RESUMO
Aim: Fusidic acid (FA) is a narrow-spectrum bacteriostatic antibiotic. We inadvertently discovered that a FA derivative modified by an amino-terminal group at the 3-OH position, namely 2, inhibited the growth of Cryptococcus neoformans. Methods & results: Multiscale molecular modeling approaches were used to analyze the binding modes of 2 with eEF2. FA derivatives modified at the 3-OH position were designed based on in silico models; seven derivatives possessing different amino-terminal groups were synthesized and tested in vitro for antifungal activity against C. neoformans. Conclusion: Compound 7 had the strongest minimum inhibitory concentration. Two protonated nitrogen atoms of 7 interacted with a negative electrostatic pocket of eEF2 likely explain the superiority of 7-2.
Assuntos
Antifúngicos/farmacologia , Cryptococcus neoformans/efeitos dos fármacos , Ácido Fusídico/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Ácido Fusídico/síntese química , Ácido Fusídico/química , Testes de Sensibilidade Microbiana , Conformação MolecularRESUMO
In this study, we synthesized 23 fusidic acid (FA) derivatives and screened them for tumor drug resistance reversal activity and cytotoxicity toward the KBV (multidrug-resistant oral epidermoid carcinoma) cell line based on MTT assay. Tumor resistance reversal activity of fusidic acid (FA) derivatives was discovered for the first time. Our results showed that compound 1 enhanced the cytotoxicity of paclitaxel toward the drug-resistant KBV cells at a concentration of 5⯵M. And compound 1 sensitized KBV cells toward paclitaxel in arresting cells in the G2/M phase and inducing cell apoptosis. Further researches showed that compound 1 inhibited the drug efflux activity of P-glycoprotein (P-gp) by increasing the ATPase activity of P-gp without affecting its expression. The structure-activity relationships (SARs) of the FA derivatives were also preliminarily investigated. Our findings indicate that compound 1 is a promising lead compound for designing FA derivatives with improved tumor drug resistance reversal activity in the future.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos/farmacologia , Descoberta de Drogas , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ácido Fusídico/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Ácido Fusídico/síntese química , Ácido Fusídico/química , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A series of novel fusidic acid (FA) derivatives were synthesized and screened for their in vitro cytotoxicity against the Hela, U87, KBV and MKN45 cancer cell lines. Selected FA derivatives with anti-tumor activity were firstly identified including compound 4, which exhibited good anti-proliferative activity with IC50 values in the range of 1.26-3.57⯵M. Further research revealed that compound 4 induced Hela cells to undergo apoptosis by increasing the ratio of the cells in the Sub-G0/G1 phase via decreasing the neo-synthesized proteins in a dose-dependent manner from 1 to 10⯵M. Compound 4 also showed good in vivo anti-tumor activity against the xenograft tumor of Hela cells and had no apparent toxicity. This study highlights the advantage of introducing the medium-length amino-terminal groups at the 3-OH position of FA to enhance its anti-tumor activity and suggests that compound 4 provides a starting point for designing more potent derivatives in the future.
Assuntos
Antineoplásicos/síntese química , Ácido Fusídico/farmacologia , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Ácido Fusídico/síntese química , Ácido Fusídico/uso terapêutico , Xenoenxertos , Humanos , Camundongos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Wide spread Plasmodium falciparum ( P. falciparum) resistance has compromised existing antimalarial therapies to varying degrees. Novel agents, able to circumvent antimalarial drug resistance, are therefore needed. Fusidic acid is a unique antibiotic with a unique mode of action, which has shown weak in vitro antiplasmodial activity. Toward identifying new fusidic acid derivatives with superior antiplasmodial activity, a 3D-QSAR model was developed based on the antiplasmodial activity of previously synthesized fusidic acid derivatives. The validated Hypo 2 model was used as the 3D-structural search query to screen a fusidic acid-based combinatorial library. On the basis of the predicted activity and pharmacophore fit value, eight virtual hit compounds were selected and synthesized, including C-21 amide and C-3 ether derivatives. All synthesized hit compounds showed superior antiplasmodial activity compared to fusidic acid. Two C-21 amide derivatives displayed significant activity against the drug-sensitive NF54 strain with IC50 values of 0.3 µM and 0.7 µM, respectively. These two derivatives also displayed activity against the multidrug-resistant K1 strain, with an IC50 value of 0.2 µM and were found to be relatively noncytotoxic.
Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Ácido Fusídico/análogos & derivados , Ácido Fusídico/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Relação Quantitativa Estrutura-Atividade , Antimaláricos/síntese química , Desenho Assistido por Computador , Desenho de Fármacos , Descoberta de Drogas , Ácido Fusídico/síntese química , Humanos , Malária Falciparum/tratamento farmacológico , Modelos Biológicos , Modelos MolecularesRESUMO
A series of novel fusidic acid (FA) derivatives was synthesized by replacing the carboxylic acid group with various ester and amide groups and evaluated in vitro for their antiplasmodial activity against the chloroquine-sensitive NF54 and multidrug-resistant K1 strains of the malarial parasite Plasmodium falciparum. Most of these derivatives showed a 4-49 and 5-17-fold increase in activity against NF54 and KI strains, respectively, as compared to FA and had a good selectivity index. These derivatives are stable over the incubation period and do not appear to be prodrugs of fusidic acid.
Assuntos
Amidas/química , Ésteres/química , Ácido Fusídico/química , Ácido Fusídico/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Amidas/farmacologia , Antimaláricos/síntese química , Antimaláricos/química , Antimaláricos/farmacologia , Cloroquina/farmacologia , Resistência a Medicamentos/efeitos dos fármacos , Ésteres/farmacologia , Ácido Fusídico/síntese química , Relação Estrutura-AtividadeRESUMO
Two steroid acids, cephalosporin P1 and isocephalosporin P1, were isolated from Hapsidospora irregularis FERM BP-2511. These compounds are structurally related to fusidic acid. Their NMR data were completely assigned on the basis of the 2D NMR spectra. Incubation of these two compounds with Microbacterium oxydans CGMCC 1788 in Luria-Bertani broth yielded the same set of three new 3-dehydrogenated products, 3-keto-isocephalosporin P1, 3-keto-cephalosporin P1 and 6-deacetyl-3-keto-cephalosporin P1. The final pH of the bacterial culture was 9.0. Incubation of 3-keto-isocephalosporin P1 or 3-keto-cephalosporin P1 in Tris-HCl buffer (pH 9.0) revealed that these two compounds can convert to each other by shifting the acetyl group between C-6 and C-7. The acetyl group at C-6 or C-7 can also be removed by hydrolysis to yield the minor product 6-deacetyl-3-keto-cephalosporin P1. These fusidic acid derivatives were tested for the antibacterial activity against the Gram-positive pathogen Staphylococcus aureus. 3-Keto-cephalosporin P1 showed the highest activity among the five compounds, with a minimal inhibition concentration (MIC) of 4 µg/mL, which is more potent than the substrate cephalosporin P1. Both cephalosporin P1 and 3-keto-cephalosporin P1 were active against methicillin-resistant S. aureus, with the same MIC of 8 µg/mL.
Assuntos
Antibacterianos/farmacologia , Ácido Fusídico/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Ácido Fusídico/síntese química , Ácido Fusídico/química , Testes de Sensibilidade Microbiana , Estrutura MolecularRESUMO
While thermolysis of the macrobicyclic triene lactone 12 did not produce the expected bicyclic transannular Diels-Alder (BTADA) product 13, heating the corresponding ether 18 to 110 °C for 4 h afforded a quantitative yield of the desired cycloadduct 19, which could be easily reduced to the perhydrophenanthrene, an ABC ring analogue of fusidic acid 1. Theoretical calculations with hybrid density functional theory (B3LYP/6-31G(d)) help rationalize why the lactone does not cyclize whereas the ether does.
Assuntos
Ácido Fusídico/síntese química , Fenantrenos/síntese química , Cristalografia por Raios X , Ácido Fusídico/química , Modelos Moleculares , Simulação de Dinâmica Molecular , Estrutura Molecular , Fenantrenos/química , EstereoisomerismoRESUMO
Novel photoaffinity labeled fusidic acid analogues were obtained by a synthetic sequence employing a Wittig reaction between a fusidic acid aldehyde and benzyl bromides in the key step. Three commonly used photoreactive groups, benzophenone, trifluoromethyldiazirine, and aryl azide, were used. The photoaffinity labeled fusidic acid analogues demonstrated a potent antibacterial activity (MIC 0.016-4 microg/mL) and therefore represent a potential tool for the elucidation of the interactions between fusidic acid and its receptor EF-G.
Assuntos
Antibacterianos/síntese química , Azidas/síntese química , Benzofenonas/síntese química , Diazometano/análogos & derivados , Diazometano/síntese química , Ácido Fusídico/análogos & derivados , Ácido Fusídico/síntese química , Marcadores de Fotoafinidade/síntese química , Marcadores de Fotoafinidade/farmacologia , Antibacterianos/farmacologia , Azidas/farmacologia , Benzofenonas/farmacologia , Corynebacterium/efeitos dos fármacos , Diazometano/farmacologia , Ácido Fusídico/farmacologia , Testes de Sensibilidade Microbiana , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus epidermidis/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
A novel fusidic acid type antibiotic having the side chain linked to the tetracyclic ring system via a spiro-cyclopropane system is described. 17S,20S-Methanofusidic acid is obtained by an efficient synthetic route including cyclopropanation of the Delta17(20) bond with attack solely from the least hindered alpha-face. The spiro-cyclopropane system orients the side chain into a bioactive conformational space. The new 17S,20S-methanofusidic acid exerts antibacterial activity against several Gram-positive species with potency essentially equal to natural fusidic acid.
Assuntos
Antibacterianos/síntese química , Ácido Fusídico/análogos & derivados , Ácido Fusídico/síntese química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Farmacorresistência Bacteriana , Ácido Fusídico/farmacologia , Testes de Sensibilidade Microbiana , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
Novel fusidic acid type antibiotics having flexible side chains are described. Saturation of the double bond between C-17 and C-20 of fusidic acid produces four stereoisomers differing in the configuration at C-17 and C-20. The structure-activity relationship of the stereoisomers was studied using computer-assisted analyses of low-energy conformations and crystallographic data. Only one of the four stereoisomers showed potent antibiotic activity comparable with that of fusidic acid, whereas the other three stereoisomers retained little or no activity. The orientation of the side chain is crucial, and there is only a limited space for bioactive side chain conformations. This investigation demonstrates the essential role of the side chain conformations in relation to antibacterial activity and contradicts earlier assumptions that the Delta17(20) bond is an essential feature in the molecule.