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1.
Int J Mol Sci ; 25(3)2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38338643

RESUMO

The process of drug discovery constitutes a highly intricate and formidable undertaking, encompassing the identification and advancement of novel therapeutic entities [...].


Assuntos
Desenho de Fármacos , Descoberta de Drogas
2.
Int J Mol Sci ; 24(24)2023 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-38139304

RESUMO

Thiadiazole derivatives have garnered significant attention in the field of medicinal chemistry due to their diverse pharmacological activities, including anticancer properties. This article presents the synthesis of a series of thiadiazole derivatives and investigates their chemical characterization and potential anticancer effects on various cell lines. The results of the nuclear magnetic resonance (NMR) analyses confirmed the successful formation of the target compounds. The anticancer potential was evaluated through in silico and in vitro cell-based assays using LoVo and MCF-7 cancer lines. The assays included cell viability, proliferation, apoptosis, and cell cycle analysis to assess the compounds' effects on cancer cell growth and survival. Daphnia magna was used as an invertebrate model for the toxicity evaluation of the compounds. The results revealed promising anticancer activity for several of the synthesized derivatives, suggesting their potential as lead compounds for further drug development. The novel compound 2g, 5-[2-(benzenesulfonylmethyl)phenyl]-1,3,4-thiadiazol-2-amine, demonstrated good anti-proliferative effects, exhibiting an IC50 value of 2.44 µM against LoVo and 23.29 µM against MCF-7 after a 48-h incubation and little toxic effects in the Daphnia test.


Assuntos
Antineoplásicos , Tiadiazóis , Estrutura Molecular , Relação Estrutura-Atividade , Antineoplásicos/química , Tiadiazóis/química , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Linhagem Celular Tumoral
3.
Pharmaceuticals (Basel) ; 16(11)2023 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-38004429

RESUMO

Osteoarthritis is characterized by progressive articular cartilage degradation, subchondral bone changes, and synovial inflammation, and affects various joints, causing pain and disability. Current osteoarthritis therapies, primarily focused on pain management, face limitations due to limited effectiveness and high risks of adverse effects. Safer and more effective treatments are urgently needed. Considering that the endocannabinoid 2-arachidonoyl glycerol is involved in pain processing, increasing its concentration through monoacylglycerol lipase (MAGL) inhibition reduces pain in various animal models. Furthermore, drug repurposing approaches leverage established drug safety profiles, presenting a cost-effective route to accelerate clinical application. To this end, cetirizine and levetiracetam were examined for their MAGL inhibitory effects. In vitro studies revealed that cetirizine and levetiracetam inhibited MAGL with IC50 values of 9.3931 µM and 3.0095 µM, respectively. In vivo experiments demonstrated that cetirizine, and to a lesser extent levetiracetam, reduced mechanical and thermal nociception in complete Freund adjuvant (CFA)-induced osteoarthritis in rats. Cetirizine exhibited a notable anti-inflammatory effect, reducing CFA-induced inflammation, as well as the inflammatory infiltrate and granuloma formation in the affected paw. These findings suggest that cetirizine may serve as a promising starting point for the development of novel compounds for osteoarthritis treatment, addressing both pain and inflammation.

4.
Life (Basel) ; 13(8)2023 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-37629492

RESUMO

PIM-1 kinase is a serine-threonine phosphorylating enzyme with implications in multiple types of malignancies, including prostate, breast, and blood cancers. Developing better search methodologies for PIM-1 kinase inhibitors may be a good strategy to speed up the discovery of an oncological drug approved for targeting this specific kinase. Computer-aided screening methods are promising approaches for the discovery of novel therapeutics, although certain limitations should be addressed. A frequent omission that is encountered in molecular docking is the lack of proper implementation of scoring functions and algorithms on the post-docking results, which usually alters the outcome of the virtual screening. The current study suggests a method for post-processing docking results, expressed either as binding affinity or score, that considers different binding modes of known inhibitors to the studied targets while making use of in vitro data, where available. The docking protocol successfully discriminated between known PIM-1 kinase inhibitors and decoy molecules, although binding energies alone were not sufficient to ensure a successful prediction. Logistic regression models were trained to predict the probability of PIM-1 kinase inhibitory activity based on binding energies and the presence of interactions with identified key amino acid residues. The selected model showed 80.9% true positive and 81.4% true negative rates. The discussed approach can be further applied in large-scale molecular docking campaigns to increase hit discovery success rates.

5.
Plants (Basel) ; 12(16)2023 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-37631147

RESUMO

The use of natural compounds as an alternative to synthetic molecules has become a significant subject of interest in recent decades. Stilbenoids are a group of phenolic compounds found in many plant species and they have recently gained the focus of a multitude of studies in medicine and chemistry, resveratrol being the most representative molecule. In this review, we focused on the research that illustrates the therapeutic potential of this class of natural molecules considering various diseases with higher incidence rates. PubChem database was searched for bioactivities of natural stilbenoids, while several keywords (i.e., "stilbenoids", "stilbenoid anticancer") were used to query PubMed database for relevant studies. The diversity and the simplicity of stilbenes' chemical structures together with the numerous biological sources are key elements that can simplify both the isolation of these compounds and the drug design of novel bioactive molecules. Resveratrol and other related compounds are heterogeneously distributed in plants and are mainly found in grapes and wine. Natural stilbenes were shown to possess a wide range of biological activities, such as antioxidant, anti-inflammatory, antihyperglycemic, cardioprotective, neuroprotective, and antineoplastic properties. While resveratrol is widely investigated for its benefits in various disorders, further studies are warranted to properly harness the therapeutic potential of less popular stilbenoid compounds.

6.
Int J Mol Sci ; 24(14)2023 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-37511401

RESUMO

New pyrrolo[1,2-b]pyridazines were synthesized by 3 + 2 cycloaddition reaction between mesoionic oxazolo-pyridazinones and methyl/ethyl propiolate. The mesoionic compounds were generated in situ by action of acetic anhydride on 3(2H)pyridazinone acids obtained from corresponding esters by alkaline hydrolysis followed by acidification. The structures of the compounds were confirmed by elemental analyses and IR, 1H-NMR, 13C-NMR, and X-ray diffraction data. The regioselectivity of cycloaddition was evidenced by NMR spectroscopy and confirmed by X-ray analysis. The compounds were evaluated for their cytotoxicity on plant cells (Triticum aestivum L.) and crustacean animal cells (Artemia franciscana Kellogg and Daphnia magna Straus). The results indicated that the tested compounds exhibited low toxicity on the plant cell (IC50 values higher than 200 µM), while on Artemia nauplii no lethality was observed. Daphnia magna assay showed that pyrrolo[1,2-b]pyridazines 5a and 5c could exhibit toxic effects, whereas, for the other compounds, toxicity was low to moderate. Also, the cytotoxic effects of the compounds were tested on three human adenocarcinoma-derived adherent cell lines (colon LoVo, ovary SK-OV-3, breast MCF-7). The in vitro compound-mediated cytotoxicity assays, performed by the MTS technique, demonstrated dose- and time-dependent cytotoxic activity for several compounds, the highest anti-tumor activity being observed for 5a, 2c, and 5f, especially against colon cancer cells.


Assuntos
Antineoplásicos , Piridazinas , Animais , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Piridazinas/química , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células , Antineoplásicos/química
7.
Molecules ; 28(14)2023 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-37513232

RESUMO

The altered activation or overexpression of protein kinases (PKs) is a major subject of research in oncology and their inhibition using small molecules, protein kinases inhibitors (PKI) is the best available option for the cure of cancer. The pyrazole ring is extensively employed in the field of medicinal chemistry and drug development strategies, playing a vital role as a fundamental framework in the structure of various PKIs. This scaffold holds major importance and is considered a privileged structure based on its synthetic accessibility, drug-like properties, and its versatile bioisosteric replacement function. It has proven to play a key role in many PKI, such as the inhibitors of Akt, Aurora kinases, MAPK, B-raf, JAK, Bcr-Abl, c-Met, PDGFR, FGFRT, and RET. Of the 74 small molecule PKI approved by the US FDA, 8 contain a pyrazole ring: Avapritinib, Asciminib, Crizotinib, Encorafenib, Erdafitinib, Pralsetinib, Pirtobrutinib, and Ruxolitinib. The focus of this review is on the importance of the unfused pyrazole ring within the clinically tested PKI and on the additional required elements of their chemical structures. Related important pyrazole fused scaffolds like indazole, pyrrolo[1,2-b]pyrazole, pyrazolo[4,3-b]pyridine, pyrazolo[1,5-a]pyrimidine, or pyrazolo[3,4-d]pyrimidine are beyond the subject of this work.


Assuntos
Antineoplásicos , Desenho de Fármacos , Inibidores de Proteínas Quinases , Pirazóis , Pirazóis/química , Pirazóis/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/classificação , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Relação Estrutura-Atividade , Humanos , Animais
8.
Molecules ; 28(12)2023 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-37375389

RESUMO

This paper describes the synthesis of new heterocycles from oxazol-5(4H)-one and 1,2,4-triazin-6(5H)-one classes containing a phenyl-/4-bromophenylsulfonylphenyl moiety. The oxazol-5(4H)-ones were obtained via condensation of 2-(4-(4-X-phenylsulfonyl)benzamido)acetic acids with benzaldehyde/4-fluorobenzaldehyde in acetic anhydride and in the presence of sodium acetate. The reaction of oxazolones with phenylhydrazine, in acetic acid and sodium acetate, yielded the corresponding 1,2,4-triazin-6(5H)-ones. The structures of the compounds were confirmed using spectral (FT-IR, 1H-NMR, 13C-NMR, MS) and elemental analysis. The toxicity of the compounds was evaluated on Daphnia magna Straus crustaceans and on the budding yeast Saccharomyces cerevisiae. The results indicate that both the heterocyclic nucleus and halogen atoms significantly influenced the toxicity against D. magna, with the oxazolones being less toxic than triazinones. The halogen-free oxazolone had the lowest toxicity, and the fluorine-containing triazinone exhibited the highest toxicity. The compounds showed low toxicity against yeast cells, apparently due to the activity of plasma membrane multidrug transporters Pdr5 and Snq2. The predictive analyses indicated an antiproliferative effect as the most probable biological action. The PASS prediction and CHEMBL similarity studies show evidence that the compounds could inhibit certain relevant oncological protein kinases. These results correlated with toxicity assays suggest that halogen-free oxazolone could be a good candidate for future anticancer investigations.


Assuntos
Oxazolona , Triazinas , Oxazolona/química , Triazinas/toxicidade , Acetato de Sódio , Espectroscopia de Infravermelho com Transformada de Fourier , Saccharomyces cerevisiae
9.
Life (Basel) ; 12(12)2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36556479

RESUMO

Bacterial virulence factors are mediating bacterial pathogenesis and infectivity. Collagenases are virulence factors secreted by several bacterial stains, such as Clostridium, Bacillus, Vibrio and Pseudomonas. These enzymes are among the most efficient degraders of collagen, playing a crucial role in host colonization. Thus, they are an important target for developing new anti-infective agents because of their pivotal roles in the infection process. A primary screening using a fluorescence resonance energy-transfer assay was used to experimentally evaluate the inhibitory activity of 77 compounds on collagenase A. Based on their inhibitory activity and chemical diversity, a small number of compounds was selected to determine the corresponding half maximal inhibitory con-centration (IC50). Additionally, we used molecular docking to get a better understanding of the enzyme-compound interaction. Several natural compounds (capsaicin, 4',5-dihydroxyflavone, curcumin, dihydrorobinetin, palmatine chloride, biochanin A, 2'-hydroxychalcone, and juglone) were identified as promising candidates for further development into useful anti-infective agents against infections caused by multi-drug-resistant bacterial pathogens which include collagenase A in their enzymatic set.

10.
Molecules ; 27(24)2022 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-36557851

RESUMO

Due to the structure of acylhydrazones both by the pharmacophore -CO-NH-N= group and by the different substituents present in the molecules of compounds of this class, various pharmacological activities were reported, including antitumor, antimicrobial, antiviral, antiparasitic, anti-inflammatory, immunomodulatory, antiedematous, antiglaucomatous, antidiabetic, antioxidant, and actions on the central nervous system and on the cardiovascular system. This fragment is found in the structure of several drugs used in the therapy of some diseases that are at the top of public health problems, like microbial infections and cardiovascular diseases. Moreover, the acylhydrazone moiety is present in the structure of some compounds with possible applications in the treatment of other different pathologies, such as schizophrenia, Parkinson's disease, Alzheimer's disease, and Huntington's disease. Considering these aspects, we consider that a study of the literature data regarding the structural and biological properties of these compounds is useful.


Assuntos
Doença de Alzheimer , Anti-Infecciosos , Doença de Huntington , Doença de Parkinson , Humanos , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Anti-Infecciosos/farmacologia , Anti-Infecciosos/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Doença de Huntington/tratamento farmacológico
11.
Pharmaceutics ; 14(12)2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36559057

RESUMO

Pain is one of the most common symptoms experienced by patients. The use of current analgesics is limited by low efficacy and important side effects. Transient receptor potential vanilloid-1 (TRPV1) is a non-selective cation channel, activated by capsaicin, heat, low pH or pro-inflammatory agents. Since TRPV1 is a potential target for the development of novel analgesics due to its distribution and function, we aimed to develop an in silico drug repositioning framework to predict potential TRPV1 ligands among approved drugs as candidates for treating various types of pain. Structures of known TRPV1 agonists and antagonists were retrieved from ChEMBL databases and three datasets were established: agonists, antagonists and inactive molecules (pIC50 or pEC50 < 5 M). Structures of candidates for repurposing were retrieved from the DrugBank database. The curated active/inactive datasets were used to build and validate ligand-based predictive models using Bemis−Murcko structural scaffolds, plain ring systems, flexophore similarities and molecular descriptors. Further, molecular docking studies were performed on both active and inactive conformations of the TRPV1 channel to predict the binding affinities of repurposing candidates. Variables obtained from calculated scaffold-based activity scores, molecular descriptors criteria and molecular docking were used to build a multi-class neural network as an integrated machine learning algorithm to predict TRPV1 antagonists and agonists. The proposed predictive model had a higher accuracy for classifying TRPV1 agonists than antagonists, the ROC AUC values being 0.980 for predicting agonists, 0.972 for antagonists and 0.952 for inactive molecules. After screening the approved drugs with the validated algorithm, repaglinide (antidiabetic) and agomelatine (antidepressant) emerged as potential TRPV1 antagonists, and protokylol (bronchodilator) as an agonist. Further studies are required to confirm the predicted activity on TRPV1 and to assess the candidates' efficacy in alleviating pain.

12.
Plants (Basel) ; 11(18)2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36145799

RESUMO

Since medicinal plants are widely used in treating various diseases, phytoconstituents enrichment strategies are of high interest for plant growers. First of all, we investigated the impact of phytosociological cultivation on polyphenolic content (total flavonoids-TFL, and total polyphenols-TPC) of peppermint (Mentha piperita L.) and lemon balm (Melissa officinalis L.) leaves, using spectrophotometric methods. Secondly, the influence of chemical (NPK) and organic (BIO) fertilization on polyphenolic content and plant material quality was also assessed. Dry extracts were obtained from harvested leaves using hydroethanolic extraction solvents for further qualitative and quantitative assessment of phytoconstituents by FT-ICR MS and UHPLC-MS. Furthermore, the antioxidant activity of leaf extracts was determined in vitro using DPPH, ABTS and FRAP methods. Molecular docking simulations were employed to further evaluate the antioxidant potential of obtained extracts, predicting the interactions of identified phytochemicals with sirtuins. The concentration of polyphenols was higher in the plant material harvested from the phytosociological culture. Moreover, the use of BIO fertilizer led to the biosynthesis of a higher content of polyphenols. Higher amounts of phytochemicals, such as caffeic acid, were determined in extracts obtained from phytosociological crops. The antioxidant activity was dependent on polyphenols concentration, more potent inhibition values being observed for the extracts obtained from the phytosociological batches. Molecular docking studies and MM/PBSA calculations revealed that the obtained extracts have the potential to directly activate sirtuins 1, 5 and 6 through several polyphenolic compounds, such as rosmarinic acid, thus complementing the free radical scavenging activity with the potential stimulation of endogenous antioxidant defense mechanisms. In conclusion, growing medicinal plants in phytosociological cultures treated with biofertilizers can have a positive impact on plant material quality, concentration in active constituents and biological activity.

13.
Mol Med Rep ; 26(3)2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35920188

RESUMO

Methicillin­resistant Staphylococcus aureus (MRSA) infections are usually found in hospital settings and, frequently, in patients with open wounds. One of the most critical virulence factors affecting the severity and recurrence of infections is the biofilm; increasing antibiotic resistance due to biofilm formation has led to the search for alternative compounds to antibiotics. The present study aimed to use boric acid and potassium metaborate against MRSA infection in a fibroblast wound model. For this purpose, a two­part experiment was designed: First, MRSA strains were used for the test, and both boric acid and potassium metaborate were prepared in microdilution. In the second step, an MRSA wound model was prepared using a fibroblast culture, and treatments with boric acid and potassium metaborate were applied for 24 h. For the evaluation of the effects of treatment, cell viability assay (MTT assay), analysis of redox stress parameters, including total oxidant status and total antioxidant capacity analyses, lactate dehydrogenase analysis and immunohistochemical staining were performed. In addition, IL­1ß and IL­10 gene expression levels were assayed. According to the results, potassium metaborate was more effective and exhibited a lower toxicity to fibroblast cells compared to boric acid; moreover, potassium metaborate decreased the level of prooxidant species and increased the antioxidant status more effectively than boric acid. The IL­1ß level in the bacteria group was high; however, boric acid and potassium metaborate significantly decreased the expression levels of inflammatory markers, exhibiting the potential to improve the resolution of the lesion. On the whole, the findings of the present study suggest that boric acid and potassium metaborate may be effective on the tested microorganisms.


Assuntos
Ácidos Bóricos , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Antioxidantes/farmacologia , Biofilmes , Ácidos Bóricos/farmacologia , Humanos , Oxirredução , Potássio , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia
14.
Pharmaceuticals (Basel) ; 15(8)2022 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-36015158

RESUMO

"Drug repositioning" is a modern strategy used to uncover new applications for out-of-date drugs. In this context, nalidixic acid, the first member of the quinolone class with limited use today, has been selected to obtain nine new metal complexes with lanthanide cations (La3+, Sm3+, Eu3+, Gd3+, Tb3+); the experimental data suggest that the quinolone acts as a bidentate ligand, binding to the metal ion via the keto and carboxylate oxygen atoms, findings that are supported by DFT calculations. The cytotoxic activity of the complexes has been studied using the tumoral cell lines, MDA-MB-231 and LoVo, and a normal cell line, HUVEC. The most active compounds of the series display selective activity against LoVo. Their affinity for DNA and the manner of binding have been tested using UV-Vis spectroscopy and competitive binding studies; our results indicate that major and minor groove binding play a significant role in these interactions. The affinity towards serum proteins has also been evaluated, the complexes displaying higher affinity towards albumin than apotransferrin.

15.
Antibiotics (Basel) ; 11(8)2022 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-36009963

RESUMO

A new series of pyrazolo-benzimidazole hybrid Mannich bases were synthesized, characterized by 1H-NMR, 13C-NMR, IR, UV-Vis, MS, and elemental analysis. In vitro cytotoxicity of the new compounds studied on fibroblast cells showed that the newly synthesized pyrazolo-benzimidazole hybrid derivatives were noncytotoxic until the concentration of 1 µM and two compounds presented a high degree of biocompatibility. The antibacterial and antibiofilm activity of the newly synthesized compounds was assayed on Gram-positive Staphylococcus aureus ATCC25923, Enterococcus faecalis ATCC29212, and Gram-negative Pseudomonas aeruginosa ATCC27853, Escherichia coli ATCC25922 strains. All synthesized compounds 5a-g are more active against all three tested bacterial strains Staphylococcus aureus ATCC25923, Enterococcus faecalis ATCC29212, and Escherichia coli ATCC25922 than reference drugs (Metronidazole, Nitrofurantoin), with the exception of compounds 5d and 5g, which are less active compared to Nitrofurantoin, and all synthesized compounds 5a-g are more active against Pseudomonas aeruginosa ATCC27853 compared to reference drugs (Metronidazole, Nitrofurantoin). Compound 5f showed the best activity against Staphylococcus aureus ATCC 25923, with a MIC of 150 µg/mL and has also inhibited the biofilm formed by all the bacterial strains, having an MBIC of 310 µg/mL compared to the reference drugs (Metronidazole, Nitrofurantoin).

16.
Int J Mol Sci ; 23(16)2022 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-36012121

RESUMO

The current study describes the synthesis, physicochemical characterization and cytotoxicity evaluation of a new series of pyrrole derivatives in order to identify new bioactive molecules. The new pyrroles were obtained by reaction of benzimidazolium bromide derivatives with asymmetrical acetylenes in 1,2-epoxybutane under reflux through the Huisgen [3 + 2] cycloaddition of several ylide intermediates to the corresponding dipolarophiles. The intermediates salts were obtained from corresponding benzimidazole with bromoacetonitrile. The structures of the newly synthesized compounds were confirmed by elemental analysis, spectral techniques (i.e., IR, 1H-NMR and 13C-NMR) and single-crystal X-ray analysis. The cytotoxicity of the synthesized compounds was evaluated on plant cells (i.e., Triticum aestivum L.) and animal cells using aquatic crustaceans (i.e., Artemia franciscana Kellogg and Daphnia magna Straus). The potential antitumor activity of several of the pyrrole derivatives was studied by performing in vitro cytotoxicity assays on human adenocarcinoma-derived cell lines (i.e., LoVo (colon), MCF-7 (breast), and SK-OV-3 (ovary)) and normal human umbilical vein endothelial cells (HUVECs). The obtained results of the cytotoxicity assessment indicated that the tested compounds had nontoxic activity on Triticum aestivum L., while on Artemia franciscana Kellogg nauplii, only compounds 2c and 4c had moderate toxicity. On Daphnia magna, 4b and 4c showed high toxicity; 2a, 2b, and 2c moderate to high toxicity; only 4a and 4d were nontoxic. The compound-mediated cytotoxicity assays showed that several pyrrole compounds demonstrated dose- and time-dependent cytotoxic activity against all tested tumor cell lines, the highest antitumor properties being achieved by 4a and its homologue 4d, especially against LoVo colon cells.


Assuntos
Antineoplásicos , Pirróis , Animais , Antineoplásicos/química , Fatores Biológicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Células Endoteliais , Feminino , Humanos , Estrutura Molecular , Pirróis/química , Relação Estrutura-Atividade
17.
Molecules ; 27(10)2022 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-35630776

RESUMO

The current work presents an objective overview of the impact of one important heterocyclic structure, the pyrazole ring, in the development of anti-proliferative drugs. A set of 1551 pyrazole derivatives were extracted from the National Cancer Institute (NCI) database, together with their growth inhibition effects (GI%) on the NCI's panel of 60 cancer cell lines. The structures of these derivatives were analyzed based on the compounds' averages of GI% values across NCI-60 cell lines and the averages of the values for the outlier cells. The distribution and the architecture of the Bemis-Murcko skeletons were analyzed, highlighting the impact of certain scaffold structures on the anti-proliferative effect's potency and selectivity. The drug-likeness, chemical reactivity and promiscuity risks of the compounds were predicted using AMDETlab. The pyrazole ring proved to be a versatile scaffold for the design of anticancer drugs if properly substituted and if connected with other cyclic structures. The 1,3-diphenyl-pyrazole emerged as a useful scaffold for potent and targeted anticancer candidates.


Assuntos
Antineoplásicos , Pirazóis , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Pirazóis/química , Pirazóis/farmacologia
18.
Molecules ; 26(23)2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34885677

RESUMO

Staphylococcus aureus (S. aureus) is a causative agent of many hospital- and community-acquired infections with the tendency to develop resistance to all known antibiotics. Therefore, the development of novel antistaphylococcal agents is of urgent need. Sortase A is considered a promising molecular target for the development of antistaphylococcal agents. The main aim of this study was to identify novel sortase A inhibitors. In order to find novel antistaphylococcal agents, we performed phenotypic screening of a library containing 15512 compounds against S. aureus ATCC43300. The molecular docking of hits was performed using the DOCK program and 10 compounds were selected for in vitro enzymatic activity inhibition assay. Two inhibitors were identified, N,N-diethyl-N'-(5-nitro-2-(quinazolin-2-yl)phenyl)propane-1,3-diamine (1) and acridin-9-yl-(1H-benzoimidazol-5-yl)-amine (2), which decrease sortase A activity with IC50 values of 160.3 µM and 207.01 µM, respectively. It was found that compounds 1 and 2 possess antibacterial activity toward 29 tested multidrug resistant S. aureus strains with MIC values ranging from 78.12 to 312.5 mg/L. These compounds can be used for further structural optimization and biological research.


Assuntos
Aminoaciltransferases/antagonistas & inibidores , Proteínas de Bactérias/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Aminoaciltransferases/genética , Antibacterianos/uso terapêutico , Proteínas de Bactérias/genética , Cisteína Endopeptidases/genética , Inibidores Enzimáticos/química , Humanos , Staphylococcus aureus Resistente à Meticilina , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/enzimologia , Staphylococcus aureus/patogenicidade
19.
Molecules ; 26(21)2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34770844

RESUMO

A series of new pyrrole derivatives were designed as chemical analogs of the 1,4-dihydropyridines drugs in order to develop future new calcium channel blockers. The new tri- and tetra-substituted N-arylpyrroles were synthesized by the one-pot reaction of 1-methyl-3-cyanomethyl benzimidazolium bromide with substituted alkynes having at least one electron-withdrawing substituent, in 1,2-epoxybutane, acting both as the solvent and reagent to generate the corresponding benzimidazolium N3-ylide. The structural characterization of the new substituted pyrroles was based on IR, NMR spectroscopy as well as on single crystal X-ray analysis. The toxicity of the new compounds was assessed on the plant cell using Triticum aestivum L. species and on the animal cell using Artemia franciscana Kellogg and Daphnia magna Straus crustaceans. The compounds showed minimal phytotoxicity on Triticum rootlets and virtually no acute toxicity on Artemia nauplii, while on Daphnia magna, it induced moderate to high toxicity, similar to nifedipine. Our research indicates that the newly synthetized pyrrole derivatives are promising molecules with biological activity and low acute toxicity.


Assuntos
Alcinos/química , Benzimidazóis/química , Brometos/química , Pirróis/síntese química , Pirróis/toxicidade , Técnicas de Química Sintética , Modelos Moleculares , Estrutura Molecular , Pirróis/química , Análise Espectral , Testes de Toxicidade , Toxicologia/métodos
20.
Molecules ; 26(18)2021 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-34577139

RESUMO

Neurological and neurodegenerative diseases are debilitating conditions, and frequently lack an effective treatment. Monoacylglycerol lipase (MAGL) is a key enzyme involved in the metabolism of 2-AG (2-arachidonoylglycerol), a neuroprotective endocannabinoid intimately linked to the generation of pro- and anti-inflammatory molecules. Consequently, synthesizing selective MAGL inhibitors has become a focus point in drug design and development. The purpose of this review was to summarize the diverse synthetic scaffolds of MAGL inhibitors concerning their potency, mechanisms of action and potential therapeutic applications, focusing on the results of studies published in the past five years. The main irreversible inhibitors identified were derivatives of hexafluoroisopropyl alcohol carbamates, glycol carbamates, azetidone triazole ureas and benzisothiazolinone, whereas the most promising reversible inhibitors were derivatives of salicylketoxime, piperidine, pyrrolidone and azetidinyl amides. We reviewed the results of in-depth chemical, mechanistic and computational studies on MAGL inhibitors, in addition to the results of in vitro findings concerning selectivity and potency of inhibitors, using the half maximal inhibitory concentration (IC50) as an indicator of their effect on MAGL. Further, for highlighting the potential usefulness of highly selective and effective inhibitors, we examined the preclinical in vivo reports regarding the promising therapeutic applications of MAGL pharmacological inhibition.


Assuntos
Monoacilglicerol Lipases , Doenças Neurodegenerativas , Animais , Inibidores Enzimáticos/farmacologia , Humanos
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