RESUMO
Antibiotic resistance in bacteria has been an emerging public health problem, thus discovery of novel and effective antibiotics is urgent. A series of novel hybrids of N-aryl pyrrothine-base α-pyrone hybrids was designed, synthesized and evaluated as bacterial RNA polymerase (RNAP) inhibitors. Among them, compound 13c exhibited potent antibacterial activity against antibiotic-resistant S. aureus with the minimum inhibitory concentration (MIC) in the range of 1-4 µg/mL. Moreover, compound 13c exhibited strong inhibitory activity against E.coli RNAP with IC50 value of 16.06 µM, and cytotoxicity in HepG2 cells with IC50 value of 7.04 µM. The molecular docking study further suggested that compound 13c binds to the switch region of bacterial RNAP. In summary, compound 13c is a novel bacterial RNAP inhibitor, and a promising lead compound for further optimization.
Assuntos
Antibacterianos/síntese química , RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/química , Escherichia coli/enzimologia , Pironas/química , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Sítios de Ligação , Candida albicans/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , RNA Polimerases Dirigidas por DNA/metabolismo , Inibidores Enzimáticos/metabolismo , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Células Hep G2 , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Pironas/metabolismo , Pironas/farmacologia , Relação Estrutura-AtividadeRESUMO
Most of reported steroidal FXR antagonists are restricted due to low potency. We described the design and synthesis of novel nonsteroidal scaffold SIPI-7623 derivatives as FXR antagonists. The most potent compound A-11 (IC50 = 7.8 ± 1.1 µM) showed better activity compared to SIPI-7623 (IC50 = 40.8 ± 1.7 µM) and guggulsterone (IC50 = 45.9 ± 1.1 µM). Docking of A-11 in FXR's ligand-binding domain was also studied.
Assuntos
Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Valeratos/química , Valeratos/farmacologia , Humanos , Simulação de Acoplamento Molecular , Receptores Citoplasmáticos e Nucleares/metabolismoRESUMO
Fourteen novel compounds were prepared and their antagonistic activities against liver X receptors (LXR) α/ß were tested in vitro. Compound 26 had an IC50 value of 6.4 µM against LXRα and an IC50 value of 5.6 µM against LXRß. Docking studies and the results of structure-activity relationships support the further development of this chemical series as LXRα/ß antagonists.
Assuntos
Fenofibrato/análogos & derivados , Hipolipemiantes/química , Receptores Nucleares Órfãos/antagonistas & inibidores , Descoberta de Drogas , Fenofibrato/farmacologia , Humanos , Hipolipemiantes/farmacologia , Ligantes , Receptores X do Fígado , Simulação de Acoplamento Molecular , Receptores Nucleares Órfãos/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of 5,7-dimethyl-oxazolo[5,4-d]pyrimidine-4,6(5H,7H)-dione derivatives, N5a-5l, was designed, synthesized and evaluated for their FGFR1-inhibition ability as well as cytotoxicity against three cancer cell lines (H460, B16F10 and A549) in vitro. Several compounds displayed good-to-excellent potency against these cancer cell lines compared to SU5402. Structure-activity relationship analyses indicated that compounds with a rigid structure and more heteroatoms at the side chain of the parent ring were more effective than those without these substitutions. The compound N5g (37.4% FGFR1 inhibition at 1.0 µM) was identified to have the most potent antitumor activities, with IC50 values of 5.472, 4.260 and 5.837 µM against H460, B16F10 and A549 cell lines, respectively. Together, our results suggest that 5,7-dimethyl-oxazolo[5,4-d]pyrimidine-4,6(5H,7H)-dione derivatives may serve as potential agents for the treatment of FGFR1-mediated cancers.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Oxazóis/farmacologia , Pirimidinas/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Estrutura Molecular , Oxazóis/síntese química , Oxazóis/química , Pirimidinas/síntese química , Pirimidinas/química , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Relação Estrutura-AtividadeRESUMO
In this study, a series of amide derivatives were synthesized and evaluated for their S-adenosyl-L-homocysteine hydrolase (SAHase) inhibitory activities. The results demonstrated that most of compounds displayed potent SAHase inhibitory activities. Interestingly, compounds 11 and 14 exhibited more potent inhibitory effects than the aristeromycin, one of the most potent SAHase inhibitors known so far. Compounds 12, 13, 15 and 17 exhibited a moderate effect (IC50<10.0 µM). The structure-activity relationship found that compounds with substituted indazole-5-yl group at Ar position and ethylamino group at the side chain showed better SAHase inhibitory activities.
Assuntos
Amidas/química , Amidas/farmacologia , Homocisteína/antagonistas & inibidores , Hidrolases/antagonistas & inibidores , Adenosina/análogos & derivados , Adenosina/farmacologia , Relação Estrutura-AtividadeRESUMO
The design and synthesis of a series of substituted 6-amino-4-(2,4-dimethoxyphenyl)-[1,2]dithiolo[4,3-b]pyrrol-5-ones are described. All the synthesized compounds were evaluated for raising leukocyte count activities in normal mice. Four compounds (8a, b, d, h) exhibited raising leukocyte count activities close or higher than positive control recombinant human granulocyte colony stimulating factor (rhG-CSF), and some (8e-g, k, p, r) had a moderate effect. Among them, the most potent compound 8a was evaluated for its antileukopenia activity in cyclophosphamide (CTX) treated mice. Interestingly, 8a exhibited significant antileukopenia activity as compared to rhG-CSF. The results suggest that this kind of compounds might be utilized for the development of new candidate for treatment of leukocytopenia.
Assuntos
Leucócitos/efeitos dos fármacos , Leucopenia/tratamento farmacológico , Pirróis/síntese química , Animais , Ciclofosfamida/farmacologia , Fator Estimulador de Colônias de Granulócitos/metabolismo , Contagem de Leucócitos , Leucócitos/citologia , Leucócitos/metabolismo , Leucopenia/sangue , Camundongos , Camundongos Endogâmicos BALB C , Pirróis/farmacologia , Proteínas Recombinantes/metabolismoRESUMO
The design and synthesis of two series of 8-(substituted styrol-formamido)phenyl-xanthine derivatives are described. Their in vitro monoamine oxidase B (MAO-B) inhibition were tested and the effect of substituents on the N-7, phenyl and the substituted positions are discussed. It was observed that compound 9b displayed significant MAO-B inhibition activity and selectivity, fluorine substitution plays a key role in the selectivity of MAO-B inhibition, and the styrol-formamido group at position-3' may enhance the activity and selectivity of 8-phenyl-xanthine analogues. These results suggest that such compounds may be utilized for the development of new candidate MAO-B inhibitors for treatment of Parkinson's disease.
Assuntos
Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Xantina/síntese química , Xantina/farmacologia , Flúor/química , Inibidores da Monoaminoxidase/química , Relação Estrutura-Atividade , Estireno/química , Xantina/químicaRESUMO
Monoamine oxidase-B (MAO-B) inhibitor has been used as neuroprotectants to treat the motor deficits of Parkinson's disease (PD). We designed and synthesized a class of 8-substituted benzamido-phenylxanthine derivatives as MAO-B inhibitors. The compounds have various inhibitory effects, with compound 6a having a K(i) value of 0.26 µM. Their promising activity in vitro suggests potential use in the treatment of PD.