RESUMO
In pharmaceutical science and drug design the versatility of the pyrrolidine scaffold relating to spatial arrangement, synthetic accessibility and pharmacological profile is a largely explored and most likely interesting one. Nonetheless, few evidences suggest the pivotal role of pyrrolidine as scaffold for multipotent agents in neurodegenerative diseases. We then challenged the enrolling in the field of Alzheimer disease of so far not ravelled targets of this chemical cliché with a structure based and computer-aided design strategy focusing on multi-target action, versatile synthesis as well as pharmacological safeness. To achieve these hits, ten enantiomeric pairs of compounds were obtained and tested, and the biological data will be here presented and discussed. Among the novel compounds, coumarin and sesamol scaffolds containing analogues resulted promising perspectives.
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Doença de Alzheimer , Doenças Neurodegenerativas , Pirrolidinas , Pirrolidinas/química , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Humanos , Doença de Alzheimer/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Estereoisomerismo , Estrutura Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/síntese química , Animais , Relação Estrutura-AtividadeRESUMO
Cadmium (Cd) toxicity poses a significant threat to cellular health, leading to oxidative stress and cell damage. Antioxidant agents, particularly those of natural origin, have been studied as a potential alternative for mitigating heavy metal toxicity. This study aimed to evaluate the cytoprotective effects of the antioxidant melatonin (MLT) in comparison with Vitamin E (VitE) and Trolox against Cd2+-induced cellular toxicity. The MTT assay was employed to assess cell viability in neuronal SH-SY5Y, colorectal HCT 116, and hepatic HepG2 cell lines. The results showed that all three antioxidants offered some level of protection against Cd toxicity, with Vitamin E proving to be the most effective. MLT also demonstrated a substantial cytoprotective effect, especially at the highest Cd concentration of 30 µM. These findings suggest that MLT, alongside Vit E and Trolox, could be valuable in mitigating the detrimental effects of Cd exposure by reducing the oxidative stress in these cellular models.
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Antioxidantes , Cádmio , Sobrevivência Celular , Cromanos , Melatonina , Estresse Oxidativo , Vitamina E , Humanos , Melatonina/farmacologia , Cromanos/farmacologia , Vitamina E/farmacologia , Cádmio/toxicidade , Antioxidantes/farmacologia , Células Hep G2 , Estresse Oxidativo/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Células HCT116 , Linhagem Celular TumoralRESUMO
In a previous paper, we demonstrated the synergistic action of the anti-ischemic lubeluzole (Lube S) on the cytotoxic activity of doxorubicin (Dox) and paclitaxel in human ovarian cancer A2780 and lung cancer A549 cells. In the present paper, we extended in vitro the study to the multi-drug-resistant A2780/DX3 cell line to verify the hypothesis that the Dox and Lube S drug association may potentiate the antitumor activity of this anticancer compound also in the context of drug resistance. We also evaluated some possible mechanisms underlying this activity. We analyzed the antiproliferative activity in different cancer cell lines. Furthermore, apoptosis, Dox accumulation, MDR1 downregulation, ROS, and NO production in A2780/DX3 cells were also evaluated. Our results confirm that Lube S improves Dox antiproliferative and apoptotic activities through different mechanisms of action, all of which may contribute to the final antitumor effect. Moderate stereoselectivity was found, with Lube S significantly more effective than its enantiomer (Lube R) and the corresponding racemate (Lube S/R). Docking simulation studies on the ABCB1 Cryo-EM structure supported the hypothesis that Lube S forms a stable MDR1-Dox-Lube S complex, which hampers the protein transmembrane domain flipping and blocks the efflux of Dox from resistant A2780/DX3 cells. In conclusion, our in vitro studies reinforce our previous hypothesis for repositioning the anti-ischemic Lube S as a potentiating agent in anticancer chemotherapy.
Assuntos
Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Linhagem Celular Tumoral , Carcinoma Epitelial do Ovário/tratamento farmacológico , Piperidinas/uso terapêutico , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêuticoRESUMO
A new series of aryloxyacetic acids was prepared and tested as peroxisome proliferator-activated receptors (PPARs) agonists and fatty acid amide hydrolase (FAAH) inhibitors. Some compounds exhibited an interesting dual activity that has been recently proposed as a new potential therapeutic strategy for the treatment of Alzheimer's disease (AD). AD is a multifactorial pathology, hence multi-target agents are currently one of the main lines of research for the therapy and prevention of this disease. Given that cholinesterases represent one of the most common targets of recent research, we decided to also evaluate the effects of our compounds on the inhibition of these specific enzymes. Interestingly, two of these compounds, (S)-5 and 6, showed moderate activity against acetylcholinesterase (AChE) and even some activity, although at high concentration, against Aß peptide aggregation, thus demonstrating, in agreement with the preliminary dockings carried out on the different targets, the feasibility of a simultaneous multi-target activity towards PPARs, FAAH, and AChE. As far as we know, these are the first examples of molecules endowed with this pharmacological profile that might represent a promising line of research for the identification of novel candidates for the treatment of AD.
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Ácido Acético/química , Acetilcolinesterase/química , Amidoidrolases/antagonistas & inibidores , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Inibidores da Colinesterase , HumanosRESUMO
In recent years, Peroxisome Proliferator-Activated Receptors (PPARs) have been connected to the endocannabinoid system. These nuclear receptors indeed mediate the effects of anandamide and similar substances such as oleoyl-ethanolamide and palmitoyl-ethanolamide. An increasing body of literature describing the interactions between the endocannabinoid system and PPARs has slowly but surely been accumulating over the past decade, and a multitarget approach involving these receptors and endocannabinoid degrading enzyme FAAH has been proposed for the treatment of inflammatory states, cancer, and Alzheimer's disease. The lack of knowledge about compounds endowed with such an activity profile therefore led us to investigate a library of readily available, well-characterized PPAR agonists that we had synthesized over the years in order to find a plausible lead compound for further development. Moreover, we propose a rationalization of our results via a docking study, which sheds some light on the binding mode of these PPAR agonists to FAAH and opens the way for further research in this field.
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Amidoidrolases/antagonistas & inibidores , Inibidores Enzimáticos , PPAR alfa/agonistas , PPAR delta/agonistas , PPAR gama/agonistas , Amidoidrolases/metabolismo , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Células Hep G2 , Humanos , LigantesRESUMO
A series of 4-aminomethyl-7-benzyloxy-2H-chromen-2-ones was investigated with the aim of identifying multiple inhibitors of cholinesterases (acetyl- and butyryl-, AChE and BChE) and monoamine oxidase B (MAO B) as potential anti-Alzheimer molecules. Starting from a previously reported potent MAO B inhibitor (3), we studied single-point modifications at the benzyloxy or at the basic moiety. The in vitro screening highlighted triple-acting compounds (6, 8, 9, 16, 20) showing nanomolar and selective MAO B inhibition along with IC50 against ChEs at the low micromolar level. Enzyme kinetics analysis toward AChE and docking simulations on the target enzymes were run in order to get insight into the mechanism of action and plausible binding modes.
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Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Cumarínicos/química , Cumarínicos/farmacologia , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/farmacologia , para-Aminobenzoatos/química , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The enantiomer separation of a number of racemic 7-[(1-alkylpiperidin-3-yl)methoxy]coumarin derivatives, some of which show outstanding in vitro multitarget neuroprotective activities, was successfully achieved on a polysaccharide-based chiral stationary phase, bearing amylose tris(3,5-dimethylphenylcarbamate) as a chiral selector, in normal polar mode (methanol and acetonitrile as the mobile phases). The majority of the screened selectands, especially those bearing 1-(3-X-benzyl)piperidin-3-yl moieties, showed baseline enantiomer separations, and compound 8 (X = NO2 ) was the best resolved (α = 2.01; RS = 4.27). Linear free energy relationships, usefully complemented by molecular docking calculations, have the key role in enantioselective retention of aromatic interactions between π-donor moieties in the chiral selector and π-acceptor moieties in selectand, strengthened by hydrogen bond interaction between a hydrogen bond donor in the chiral selector and the hydrogen bond acceptor group(s) in the selectand. Statistically, reliable equations highlighted the importance of the substituent's size and substitution pattern (meta better than para) to affect the enantiorecognition of the title compounds. The chromatographic data support the scalability of the optimized experimental conditions for preparative purposes.
Assuntos
Amilose/química , Cumarínicos/química , Piperidinas/química , Cromatografia Líquida de Alta Pressão , Ligação de Hidrogênio , Simulação de Acoplamento Molecular , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Candida spp. are responsible for many biomaterial-related infections; they give rise to infective pathologies typically associated with biofilm formation. We recently reported that the echinocandin anidulafungin (ANF) showed a strong in vitro activity against both planktonic and biofilms cells. Herein, we report the antifungal activities of ANF alone and in association with some non-steroidal anti-inflammatory drugs (NSAIDs) against nine Candida strain biofilms: four Candida albicans, two Candida glabrata and three Candida guilliermondii. The activity of ANF was assessed using an in vitro microbiological model relevant for clinical practice. ANF proved oneself to be active against biofilms cells, and a clear-cut synergism was found against Candida species biofilms when ANF was used in combination with three NSAIDs: aspirin, diclofenac, ibuprofen. The positive synergism against Candida spp. of ANF in association with aspirin or the other NSAIDs proved to be a very effective antifungal treatment (FICI<0.5). These results may provide the starting point for new combination therapies of ANF with NSAIDs against Candida biofilm pathologies.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Candidíase/tratamento farmacológico , Equinocandinas/farmacologia , Anidulafungina , Aspirina/farmacologia , Biofilmes/efeitos dos fármacos , Candida/fisiologia , Candidíase/microbiologia , Sinergismo Farmacológico , HumanosRESUMO
The goal of the present paper is to establish and validate the link between cancer diagnosis and therapy by microRNAs detection. The induction in vitro of some specific microRNAs after treatment with MDR ligands has been outlined. Starting from the results obtained by in vitro induction of MDCK and MDCK-MDR1 cells treated by a MDR1 ligand, a new scenario in the early diagnosis and chemotherapy could be disclosed. To corroborate this perspective a short overview on pancreatic cancer diagnosis and chemotherapeutic treatment has been reported.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , MicroRNAs/genética , Animais , Cães , Humanos , Células Madin Darby de Rim Canino , Neoplasias/tratamento farmacológico , Neoplasias/genéticaRESUMO
The title compound, C24H25NO3·2CH3OH, which crystallized as a methanol disolvate, has applications as a PET radiotracer in the early diagnosis of Alzheimer's disease. The dihedral angle between the biphenyl rings is 8.2â (2)° and the heterocyclic ring adopts a half-chair conformation with the N atom adopting a pyramidal geometry (bond-angle sum = 327.6°). The C atoms of both meth-oxy groups lie close to the plane of their attached ring [deviations = 0.107â (6) and 0.031â (6)â Å]. In the crystal, the components are linked by O-Hâ¯O and O-Hâ¯N hydrogen bonds, generating [010] chains. C-Hâ¯O inter-actions are also observed.
RESUMO
Due to the putative role of butyrylcholinesterase (BChE) in regulation of acetylcholine levels and functions in the late stages of the Alzheimer's disease (AD), the potential of selective inhibitors (BChEIs) has been envisaged as an alternative to administration of acetylcholinesterase inhibitors (AChEIs). Starting from our recent findings, herein the synthesis and in vitro evaluation of cholinesterase (ChE) inhibition of a novel series of some twenty 3,4,5,6-tetrahydroazepino[4,3-b]indol-1(2H)-one derivatives, bearing at the indole nitrogen diverse alkyl-bridged 4-arylalkylpiperazin-1-yl chains, are reported. The length of the spacers, as well as the type of arylalkyl group affected the enzyme inhibition potency and BChE/AChE selectivity. Two compounds, namely 14c (IC50 = 163 nM) and 14d (IC50 = 65 nM), bearing at the nitrogen atom in position 6 a n-pentyl- or n-heptyl-bridged 4-phenethylpiperazin-1-yl chains, respectively, proved to be highly potent mixed-type inhibitors of both equine and human BChE isoforms, showing more than two order magnitude of selectivity over AChE. The study of binding kinetics through surface plasmon resonance (SPR) highlighted differences in their BChE residence times (8 and 47 s for 14c and 14d, respectively). Moreover, 14c and 14d proved to hit other mechanisms known to trigger neurodegeneration underlying AD and other CNS disorders. Unlike 14c, compound 14d proved also capable of inhibiting by more than 60% the in vitro self-induced aggregation of neurotoxic amyloid-ß (Aß) peptide at 100 µM concentration. On the other hand, 14c was slightly better than 14d in counteracting, at 1 and 10 µM concentration, glutamate excitotoxicity, due to over-excitation of NMDA receptors, and hydrogen peroxide-induced oxidative stress assessed in neuroblastoma cell line SH-SY5Y. This paper is dedicated to Prof. Marcello Ferappi, former dean of the Faculty of Pharmacy of the University of Bari, in the occasion of his 90th birthday.
Assuntos
Doença de Alzheimer , Neuroblastoma , Humanos , Animais , Cavalos , Inibidores da Colinesterase/química , Butirilcolinesterase/metabolismo , Acetilcolinesterase/metabolismo , Peptídeos beta-Amiloides/metabolismo , Doença de Alzheimer/tratamento farmacológico , Linhagem Celular Tumoral , Nitrogênio , Relação Estrutura-Atividade , Simulação de Acoplamento MolecularRESUMO
Previous studies have shown that some lamellarin-resembling annelated azaheterocyclic carbaldehydes and related imino adducts, sharing the 1-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline (1-Ph-DHPIQ) scaffold, are cytotoxic in some tumor cells and may reverse multidrug resistance (MDR) mediated by P-glycoprotein (P-gp). Herein, several novel substituted 1-Ph-DHPIQ derivatives were synthesized which carry carboxylate groups (COOH, COOEt), nitrile (CN) and Mannich bases (namely, morpholinomethyl derivatives) in the C2 position, as replacements of the already reported aldehyde group. They were evaluated for antiproliferative activity in four tumor cell lines (RD, HCT116, HeLa, A549) and for the ability of selectively inhibiting P-gp-mediated MDR. Lipophilicity descriptors and molecular docking calculations helped us in rationalizing the structure-activity relationships in the P-gp inhibition potency of the investigated 1-Ph-DHPIQs. As a main outcome, a morpholinomethyl Mannich base (8c) was disclosed which proved to be cytotoxic to all the tested tumor cell lines in the low micromolar range (IC50 < 20 µM) and to inhibit in vitro the efflux pumps P-gp and MRP1 responsible for MDR, with IC50s of 0.45 and 12.1 µM, respectively.
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Lubeluzole, a neuroprotective anti-ischemic drug, and its enantiomer were prepared following a convenient procedure based on hydrolytic kinetic resolution. The ee values were >99% and 96%, respectively, as assessed by HPLC analysis. The chemosensitizing effects of both enantiomers were evaluated in combination with either doxorubicin (human ovarian adenocarcinoma A2780 cells) or paclitaxel (human lung carcinoma A549 cells) by the MTT assay. At the lowest concentrations used, lubeluzole showed an overall and remarkable tendency to synergize with both anticancer drugs. In ovarian cancer cells a clear prevalence of antagonistic effect was observed for the R-enantiomer. The synergistic effects of lubeluzole for both drugs were observed over a wide concentration window (0.005-5 µM), the lowest limit being at least 40 times lower than human plasma concentrations previously reported as causing serious side effects.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Piperidinas/química , Piperidinas/farmacologia , Tiazóis/química , Tiazóis/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Sinergismo Farmacológico , Feminino , Humanos , Paclitaxel/farmacologia , Piperidinas/síntese química , Estereoisomerismo , Tiazóis/síntese químicaRESUMO
Oxidative stress has been reported to be involved in the onset and development of several diseases, including neurodegenerative and cardiovascular disorders, some types of cancer, and diabetes. Therefore, finding strategies to detoxify free radicals is an active area of research. One of these strategies is the use of natural or synthetic antioxidants. In this context, melatonin (MLT) has been proven to possess most of the required characteristics of an efficient antioxidant. In addition, its protection against oxidative stress continues after being metabolized, since its metabolites also exhibit antioxidant capacity. Based on the appealing properties of MLT and its metabolites, various synthetic analogues have been developed to obtain compounds with higher activity and lower side effects. This review addresses recent studies with MLT and related compounds as potential antioxidants.
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The benzothiazole nucleus is a major heterocyclic scaffold whose therapeutic potential has been thoroughly explored due to its structural simplicity and ease of synthesis. In fact, several benzothiazole derivatives have been synthesized over time, demonstrating numerous pharmacological properties such as anticancer, antimicrobial, anti-inflammatory, and antioxidant activities. Herein, we propose a new series of benzothiazole-phthalimide hybrids obtained by linking the phthalimide moiety to differently substituted benzothiazole nuclei through the N atom. These compounds have been screened for their anticancer properties against two human breast cancer cell lines. Furthermore, we delved into the mechanism of action of the most active hybrid, compound 3h, by assessing its capability to damage the nuclear DNA, trigger the apoptotic process in the high metastatic MDA-MB-231 cells, and prevent cellular migration. Moreover, in view of the documented antimicrobial activities of the two scaffolds involved, we explored the antibacterial and antifungal effects of the studied compounds by means of the broth microdilution method. Among the studied compounds, 3h showed the highest antimicrobial activity, both against gram-positive and gram-negative bacterial strains belonging to the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) and against fungal strains of the Candida species with MICs values ranging from 16 to 32 µg/mL.
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Systemic fungal infections have risen in recent decades and most of them are caused by Candida species, which are becoming increasingly resistant to conventional antifungal drugs. Biofilm production has been considered the most common growth form of Candida cells and is associated with a high level of antifungal resistance. At present, international research reports on the antifungal activity of non-traditional antimicrobial drugs and their potential use against life-threatening resistant fungal infections. Indeed, drug repurposing has led to the consideration of well-known compounds as a last-line therapy. The goal of this work is to evaluate the potential synergistic antifungal biofilm activity of new combinations between diclofenac sodium salt (DSS), a widely used non-steroidal anti-inflammatory drug (NSAID), with the essential oils (EOs) of Mentha piperita, Pelargonium graveolens, and Melaleuca alternifolia, whose antifungal activity has been well documented over the years. The in vitro antifungal activity of DSS and EOs was determined on different Candida strains. Susceptibility testing and the synergism of DSS and EOs versus biofilm cells was performed by using the broth microdilution assay and checkerboard methods. Minimum inhibitory concentrations (sMIC50) of DSS alone ranged from 1.25 to 2.05 mg/mL for all the strains considered. These values significantly decreased when the drug was used in combination with the EOs. The fractional inhibitory concentration index (FICI) was lower than 0.5 for almost all the associations, thus indicating a significant synergism, particularly for the DSS-Pelargonium graveolens combination towards the Candida strains examined. These preliminary results show that the combination of the EOs with DSS improves the antifungal activity on all the tested Candida strains, significantly lowering the concentrations of the components used and thus allowing any toxic effects to be overcome.
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Alzheimer's disease is becoming a growing problem increasing at a tremendous rate. Serotonin 5-HT6 receptors appear to be a particularly attractive target from a therapeutic perspective, due to their involvement not only in cognitive processes, but also in depression and psychosis. In this work, we present the synthesis and broad biological characterization of a new series of 18 compounds with a unique 1,3,5-triazine backbone, as potent 5-HT6 receptor ligands. The main aim of this research is to compare the biological activity of the newly synthesized sulfur derivatives with their oxygen analogues and their N-demethylated O- and S-metabolites obtained for the first time. Most of the new triazines displayed high affinity (Ki < 200 nM) and selectivity towards 5-HT6R, with respect to 5-HT2AR, 5-HT7R, and D2R, in the radioligand binding assays. For selected, active compounds crystallographic studies, functional bioassays, and ADME-Tox profile in vitro were performed. The exciting novelty is that the sulfur derivatives exhibit an agonistic mode of action contrary to all other compounds obtained to date in this chemical class herein and previously reported. Advanced computational studies indicated that this intriguing functional shift might be caused by presence of chalcogen bonds formed only by the sulfur atom. In addition, the N-demethylated derivatives have emerged highly potent antioxidants and, moreover, show a significant improvement in metabolic stability compared to the parent structures. The cholinesterase study present micromolar inhibitory AChE and BChE activity for both 5-HT6 agonist 19 and potent antagonist 5. Finally, the behavioral experiments of compound 19 demonstrated its antidepressant-like properties and slight ability to improve cognitive deficits, without inducing memory impairments by itself. Described pharmacological properties of both compounds (5 and 19) allow to give a design clue for the development of multitarget compounds with 5-HT6 (both agonist and antagonist)/AChE and/or BChE mechanism in the group of 1,3,5-triazine derivatives.
Assuntos
Doença de Alzheimer , Calcogênios , Humanos , Doença de Alzheimer/tratamento farmacológico , Serotonina , Estrutura Molecular , Relação Estrutura-Atividade , Receptores de Serotonina/metabolismo , Ligantes , Triazinas/química , Éteres , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Acetilcolinesterase/metabolismoRESUMO
We recently reported that the α(2)-adrenoreceptor (AR) ligand allyphenyline (9) significantly enhanced morphine analgesia (due to its α(2C)-AR agonism), was devoid of sedative side effects (due to its α(2A)-AR antagonism), prevented and reversed morphine tolerance and dependence. To highlight the molecular characteristics compatible with this behaviour and to obtain novel agents potentially useful in chronic pain and opioid addiction management, the allyl group of 9 was replaced by substituents of moderate steric bulk (MR) and positive or negative lipophilic (π) and electronic (σ) contributions in all the possible combinations. Effective novel α(2C)-agonists/α(2A)-antagonists (2, 3, 10, 12, and 17) were obtained. This study also demonstrated that contradictory combinations of the physicochemical parameters were similarly able to induce the α(2A)-activation. Since we had previously observed that the absolute configuration affected only the potency, but not the functional profile of the ligands, we hypothesized that the α(2A)-activation was governed by a ligand preferred conformation. From a structural overlay investigation it emerged that an extended conformation appeared to be associated with dual α(2C)-agonism/α(2A)-antagonism, whereas a folded conformation associated with α(2C)-/α(2A)-agonism.
Assuntos
Agonistas de Receptores Adrenérgicos alfa 2/química , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 2/química , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Compostos Alílicos/química , Compostos Alílicos/farmacologia , Imidazolinas/química , Imidazolinas/farmacologia , Receptores Adrenérgicos alfa 2/metabolismo , Animais , Células CHO , Cricetinae , Humanos , Conformação Molecular , Simulação de Dinâmica MolecularRESUMO
As part of our studies focused on the design and synthesis of new antimicrobial agents a series of 7-fluoro-3,4-dihydro-2H-1,4-benzothiazine derivatives (4a-4f, 4h) and 7-fluoro-2H-1,4-benzothiazin-3(4H)-one analogues (4j-4o) were synthesized and evaluated for their in vitro inhibitory activity against a representative panel of Gram-positive and Gram-negative bacteria strains and also toward selected fungi species. These compounds were prepared in one step from chloro-substituted-2-amino-5-fluorobenzenethiol 6a-6c. The biological screening identified in compounds 4a, 4j and 4l the most promising results of both series showing an interesting antimicrobial activity. Our antibiotic investigation was also completed by testing the key intermediates 6a-6c. Surprisingly, 6a-6c emerged as the compounds exhibiting the highest antimicrobial activity by possessing a remarkable antibacterial effect against the Gram-positive strains with MIC (minimal inhibitory concentration) values between 2 and 8 µg/mL and the fungi panel with MIC values between 2 and 8 µg/mL. These results may prove useful in the design of a novel pool of antimicrobial agents.
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Anti-Infecciosos/síntese química , Tiazinas/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Desenho de Fármacos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Fenóis/síntese química , Fenóis/farmacologia , Compostos de Sulfidrila/síntese química , Compostos de Sulfidrila/farmacologia , Tiazinas/farmacologiaRESUMO
The worldwide scenario of antibiotic resistance and the falling number of funds for the development of novel antibiotics have led research efforts toward the study of specific cost-effective strategies aimed at discovering drugs against microbial infections. Among the potential options, drug repositioning, which has already exhibited satisfactory results in other medical fields, came out as the most promising. It consists of finding new uses for previously approved medicines and, over the years, many "repurposed drugs" displayed some encouraging in vitro and in vivo results beyond their initial application. The principal theoretical justification for reusing already existing drugs is that they have known mechanisms of action and manageable side effects. Reuse of old drugs is now considered an interesting approach to overcome the drawbacks of conventional antibiotics. The purpose of this review is to offer the reader a panoramic view of the updated studies concerning the repositioning process of different classes of non-antibiotic drugs in the antimicrobial field. Several research works reported the ability of some non-steroidal anti-inflammatory drugs (NSAIDs), antidepressants, antipsychotics, and statins to counteract the growth of harmful microorganisms, demonstrating an interesting winning mode to fight infectious diseases caused by antimicrobial resistant bacteria.