RESUMO
A series of 4-methyl-5-(3-phenylacryloyl)thiazoles based on chalcones were designed, synthesized and evaluated for their influenza neuraminidase (NA) inhibitory activity in vitro. A preliminary structure-activity relationship (SAR) analysis showed that thiazoles bearing amide had greater potency. It also showed that mono-hydroxyl group at 4-position on phenyl ring was more effective than other electron-releasing groups or electron-withdraw groups. Compounds A2 and A26 were more potent against NA with IC50 values of 8.2 ± 0.5 µg/mL and 6.2 ± 1.4 µg/mL, respectively. Molecular docking study demonstrated that thiazoles skeleton was benefit for the NA inhibitory activity.
RESUMO
A convenient and efficient method for the generation of the iminoxy radical through anodic oxidation was developed for the synthesis of 3,5-disubstituted 1,2,4-oxadiazoles from N-benzyl amidoximes. The transformation proceeds through 1.5-Hydrogen Atom Transfer (1,5-HAT) and intramolecular cyclization. The process features simple operation, mild conditions, broad substrate scope and high functional group compatibility, and provides a facile and practical way for the preparation of 1,2,4-oxadiazoles.
RESUMO
A series of novel 2-oxoquinoline derivatives containing arylaminothiazole were designed and synthesized as potential antitumor agents. The synthesized compounds were evaluated for their in vitro cytotoxicity activity against HeLa, NCI-H460, T24 and SKOV3 cancer cell lines using MTT assay. Among them, compound A7 exhibited the most potent activity against the test cancer cell lines, with the IC50 values ranged from 4.4 to 8.7 µM. The results of tubulin polymerization assay showed that compound A7 could inhibit tubulin polymerization in vitro. Meanwhile, molecular docking study revealed that A7 can bind to the colchicine site of tubulin and formed hydrogen bonds with key amino acid residues in the active site. Further mechanism study demonstrated that compound A7 blocked cell cycle arrest at G2/M phase, induced cell apoptosis and depolarized mitochondria of HeLa cells. Collectively, our findings suggest that A7 could serve as a promising lead for the development of more efficient microtubule polymerization inhibitors for cancer therapy.
Assuntos
Antineoplásicos/farmacologia , Quinolonas/farmacologia , Tiazóis/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Apoptose/efeitos dos fármacos , Sítios de Ligação , Bovinos , Linhagem Celular Tumoral , Desenho de Fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Simulação de Acoplamento Molecular , Ligação Proteica , Quinolonas/síntese química , Quinolonas/metabolismo , Ratos , Tiazóis/síntese química , Tiazóis/metabolismo , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/metabolismo , Moduladores de Tubulina/farmacologiaRESUMO
Four series of ferulic acid derivatives were designed, synthesized, and evaluated for their neuraminidase (NA) inhibitory activities against influenza virus H1N1 in vitro. The pharmacological results showed that the majority of the target compounds exhibited moderate influenza NA inhibitory activity, which was also better than that of ferulic acid. The two most potent compounds were 1m and 4a with IC50 values of 12.77 ± 0.47 and 12.96 ± 1.34 µg/ml, respectively. On the basis of the biological results, a preliminary structure-activity relationship (SAR) was derived and discussed. Besides, molecular docking was performed to study the possible interactions of compounds 1p, 2d, 3b, and 4a with the active site of NA. It was found that the 4-OH-3-OMe group and the amide group (CON) of ferulic acid amide derivatives were two key pharmacophores for NA inhibitory activity. It is meaningful to further modify the natural product ferulic acid to improve its influenza NA inhibitory activity.
Assuntos
Antivirais/farmacologia , Bioensaio , Ácidos Cumáricos/farmacologia , Inibidores Enzimáticos/farmacologia , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Antivirais/síntese química , Antivirais/química , Ácidos Cumáricos/síntese química , Ácidos Cumáricos/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Vírus da Influenza A Subtipo H1N1/enzimologia , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Neuraminidase/antagonistas & inibidores , Neuraminidase/metabolismo , Relação Estrutura-AtividadeRESUMO
As a known natural product with anti-tumor activity, honokiol has been widely researched and structural modified. Lots of honokiol derivatives have been found to possess good anti-proliferative activity and showed great potential in cancer therapy, but the SAR (structure-activity relationship) was still confused. Here in, the SAR were comprehensively researched by summary of reported derivatives and synthesis of novel derivatives. Amongst novel derivatives, the promising compounds A6 and A10 exhibited potent and selective anti-proliferative activities against K562 cell line with the IC50 values of 5.04 and 7.08⯵M respectively. The SAR was discussed around honokiol and 79 derivatives by the means of CoMFA and theoretical calculation, which provided useful suggestion for further structural optimization of honokiol derivatives.
Assuntos
Compostos de Bifenilo/uso terapêutico , Lignanas/uso terapêutico , Compostos de Bifenilo/farmacologia , Humanos , Lignanas/farmacologia , Relação Estrutura-AtividadeRESUMO
Diflumetorim is a member of pyrimidinamine fungicides that possess excellent antifungal activities. Nevertheless, as reported that the activity of diflumetorim to corn rust (Puccinia sorghi) was not ideal (EC50â¯=â¯53.26â¯mg/L). Herein, a series of novel pyrimidinamine derivatives containing phenyl-thiazole/oxazole moiety were designed based on our previous study and the structural characteristics of diflumetorim, synthesized and bioassayed to discover novel fungicides with excellent antifungal activities. Among these compounds, T18 gave the optimal fungicidal activity, which respectively offers control effects with EC50 values of 0.93â¯mg/L against P. sorghi and 1.24â¯mg/L against E. graminis, significantly superior to commercial fungicides diflumetorim, tebuconazole, and flusilazole. Cell cytotoxicity results suggested that compound T18 has lower toxicities than diflumetorim. Furthermore, DFT calculation indicated that the phenyl-thiazole/oxazole moiety plays an unarguable role in the improvement of activity, which will contribute to designing and developing more potent compounds in the future.
Assuntos
Antifúngicos/farmacologia , Desenho de Fármacos , Fungicidas Industriais/farmacologia , Oxazóis/farmacologia , Pirimidinas/farmacologia , Tiazóis/farmacologia , Alternaria/efeitos dos fármacos , Antifúngicos/síntese química , Antifúngicos/química , Ascomicetos/efeitos dos fármacos , Botrytis/efeitos dos fármacos , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Fungicidas Industriais/síntese química , Fungicidas Industriais/química , Gibberella/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oxazóis/química , Phytophthora/efeitos dos fármacos , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade , Tiazóis/químicaRESUMO
A series of novel aryloxyphenoxypropionate (APP) herbicides containing benzofuran moiety were designed, synthesized and tested for herbicidal activity. The bioassay results indicated that most of target compounds possessed moderate to good herbicidal activity against monocotyledonous weeds. Compounds 5a-5d and 6a-6d showed 100% control efficiency against crabgrass (Digitaria sanguinalis) and barnyard grass (Echinochloa crus-galli) in both pre-emergence and post-emergence treatments at the dosage of 1500â¯g a.i. ha-1. Compound 6c was the most promising, with herbicidal activity better than clodinafop-propargyl. Molecular docking for compound 6c and its hydrolysis acid 1c were performed. ACCase activities of some compounds were also tested. Theoretical calculations for corresponding hydrolysis products 1a-1ewere carried out. Based on the results of molecular docking, enzyme activity test and theoretical calculation, the potential mechanism for herbicidal activity of these compounds was evaluated.
Assuntos
Benzofuranos/farmacologia , Herbicidas/farmacologia , Propionatos/farmacologia , Acetil-CoA Carboxilase/metabolismo , Benzofuranos/química , Digitaria/efeitos dos fármacos , Digitaria/fisiologia , Desenho de Fármacos , Echinochloa/efeitos dos fármacos , Echinochloa/fisiologia , Herbicidas/química , Modelos Teóricos , Simulação de Acoplamento Molecular , Proteínas de Plantas/metabolismo , Plantas Daninhas/efeitos dos fármacos , Propionatos/químicaRESUMO
Honokiol, a natural polyphenol, which was reported to have satisfactory influenza neuraminidase (NA) inhibitory activity, was structurally modified. Twenty-three compounds were synthesized and the ortho-effects in the epoxidation and hydrolyzation reactions were studied. The derivatives were evaluated for NA inhibitory activity and the benzoylhydrazone derivatives showed much better anti-NA activity than honokiol. Structure-activity relationship analysis suggested that the polyphenols exhibited better anti-NA activity than monophenols and biphenols. Furthermore, probable binding mode of drug with target revealed that the most active compound had much stronger interactions with the active site of NA than honokiol suggesting the potent anti-influenza virus activity.
Assuntos
Antivirais , Influenza Humana , Compostos de Bifenilo , Desenho de Fármacos , Humanos , Lignanas , Estrutura Molecular , NeuraminidaseRESUMO
Multidrug resistance (MDR) has been shown to reduce the effectiveness of chemotherapy. Strategies to overcoming MDR have been widely explored in the last decades, leading to a generation of numerous small molecules targeting ABC and MRP transporters. Among the ABC family, ABCB1 plays key roles in the development of drug resistance and is the most well studied. In this work, we report the discovery of non-toxic [1,2,4]triazolo[1,5-a]pyrimidin-7-one (WS-10) from our structurally diverse in-house compound collection that selectively modulates ABCB1-mediated multidrug resistance. WS-10 enhanced the intracellular accumulation of paclitaxel in SW620/Ad300 cells, but did not affect the expression of ABCB1 Protein and ABCB1 localization. The cellular thermal shift assay (CETSA) showed that WS-10 was able to bind to ABCB1, which could be responsible for the reversal effect of WS-10 toward paclitaxel and doxorubicin in SW620/Ad300 cells. Docking simulations were performed to show the possible binding modes of WS-10 within ABCB1 transporter. To conclude, WS-10 could be used as a template for designing new ABCB1 modulators to overcome ABCB1-mediated multidrug resistance.
RESUMO
Multidrug resistance (MDR) has been shown to reduce the effectiveness of chemotherapy. Strategies to overcoming MDR have been widely explored in the last decades, leading to a generation of numerous small molecules targeting ABC and MRP transporters. Among the ABC family, ABCB1 plays key roles in the development of drug resistance and is the most well studied. In this work, we report the discovery of a non-toxic [1,2,4]triazolo[1,5-a]pyrimidin-7-one (WS-10) from our structurally diverse in-house compound collection that selectively modulates ABCB1-mediated multidrug resistance. WS-10 enhanced the intracellular accumulation of paclitaxel in SW620/Ad300 cells, but did not affect the expression of ABCB1 Protein and ABCB1 localization. The cellular thermal shift assay (CETSA) showed that WS-10 was able to bind to ABCB1, which could be responsible for the reversal effect of WS-10 toward paclitaxel and doxorubicin in SW620/Ad300 cells. Docking simulations were performed to show the possible binding modes of WS-10 within ABCB1 transporter. To conclude, WS-10 could be used as a template for designing new ABCB1 modulators to overcome ABCB1-mediated multidrug resistance.
Assuntos
Azóis/farmacologia , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Pirimidinas/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/efeitos dos fármacos , Subfamília B de Transportador de Cassetes de Ligação de ATP/fisiologia , Antineoplásicos Fitogênicos/farmacologia , Azóis/química , Linhagem Celular Tumoral , Humanos , Concentração Inibidora 50 , Paclitaxel/farmacologia , Pirimidinas/químicaRESUMO
Two series of novel 2-thiazolylhydrazone derivatives were designed and synthesized via one-pot reaction of benzaldehyde derivatives, [Formula: see text]-haloketones and thiosemicarbazide. The structures of compounds 1 and 2 were characterized by [Formula: see text] NMR and [Formula: see text] NMR, and compound 1g was further confirmed by X-ray crystallography. All of the target compounds were evaluated for their NA inhibitory activity against influenza viral neuraminidase (H1N1) in vitro, and the results showed that many compounds exhibited moderate to strong inhibitory activities against influenza viral neuraminidase (H1N1). Among them, compounds 1p, 1q and 2c showed the most potent inhibitory activities with [Formula: see text] values ranging from 10.50 to [Formula: see text]. Our structure-activity relationship analysis indicated that 2-thiazolylhydrazone is an effective scaffold for NA inhibitors and that introducing an ethoxycarbonyl group to the 5-position of thiazole ring could enhance inhibitory potency. Molecular docking was performed on the most active compounds 1p and 2c to provide more insight into their mechanism of interaction.
Assuntos
Inibidores Enzimáticos/síntese química , Hidrazonas/síntese química , Vírus da Influenza A Subtipo H1N1/enzimologia , Neuraminidase/antagonistas & inibidores , Antivirais/síntese química , Antivirais/química , Antivirais/farmacologia , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Hidrazonas/química , Hidrazonas/farmacologia , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química , Tiazóis/farmacologiaRESUMO
With the aim of discovering new anticancer agents, we have designed and synthesized novel α-aminophosphonate derivatives containing a 2-oxoquinoline structure using a convenient one-pot three-component method. The newly synthesized compounds were evaluated for antitumor activities against the A549 (human lung adenocarcinoma cell), HeLa (human cervical carcinoma cell), MCF-7 (human breast cancer cell), and U2OS (human osteosarcoma cell) cancer cell lines in vitro, employing a standard 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. The results of pharmacological screening indicated that many compounds exhibited moderate to high levels of antitumor activities against the tested cancer cell lines and that most compounds showed more potent inhibitory activities comparable to 5-fluorouracil (5-FU) which was used as a positive control. The mechanism of representative compound 4u (diethyl((2-oxo-1,2-dihydroquinolin-3-yl)(phenyl-amino)methyl)phosphonate) indicated that the compound mainly arrested HeLa cells in S and G2 stages and was accompanied by apoptosis in HeLa cells. This action was confirmed by acridine orange/ethidium bromide staining, Hoechst 33342 staining, and flow cytometry.
Assuntos
Antineoplásicos/síntese química , Hidroquinonas/química , Ácidos Fosforosos/química , Células A549 , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Fluoruracila/toxicidade , Células HeLa , Humanos , Células MCF-7 , Microscopia de Fluorescência , Ácidos Fosforosos/síntese química , Ácidos Fosforosos/farmacologia , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacosRESUMO
Based on the positive effects of COX-2 inhibitors on depressive symptoms and the desirable physicochemical and biological properties of the morpholine group, a series of novel 2-(2-arylmorpholino)ethyl esters of ibuprofen hydrochlorides were designed, synthesized, and tested for their COX-2 inhibitory and serotonin reuptake inhibitory activities in vitro. The structure-activity relationships of the 2-(2-arylmorpholino)ethyl esters of ibuprofen hydrochlorides as dual COX-2 and serotonin reuptake inhibitors were determined and discussed in detail. The biological assays indicated that five of the compounds possess good COX-2 selectivity (selectivity index COX-1/COX-2 42.8-158.1). The compound 2-[2-(4-benzyloxyphenyl)morpholino]ethyl 2-(4-iso-butylphenyl)-propanoate hydrochloride (1k) shows better COX-2 inhibitory activity (IC50 = 0.78 µM) than ibuprofen (IC50 = 7.6 µM), and it simultaneously possesses favorable serotonin reuptake inhibitory activity.
Assuntos
Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ésteres/síntese química , Ésteres/farmacologia , Ibuprofeno/síntese química , Ibuprofeno/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Animais , Células CACO-2 , Ciclo-Oxigenase 2/metabolismo , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Ibuprofeno/análogos & derivados , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/enzimologia , Camundongos , Estrutura Molecular , Proteínas de Ligação a RNA/antagonistas & inibidores , Proteínas de Ligação a RNA/metabolismo , Ratos , Proteínas da Membrana Plasmática de Transporte de Serotonina/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Relação Estrutura-AtividadeRESUMO
With a convenient and economical method, two series of 1,3-thiazine derivatives 1 and 2 were synthesized, and their neuraminidase (NA) inhibitory activities were evaluated. The pharmacological results showed that most of the compounds have potent NA inhibitory activity. Especially, 1g exhibited the best activity against influenza virus A (H1N1) NA (IC50=29.06 µg/mL), and its crystal structure was determined by single-crystal X-ray diffraction. The preliminary biological assay indicated that 1,3-thiazine could be used as a core structure to design novel influenza NA inhibitors.
Assuntos
Antivirais/farmacologia , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Neuraminidase/antagonistas & inibidores , Tiazinas/farmacologia , Antivirais/síntese química , Antivirais/química , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Concentração Inibidora 50 , Relação Estrutura-Atividade , Tiazinas/síntese química , Tiazinas/químicaRESUMO
The title compound, C(21)H(22)O(5), crystallizes with three mol-ecules in the asymmetric unit. In one mol-ecule, two methyl groups are disordered over two positions with a site occupation factor of 0.72â (2) for the major occupancy site. The benzene rings make dihedral angles of 35.3â (6), 29.7â (6) and 40.6â (7)° in the three molecules.
RESUMO
A series of 4-thiazolinone derivatives (D1-D58) were designed and synthesized. All of the derivatives were evaluated in vitro for neuraminidase (NA) inhibitory activities against influenza virus A (H1N1), and the inhibitory activities of the five most potent compounds were further evaluated on NA from two different influenza viral subtypes (H3N2 and B), and then their in vitro anti-viral activities were evaluated using the cytopathic effect (CPE) reduction assay. The results showed that the majority of the target compounds exhibited moderate to good NA inhibitory activity. Compound D18 presented the most potent inhibitory activity with IC50 values of 13.06 µM against influenza H1N1 subtype. Among the selected compounds, D18 and D41 turned out to be the most potent inhibitors against influenza virus H3N2 subtype (IC50 = 15.00 µM and IC50 = 14.97 µM, respectively). D25 was the most potent compound against influenza B subtype (IC50 = 16.09 µM). In addition, D41 showed low toxicity and greater potency than reference compounds Oseltamivir and Amantadine against N1-H275Y variant in cellular assays. The structure-activity relationship (SAR) analysis showed that introducing 4-CO2H, 4-OH, 3-OCH3-4-OH substituted benzyl methylene can greatly improve the activity of 4-thiazolinones. Further SAR analysis indicated that 4-thiazolinone and ferulic acid fragments are necessary fragments of target compounds for inhibiting NA. Molecular docking was performed to study the interaction between compound D41 and the active site of NA. This study may providing important information for new drug development for anti-influenza virus including mutant influenza virus.
Assuntos
Antivirais/farmacologia , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Neuraminidase/antagonistas & inibidores , Tiazóis/farmacologia , Antivirais/síntese química , Antivirais/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Vírus da Influenza A Subtipo H3N2/enzimologia , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Neuraminidase/metabolismo , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/químicaRESUMO
In the title compound, C(12)H(14)O(4)·H(2)O, the dihydro-benzo-furan ring adopts an envelope conformation with the substituted C atom 0.142â (1)â Å out of the least-squares plane. In the crystal, the components are linked via inter-molecular O(water)-Hâ¯O and O-Hâ¯O(water) hydrogen-bonding inter-actions, forming a three-dimensional network.
RESUMO
In the title compound, C(19)H(21)NO(3), the dihedral angle between the mean planes of the two benzene rings is 38.13â (12)°. The furan ring adopts an envelope-like conformation with the C atom bonded to the dimethyl groups displaced by 0.356â (2)â Å from the plane through the other four atoms. In the crystal, mol-ecules are linked into inversion dimers by weak C-Hâ¯O inter-molecular inter-actions.
RESUMO
The title compound, C(14)H(18)O(2), was obtained as a by-product during the preparation of carbofuran phenol. The two dihydro-furan rings are in envelope conformations.
RESUMO
The asymmetric unit of the title compound, C(14)H(17)Cl(2)N(2)S(+)·Br(-), contains one cation and two Br(-) ions with site symmetry . The dihedral angle between the planes of the thia-zol and the dichloro-phenyl rings is 77.8â (6)°. In the crystal, the ions are connected by N-Hâ¯Br hydrogen bonds.