RESUMO
2-Alkyl chromanone scaffold has become prominent in pharmaceuticals and natural compounds. Consequently, devising robust strategies for synthesizing 2-alkyl chromanones remains crucial. Here, multicomponent reactions were employed to synthesize 2-alkyl chromanones containing an oxazole moiety using 3-formylchromones, amines, and N-propargylamides as reactants. This method utilizes readily available feedstocks with a catalytic amount of Zn(OTf)2 and exhibits an impressive substrate scope compared to existing methods. Importantly, the synthesized compounds demonstrated highly selective anticancer activity against the DU145 cell line.
Assuntos
Antineoplásicos , Cromonas , Ácidos de Lewis , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Humanos , Cromonas/química , Cromonas/farmacologia , Cromonas/síntese química , Linhagem Celular Tumoral , Ácidos de Lewis/química , Estrutura Molecular , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células/efeitos dos fármacos , Catálise , Relação Estrutura-AtividadeRESUMO
A series of chromone-deferiprone hybrids were designed, synthesized, and evaluated as inhibitors of human monoamine oxidase B (hMAO-B) with iron-chelating activity for the treatment of Alzheimer's disease (AD). The majority exhibited moderate inhibitory activity towards hMAO-B and potent iron-chelating properties. Particularly, compound 25c demonstrated remarkable selectivity against hMAO-B with an IC50 value of 1.58 µM and potent iron-chelating ability (pFe3+ = 18.79) comparable to that of deferiprone (pFe3+ = 17.90). Molecular modeling and kinetic studies showed that 25c functions as a non-competitive hMAO-B inhibitor. According to the predicted results, compound 25c can penetrate the blood-brain barrier (BBB). Additionally, it has been proved to display significant antioxidant activity and the ability to inhibit neuronal ferroptosis. More importantly, compound 25c reduced the cognitive impairment induced by scopolamine and showed significant non-toxicity in short-term toxicity assays. In summary, compound 25c was identified as a potential anti-AD agent with hMAO-B inhibitory, iron-chelating and anti-ferroptosis activities.
Assuntos
Doença de Alzheimer , Cromonas , Deferiprona , Quelantes de Ferro , Inibidores da Monoaminoxidase , Monoaminoxidase , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/síntese química , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Quelantes de Ferro/farmacologia , Quelantes de Ferro/química , Quelantes de Ferro/síntese química , Deferiprona/farmacologia , Deferiprona/química , Monoaminoxidase/metabolismo , Humanos , Cromonas/química , Cromonas/farmacologia , Cromonas/síntese química , Relação Estrutura-Atividade , Animais , Antioxidantes/farmacologia , Antioxidantes/química , Antioxidantes/síntese química , Ferroptose/efeitos dos fármacos , Estrutura Molecular , Simulação de Acoplamento Molecular , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Relação Dose-Resposta a DrogaRESUMO
Chromone-based compounds have established cytotoxic, antiproliferative, antimetastatic, and antiangiogenic effects on various cancer cell types via modulating different molecular targets. Herein, 17 novel chromone-2-carboxamide derivatives were synthesized and evaluated for their in vitro anticancer activity against 15 human cancer cell lines. Among the tested cell lines, MDA-MB-231, the triple-negative breast cancer cell line, was found to be the most sensitive, where the N-(2-furylmethylene) (15) and the α-methylated N-benzyl (17) derivatives demonstrated the highest growth inhibition with GI50 values of 14.8 and 17.1 µM, respectively. In vitro mechanistic studies confirmed the significant roles of compounds 15 and 17 in the induction of apoptosis and suppression of EGFR, FGFR3, and VEGF protein levels in MDA-MB-231 cancer cells. Moreover, compound 15 exerted cell cycle arrest at both the G0-G1 and G2-M phases. The in vivo efficacy of compound 15 as an antitumor agent was further investigated in female mice bearing Solid Ehrlich Carcinoma. Notably, administration of compound 15 resulted in a marked decrease in both tumor weight and volume, accompanied by improvements in biochemical, hematological, histological, and immunohistochemical parameters that verified the repression of both angiogenesis and inflammation as additional Anticancer mechanisms. Moreover, the binding interactions of compounds 15 and 17 within the binding sites of all three target receptors (EGFR, FGFR3, and VEGF) were clearly illustrated using molecular docking.
Assuntos
Antineoplásicos , Cromonas , Receptores ErbB , Simulação de Acoplamento Molecular , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos , Neoplasias de Mama Triplo Negativas , Fator A de Crescimento do Endotélio Vascular , Humanos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Feminino , Animais , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Camundongos , Cromonas/farmacologia , Cromonas/síntese química , Cromonas/química , Cromonas/uso terapêutico , Desenho de Fármacos , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacosRESUMO
The chromenopyridine scaffold represents an important class of heterocyclic compounds exhibiting a broad spectrum of biological properties. This review describes novel and efficient procedures for the synthesis of this scaffold. Herein, several methods were detailed and grouped according to their starting material (e.g., salicylaldehydes, chromones, chromanones and coumarins) and respective biological activity, when reported. This review highlights the potential of the reported synthetic strategies for preparing chromenopyridine derivatives with promising biological activity, paving the way for further developments in drug discovery.
Assuntos
Desenho de Fármacos , Piridinas , Piridinas/química , Piridinas/síntese química , Piridinas/farmacologia , Humanos , Estrutura Molecular , Cromonas/química , Cromonas/síntese química , Cromonas/farmacologia , Cumarínicos/química , Cumarínicos/farmacologia , Cumarínicos/síntese química , Relação Estrutura-AtividadeRESUMO
Overexpression of Bcl-2 protein is a predominant hallmark of disturbed apoptotic pathway in most of the cancers. Herein, chromone-linked thiazolidinediones were designed and synthesized to target Bcl-2 for regulating anti-apoptotic proteins. The study on in vitro cancer cell lines revealed the presence of compounds 8a, 8k, 8l, and 8n, which were found to have good to moderate anti-proliferative activity (with an IC50 concentration less than 10 µM). Among them, 8l depicted the highest cytotoxicity on the A549 cell line with an IC50 of 6.1 ± 0.02 µM. Aberrantly, the compounds displayed less toxicity towards human embryonic kidney HEK cells underlining its selectivity. The DCFDA study revealed a gradual increase in the ROS generation of 8l, followed by its quantification by flow analysis. Similarly, the studies including DAPI, AO/EtBr and Annexin-V binding clearly elucidated the DNA damage, membrane integrity prospects, and insights for early and late apoptotic phases. Markedly, the Bcl-2-FITC anti-body study revealed that compound 8l reduced the expression of anti-apoptotic proteins by 79.1 % compared to the control at 9 µM concentration. In addition, the molecular docking study provided the impending scope of these hybrids, showing promising interaction with the Mcl-1 target (member of the Bcl-2 family) with comparable binding affinities.
Assuntos
Antineoplásicos , Apoptose , Proliferação de Células , Cromonas , Ensaios de Seleção de Medicamentos Antitumorais , Tiazolidinedionas , Humanos , Apoptose/efeitos dos fármacos , Cromonas/farmacologia , Cromonas/química , Cromonas/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Tiazolidinedionas/farmacologia , Tiazolidinedionas/química , Tiazolidinedionas/síntese química , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Estrutura Molecular , Relação Dose-Resposta a Droga , Simulação de Acoplamento Molecular , Células HEK293 , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Linhagem Celular TumoralRESUMO
Diabetes is a serious metabolic disorder affecting individuals of all age groups and prevails globally due to the failure of previous treatments. This study aims to address the most prevalent form of type 2 diabetes mellitus (T2DM) by reporting on the design, synthesis, and in vitro as well as in silico evaluation of chromone-based thiosemicarbazones as potential α-glucosidase inhibitors. In vitro experiments showed that the tested compounds were significantly more potent than the standard acarbose, with the lead compound 3n exhibiting an IC50 value of 0.40 ± 0.02 µM, ~2183-fold higher than acarbose having an IC50 of 873.34 ± 1.67 µM. A kinetic mechanism analysis demonstrated that compound 3n exhibited reversible inhibition of α-glucosidase. To gain deeper insights, in silico molecular docking, pharmacokinetics, and molecular dynamics simulations were conducted for the investigation of the interactions, orientation, stability, and conformation of the synthesized compounds within the active pocket of α-glucosidase.
Assuntos
Cromonas , Diabetes Mellitus Tipo 2 , Desenho de Fármacos , Inibidores de Glicosídeo Hidrolases , Hipoglicemiantes , Simulação de Acoplamento Molecular , Tiossemicarbazonas , alfa-Glucosidases , Inibidores de Glicosídeo Hidrolases/farmacologia , Inibidores de Glicosídeo Hidrolases/síntese química , Inibidores de Glicosídeo Hidrolases/química , Hipoglicemiantes/farmacologia , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Cromonas/farmacologia , Cromonas/síntese química , Cromonas/química , Relação Estrutura-Atividade , alfa-Glucosidases/metabolismo , Tiossemicarbazonas/farmacologia , Tiossemicarbazonas/química , Tiossemicarbazonas/síntese química , Diabetes Mellitus Tipo 2/tratamento farmacológico , Estrutura Molecular , Humanos , Simulação de Dinâmica Molecular , Simulação por Computador , Relação Dose-Resposta a DrogaRESUMO
In consideration of the chromones' therapeutic potential and anticancer activity, a new series of chromanone derivatives have been synthesized through a straightforward reaction between 6-formyl-7-hydroxy-5-methoxy-2-methylchromone (2) and various organic active compounds. The cytotoxic activity of the newly synthesized congeners was investigated against MCF-7 (human breast cancer), HCT-116 (colon cancer), HepG2 (liver cancer), and normal skin fibroblast cells (BJ1). The obtained data indicated that compounds 14b, 17, and 19 induce cytotoxic activity in the breast MCF7, while compounds 6a, 6b, 11 and 14c showed highly potent activity in the colon cancer cell lines. Overall, the results demonstrate that the potential cytotoxic effects of the studied compounds may be based on their ability to induce DNA fragmentation in cancer cell lines, down-regulate the expression level of CDK4 as well as the anti-apoptotic gene Bcl-2 and up-regulate the expression of the pro-apoptotic genes P53 and Bax. Furthermore, compounds 14b and 14c showed a dual mechanism of action by inducing apoptosis and cell cycle arrest. The docking studies showed that the binding affinity of the most active cytotoxic compounds within the active pocket of the CDK4 enzyme is stronger due to hydrophobic and H-bonding interactions. These results were found to be consistent with the experimental results.
Assuntos
Antineoplásicos , Apoptose , Cromonas , Simulação de Acoplamento Molecular , Humanos , Cromonas/química , Cromonas/farmacologia , Cromonas/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Células MCF-7 , Linhagem Celular Tumoral , Células HCT116 , Células Hep G2 , Quinase 4 Dependente de Ciclina/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Ensaios de Seleção de Medicamentos AntitumoraisRESUMO
A series of novel chromone derivatives of (N-(4-oxo-2-(trifluoromethyl)-4H-chromen-6-yl) benzamides) were synthesized by treating 7-amino-2-(trifluoromethyl)-4H-chromen-4-one with K2CO3 and/or NaH, suitable alkyl halides and acetonitrile and/or 1,4-dioxane. The obtained products are in high yields (87 to 96%) with various substituents in short reaction times with no more by-products and confirmed by FT-IR, 1H, and 13C-NMR Spectral data. The in vitro cytotoxic activity was examined against two human cancer cell lines, namely the human lung adenocarcinoma (A-549) and the human breast (MCF-7) cancer cell line. Compound 4h showed promising cytotoxicity against both cell lines with IC50 values of 22.09 and 6.40 ± 0.26 µg/mL respectively, compared to that of the standard drug. We also performed the in vitro antioxidant activity by DPPH radical, hydrogen peroxide, NO scavenging, and total antioxidant capacity (TAC) assay methods, and they showed significant activities. The possible binding interactions of all the synthesized chromone derivatives are also investigated against selective pharmacological targets of human beings, such as HERA protein for cytotoxic activity and Peroxiredoxins (3MNG) for antioxidant activity which showed closer binding free energies than the standard drugs and evidencing the above two types of activities.
Assuntos
Antineoplásicos , Antioxidantes , Benzamidas , Simulação de Acoplamento Molecular , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antioxidantes/farmacologia , Antioxidantes/síntese química , Antioxidantes/química , Benzamidas/farmacologia , Benzamidas/química , Benzamidas/síntese química , Células MCF-7 , Células A549 , Cromonas/química , Cromonas/farmacologia , Cromonas/síntese química , Linhagem Celular Tumoral , Relação Estrutura-AtividadeRESUMO
Herein, we present an efficient Pd-catalysed method for stereoselective synthesis of chromone C-glycosides from various glycals. We successfully applied this method to various glycals with different protecting groups, yielding the corresponding glycosides in 41-78% yields. Additionally, we investigated the potential of this approach for the late-stage modification of natural products and pharmaceutical compounds linked to glycals, leading to the synthesis of their respective glycosides. Furthermore, we extended our research to gram-scale synthesis and demonstrated its applicability in producing various valuable products, including 2-deoxy-chromone C-glycosides. In summary, our work introduces a novel library of chromone glycosides, which holds promise for advancing drug discovery efforts.
Assuntos
Cromonas , Glicosídeos , Paládio , Paládio/química , Catálise , Glicosídeos/química , Glicosídeos/síntese química , Estereoisomerismo , Cromonas/química , Cromonas/síntese química , Estrutura Molecular , Produtos Biológicos/síntese química , Produtos Biológicos/químicaRESUMO
Based on a multitarget strategy, a series of novel chromanone-1-benzyl-1,2,3,6-tetrahydropyridin hybrids were identified for the potential treatment of Alzheimer's disease (AD). Biological evaluation demonstrated that these hybrids exhibited significant inhibitory activities toward acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). The optimal compound C10 possessed excellent dual AChE/MAO-B inhibition both in terms of potency and equilibrium (AChE: IC50 = 0.58 ± 0.05 µM; MAO-B: IC50 = 0.41 ± 0.04 µM). Further molecular modeling and kinetic investigations revealed that compound C10 was a dual-binding inhibitor bound to both the catalytic anionic site and peripheral anionic site of AChE. In addition, compound C10 exhibited low neurotoxicity and potently inhibited AChE enzymatic activity. Furthermore, compound C10 more effectively protected against mitochondrial dysfunction and oxidation than donepezil, strongly inhibited AChE-induced amyloid aggregation, and moderately reduced glutaraldehyde-induced phosphorylation of tau protein in SH-SY5Y cells. Moreover, compound C10 displayed largely enhanced improvements in cognitive behaviors and spatial memory in a scopolamine-induced AD mice model with better efficacy than donepezil. Overall, the multifunctional profiles of compound C10 suggest that it deserves further investigation as a promising lead for the prospective treatment of AD.
Assuntos
Doença de Alzheimer , Inibidores da Colinesterase , Cromonas , Inibidores da Monoaminoxidase , Animais , Humanos , Camundongos , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Linhagem Celular Tumoral , Cromonas/síntese química , Cromonas/farmacologia , Cromonas/uso terapêutico , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/farmacologia , Inibidores da Monoaminoxidase/uso terapêutico , Desenho de FármacosRESUMO
This article describes a part of the results obtained from the cooperation between the University of Lyon1 (France) and the University of Antananarivo (Madagascar). It shows (among others) that useful research can be carried out in developing countries of the tropics if their social, technical, and economic conditions are taken into account. The concepts and methods associated with so-called "green chemistry" are particularly appropriated for this purpose. To illustrate this approach, two examples are shown. The first deals with industrial ecology and concerns waste transformation from the production of cashew nut into an amphiphilic product, oxyacetic derivatives. This product was obtained with a high yield and in a single step reaction. It exhibited an important surfactant property similar to those of the main fossil-based ones but with a much lower ecological impact. The second talks about chemical ecology as an alternative to insecticides and used to control dangerous mosquito populations. New substituted chromones were synthesized and showed biological activities toward Aedes albopictus mosquito species. Strong repellent properties were recorded for some alkoxylated products if others had a significant attractant effect (Kairomone) depending on their stereochemistry and the length of the alkyl chain.
Assuntos
Aedes/fisiologia , Cromonas , Repelentes de Insetos , Animais , Cromonas/síntese química , Cromonas/química , Cromonas/farmacologia , Repelentes de Insetos/síntese química , Repelentes de Insetos/química , Repelentes de Insetos/farmacologia , MadagáscarRESUMO
American trypanosomiasis (Chagas disease) caused by the Trypanosoma cruzi parasite, is a severe health problem in different regions of Latin America and is currently reported to be spreading to Europe, North America, Japan, and Australia, due to the migration of populations from South and Central America. At present, there is no vaccine available and chemotherapeutic options are reduced to nifurtimox and benznidazole. Therefore, the discovery of new molecules is urgently needed to initiate the drug development process. Some acetophenones and chalcones, as well as chromane-type substances, such as chromones and flavones, are natural products that have been studied as trypanocides, but the relationships between structure and activity are not yet fully understood. In this work, 26 compounds were synthesized to determine the effect of hydroxyl and isoprenyl substituents on trypanocide activity. One of the compounds showed interesting activity against a resistant strain of T. cruzi, with a half effective concentration of 18.3 µM ± 1.1 and an index of selectivity > 10.9.
Assuntos
Acetofenonas/farmacologia , Produtos Biológicos/farmacologia , Doença de Chagas/metabolismo , Chalconas/farmacologia , Cromonas/farmacologia , Descoberta de Drogas/métodos , Flavonas/farmacologia , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Acetofenonas/síntese química , Produtos Biológicos/síntese química , Sobrevivência Celular/efeitos dos fármacos , Doença de Chagas/parasitologia , Chalconas/síntese química , Cromonas/síntese química , Flavonas/síntese química , Humanos , Tripanossomicidas/síntese química , Células U937RESUMO
Dirchromone is a bioactive vinyl sulfoxide-bearing chromone first isolated from the shrub Dirca palustris. Altogether, 32 of its derivatives were prepared to assess the effect of substitution of its chromone core upon activities against cancer cell lines, Gram-positive bacteria, and fungi (such as Candida albicans). All compounds were synthesized following a synthetic strategy involving Pummerer and soft-enolization Baker-Venkataraman rearrangements. Substituent position changes induced little variability on the activities tested. There was no correlation between cytotoxic and antibacterial effects, suggesting different underlying mechanisms of action. In particular, hydroxy group and cyanide substituents diminished cytotoxicity, with the latter featuring enhanced antibacterial activity. Higher homologues of 6-alkoxydirchromones also exhibited progressively emerging antifungal activity. Other modifications had moderate effects on cytotoxicity with some derivatives leading to increased potency. This behavior highlights the robustness of the natural dirchromone pharmacophore toward decoration, thus paving the way for more elaborate future drug design.
Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Cromonas/farmacologia , Linhagem Celular Tumoral , Cromonas/síntese química , Cromonas/química , Humanos , Relação Estrutura-AtividadeRESUMO
A number of chromone derivatives containing sulfonamide structure were designed and synthesized. Firstly, the target compounds were evaluated for anti-TSWV activities in vivo by the half-leaf method. We found that most of the compounds had good anti-TSWV activities. Among them, compound 12B had excellent anti-TSWV inactivating activity with an EC50 of 80.5 µg/mL, which was significantly better than xiangcaoliusuobingmi (765.7 µg/mL). Secondly, TSWV nucleocapsid protein (N) was expressed and purified, and the affinity between the compounds and TSWV N was tested by microscale thermophoresis (MST). Compound 12B had a good affinity for TSWV N with a Kd value of 5.02 µM, which was superior to xiangcaoliusuobingmi (29.83 µM). Finally, in order to study the mode of interaction between the compound 12B and TSWV N, we carried out molecular docking. The results indicated that compound 12B might inactivate the virus by destroying the TSWV N oligomer structure. These results lay a solid foundation for the further discovery of chromone derivatives containing sulfonamide structure with high anti-TSWV activities.
Assuntos
Antivirais/farmacologia , Cromonas/farmacologia , Descoberta de Drogas , Sulfonamidas/farmacologia , Tospovirus/efeitos dos fármacos , Antivirais/síntese química , Antivirais/química , Cromonas/síntese química , Cromonas/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
Microwave irradiation has become a popular heating technique in organic synthesis, mainly due to its short reaction times, solventless reactions, and, sometimes, higher yields. Additionally, microwave irradiation lowers energy consumption and, consequently, is ideal for optimization processes. Moreover, there is evidence that microwave irradiation can improve the regioselectivity and stereoselectivity aspects of vital importance in synthesizing bioactive compounds. These crucial features of microwave irradiation contribute to its inclusion in green chemistry procedures. Since 2003, the use of microwave-assisted organic synthesis has become common in our laboratory, making our group one of the first Portuguese research groups to implement this heating source in organic synthesis. Our achievements in the transformation of heterocyclic compounds, such as (E/Z)-3-styryl-4H-chromen-4-ones, (E)-3-(2-hydroxyphenyl)-4-styryl-1H-pyrazole, (E)-2-(4-arylbut-1-en-3-yn-1-yl)-4H-chromen-4-ones, or (E)-2-[2-(5-aryl-2-methyl-2H-1,2,3-triazol-4-yl)vinyl]-4H-chromen-4-ones, will be discussed in this review, highlighting the benefits of microwave irradiation use in organic synthesis.
Assuntos
Cromonas/síntese química , Calefação/métodos , Micro-Ondas , Pirazóis/síntese química , Quinolonas/síntese química , Química Farmacêutica/métodos , Cromonas/efeitos da radiação , Técnicas de Química Combinatória/métodos , Inibidores Enzimáticos/síntese química , Humanos , Estrutura Molecular , Pirazóis/efeitos da radiação , Quinolonas/efeitos da radiaçãoRESUMO
Chromones represent a privileged scaffold in medicinal chemistry and are an omnipresent structural motif in natural products. Chemically encoded non-natural peptidomimetics feature improved stability towards enzymatic degradation, cell permeability and binding affinity, translating into a considerable impact on pharmaceutical industry. Herein, a strategy for the sustainable assembly of chromones via electro-formyl C-H activation is presented. The rational design of the rhodaelectro-catalysis is guided by detailed mechanistic insights and provides versatile access to tyrosine-based fluorogenic peptidomimetics.
Assuntos
Cromonas/química , Peptidomiméticos/química , Benzaldeídos/síntese química , Benzaldeídos/química , Biomimética/métodos , Catálise , Cromonas/síntese química , Técnicas Eletroquímicas , Estrutura Molecular , Oxirredução , Peptidomiméticos/síntese químicaRESUMO
Chromone-3-phenylcarboxamides (Crom-1 and Crom-2) were identified as potent, selective, and reversible inhibitors of human monoamine oxidase B (hMAO-B). Since they exhibit some absorption, distribution, metabolism, and excretion (ADME)-toxicity liabilities, new derivatives were synthesized to map the chemical structural features that compose the pharmacophore, a process vital for lead optimization. Structure-activity relationship data, supported by molecular docking studies, provided a rationale for the contribution of the heterocycle's rigidity, the carbonyl group, and the benzopyran heteroatom for hMAO-B inhibitory activity. From the study, N-(3-chlorophenyl)-4H-thiochromone-3-carboxamide (31) (hMAO-B IC50 = 1.52 ± 0.15 nM) emerged as a reversible tight binding inhibitor with an improved pharmacological profile. In in vitro ADME-toxicity studies, compound 31 showed a safe cytotoxicity profile in Caco-2, SH-SY5Y, HUVEC, HEK-293, and MCF-7 cells, did not present cardiotoxic effects, and did not affect P-gp transport activity. Compound 31 also protected SH-SY5Y cells from iron(III)-induced damage. Collectively, these studies highlighted compound 31 as the first-in-class and a suitable candidate for in vivo preclinical investigation.
Assuntos
Cromonas/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Linhagem Celular , Cromonas/síntese química , Cromonas/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Relação Estrutura-AtividadeRESUMO
Herein we report the synthesis of some new 1H-1,2,4-triazole functionalized chromenols (3a-3n) via tandem reactions of 1-(alkyl/aryl)-2-(1H-1,2,4-triazole-1-yl) with salicylic aldehydes and the evaluation of their antifungal activity. In silico prediction of biological activity with computer program PASS indicate that the compounds have a high novelty compared to the known antifungal agents. We did not find any close analog among the over 580,000 pharmaceutical agents in the Cortellis Drug Discovery Intelligence database at the similarity cutoff of 70%. The evaluation of antifungal activity in vitro revealed that the highest activity was exhibited by compound 3k, followed by 3n. Their MIC values for different fungi were 22.1-184.2 and 71.3-199.8 µM, respectively. Twelve from fourteen tested compounds were more active than the reference drugs ketoconazole and bifonazole. The most sensitive fungus appeared to be Trichoderma viride, while Aspergillus fumigatus was the most resistant one. It was found that the presence of the 2-(tert-butyl)-2H-chromen-2-ol substituent on the 4th position of the triazole ring is very beneficial for antifungal activity. Molecular docking studies on C. albicans sterol 14α-demethylase (CYP51) and DNA topoisomerase IV were used to predict the mechanism of antifungal activities. According to the docking results, the inhibition of CYP51 is a putative mechanism of antifungal activity of the novel chromenol derivatives. We also showed that most active compounds have a low cytotoxicity, which allows us to consider them promising antifungal agents for the subsequent testing activity in in vivo assays.
Assuntos
Antifúngicos , Cromonas , Hypocreales/crescimento & desenvolvimento , Fungos Mitospóricos/crescimento & desenvolvimento , Simulação de Acoplamento Molecular , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Cromonas/síntese química , Cromonas/química , Cromonas/farmacologia , Avaliação Pré-Clínica de MedicamentosRESUMO
AD is one of the most typical neurodegenerative disorders that suffer many seniors worldwide. Recently, MAO inhibitors have received increasing attention not only for their roles involved in monoamine neurotransmitters metabolism and oxidative stress but also for their additional neuroprotective and neurorescue effects against AD. The curiosity in MAO inhibitors is reviving, and novel MAO-B inhibitors recently developed with ancillary activities (e.g., Aß aggregation and AChE inhibition, anti-ROS and chelating activities) have been proposed as multitarget drugs foreshadowing a positive outlook for the treatment of AD. The current review describes the recent development of the design, synthesis, and screening of multifunctional ligands based on MAO-B inhibition for AD therapy. Structure-activity relationships and rational design strategies of the synthetic or natural product derivatives (chalcones, coumarins, chromones, and homoisoflavonoids) are discussed.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/metabolismo , Animais , Chalconas/síntese química , Chalconas/química , Chalconas/farmacologia , Cromonas/síntese química , Cromonas/química , Cromonas/farmacologia , Cumarínicos/síntese química , Cumarínicos/química , Cumarínicos/farmacologia , Flavonoides/síntese química , Flavonoides/química , Flavonoides/farmacologia , Humanos , Estrutura Molecular , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/química , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Estresse Oxidativo/efeitos dos fármacosRESUMO
A new biological scaffold was produced by replacing the 6π-electron phenyl ring-B of a natural flavone skeleton with a 10π-electron benzothiophene (BT). Since aromatic rings are important for ligand protein interactions, this expansion of the π-electron system of ring-B might change the bioactivity profile. One of the resulting novel natural product-inspired compounds, 2-(benzo[b]thiophen-3-yl)-5-hydroxy-7-isopropoxy-6-methoxyflavone (6), effectively arrested the cell cycle at the G2/M phase and displayed significant antiproliferative effects with IC50 values of 0.05-0.08 µM against multiple human tumor cell lines, including a multidrug resistant line. A structure-activity relationship study revealed that a 10π-electron system with high aromaticity, juxtaposed 4-oxo and 5-hydroxy groups, and 7-alkoxy groups were important for potent antimitotic activity. Interestingly, two BT-flavonols (3-hydroxyflavone), 16 and 20, with 3-hydroxy and 5-alkoxy groups, induced distinct biological profiles affecting the cell cycle at the G1/S phase by inhibition of DNA replication through an interaction with topoisomerase I.