Inglés | MEDLINE | ID: mdl-37111580

RESUMEN

Amyotrophic lateral sclerosis (ALS) is the most prevalent motor neuron disorder in adults, which is associated with a highly disabling condition. To date, ALS remains incurable, and the only drugs approved by the FDA for its treatment confer a limited survival benefit. Recently, SOD1 binding ligand 1 (SBL-1) was shown to inhibit in vitro the oxidation of a critical residue for SOD1 aggregation, which is a central event in ALS-related neurodegeneration. In this work, we investigated the interactions between SOD1 wild-type and its most frequent variants, i.e., A4V (NP_000445.1:p.Ala5Val) and D90A (NP_000445.1:p.Asp91Val), with SBL-1 using molecular dynamics (MD) simulations. The pharmacokinetics and toxicological profile of SBL-1 were also characterized in silico. The MD results suggest that the complex SOD1-SBL-1 remains relatively stable and interacts within a close distance during the simulations. This analysis also suggests that the mechanism of action proposed by SBL-1 and its binding affinity to SOD1 may be preserved upon mutations A4V and D90A. The pharmacokinetics and toxicological assessments suggest that SBL-1 has drug-likeness characteristics with low toxicity. Our findings, therefore, suggested that SBL-1 may be a promising strategy to treat ALS based on an unprecedented mechanism, including for patients with these frequent mutations.

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