RESUMO
A series of new asymmetric bisamidine was designed, synthesized, and tested for their in-vitro antibacterial activity using a range of Gram-positive and Gram-negative pathogens. Most compounds demonstrated powerful antibacterial activity, and interestingly, some displayed better activity against several Gram-negative strains than the lead compound 1. The most potent bisamidine 8l exhibited 4-fold more potent activity against E. coli, K. pneumonia, P. aeruginosa, and C. freundii than compound 1. Especially 8l exhibited a powerful activity against K. pneumonia secreting NDM-1 enzyme with a minimum inhibitory concentration (MIC) of 2 µg/mL, while levofloxacin and vancomycin displayed resistance, with MICs > 128 µg/mL.
Assuntos
Antibacterianos/farmacologia , Furanos/farmacologia , Indóis/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Citrobacter freundii/efeitos dos fármacos , Relação Dose-Resposta a Droga , Escherichia coli/efeitos dos fármacos , Furanos/síntese química , Furanos/química , Indóis/química , Klebsiella/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pseudomonas aeruginosa/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Optimization of IG-105 (1) on the carbazole ring provided five series of new carbazole sulfonamides derivatives, 7a-e, 8a-g, 9a-g, 10a-e, and 11a-g. All of the compounds were evaluated against HepG2, MCF-7, MIA PaCa-2, and Bel-7402 cells for antiproliferative activity. Each series of compounds was 2-5 times more active against HepG2 cells (IC50: 1.00-10.0 µM) than the other three tumor cell lines. Several representative compounds, selected from each series, showed aqueous solubility (13.4-176.5 µg/mL at pH 7.4 and 2.0) better than 1, with the aqueous solubility of corresponding salts > 30 mg/mL. From the results of evaluating the effects of the compounds 7b, 8c, 9c, 10c and 11c on tubulin in vitro, we speculated that their targets were different from those of 1 and CA-4P. We tested the antitumor activity of the representative compound 7b·HCl (10 mg/kg) in an in vivo study and found that its tumor growth inhibition rate was 41.1%. The tumor growth inhibition rate of 7b·HCl (20 mg/kg) was 54.6%, whereas the tumor growth inhibition rate of CA-4P (50 mg/kg) was 48.3%. And in another batch of in vivo antitumor activity testing, 9c·HCl and 11c·HCl at doses of 10 mg/kg resulted in 61.1% and 50.0% inhibition, respectively. These promising results warrant further development of the derivatives, which may use a novel mechanism and show potential potency as antitumor drug candidates.
Assuntos
Antineoplásicos/farmacologia , Carbazóis/farmacologia , Desenho de Fármacos , Sulfonamidas/farmacologia , Moduladores de Tubulina/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Carbazóis/síntese química , Carbazóis/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Polimerização/efeitos dos fármacos , Solubilidade , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química , Água/químicaRESUMO
The current optimization of IG-105 (3) on the carbazole-ring provided a series of new carbazole sulfonamides derivatives 13a-13m. All of the compounds have been evaluated against HepG2 cells (hepatoma cancer) for antiproliferative activity. Compounds that showed activity better or comparable to that of 3 versus HepG2 were evaluated against MCF-7 (breast cancer), MIA PaCa-2 (pancreatic cancer), and Bel-7402 (hepatoma/liver cancer) for antiproliferative activity. Of the seven compounds selected for further study five (13b, 13g, 13j, 13k and 13l) were found to give IC50 values against the four cell lines comparable to those for 3. Two compounds (13f and 13i) were more active than 3 and their activity against HepG2 and MCF-7 (IC50:0.01-0.07µM) approached that of the positive controls podophyllotoxin (podo) and CA-4. Most of compounds showed aqueous solubility (0.11-19.60µg/mL at pH 7.4 and 2.0) better than 3. These promising results warrant further development of new compounds 13f and 13i as potential potent antitumor drug candidates.
Assuntos
Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Carbazóis/química , Carbazóis/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Antineoplásicos Fitogênicos/síntese química , Carbazóis/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Solubilidade , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Água/químicaRESUMO
A series of 4,4'-bis-[2-(6-N-substituted-amidino)indolyl] diphenyl ether have been synthesized and tested for their in vitro antibacterial activity including a range of Gram-positive and Gram-negative pathogens and cytotoxicity. Most of these compounds have mainly shown anti-Gram positive bacteria activities especially against drug resistant bacterial strains MRSA, MRSE and VRE. The anti-MRSA and anti-MRSE activities of compound 7a and 7j were more potent than that of the lead compound 2, levofloxacin and vancomycin. Interestingly, 7j had greatly improved anti negative bacterial activity, especially for the producing NDM-1 Klebsiella pneumonia strain and less toxic than that of the lead compound 2.
Assuntos
Antibacterianos/síntese química , Éteres Fenílicos/química , Antibacterianos/química , Antibacterianos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Éteres Fenílicos/síntese química , Éteres Fenílicos/farmacologia , Relação Estrutura-Atividade , Resistência a Vancomicina/efeitos dos fármacosRESUMO
Arylimidamide (AIA) compounds containing two pyridylimidamide terminal groups (bis-AIAs) possess outstanding in vitro antileishmanial activity, and the frontrunner bis-AIA DB766 (2,5-bis[2-(2-isopropoxy)-4-(2-pyridylimino)aminophenyl]furan) is active in visceral leishmaniasis models when given orally. Eighteen compounds containing a single pyridylimidamide terminal group (mono-AIAs) were synthesized and evaluated for their antileishmanial potential. Six of these compounds exhibited sub-micromolar potency against both intracellular Leishmania donovani and Leishmania amazonensis amastigotes, and three of these compounds also displayed selectivity indexes of 25 or greater for the parasites compared to a J774 macrophage cell line. When given orally at a dose of 100mg/kg/day for five days, compound 1b (N-(3-isopropoxy-4-(5-phenylfuran-2-yl)phenyl)picolinimidamide methanesulfonate) reduced liver parasitemia by 46% in L. donovani-infected mice. Mono-AIAs are thus a new class of candidate molecules for antileishmanial drug development.
Assuntos
Antiprotozoários/química , Antiprotozoários/farmacologia , Leishmania donovani/efeitos dos fármacos , Leishmania mexicana/efeitos dos fármacos , Administração Oral , Animais , Antiprotozoários/síntese química , Técnicas de Química Sintética , Avaliação Pré-Clínica de Medicamentos/métodos , Furanos/química , Concentração Inibidora 50 , Leishmania donovani/patogenicidade , Leishmania mexicana/patogenicidade , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/parasitologia , Macrófagos/efeitos dos fármacos , Macrófagos/parasitologia , Camundongos Endogâmicos BALB C , Parasitemia/tratamento farmacológico , Parasitemia/parasitologia , Relação Estrutura-AtividadeRESUMO
A series of novel carbazole sulfonamide derivatives were synthesized and evaluated for antiproliferative activity. Among them, compounds 7 and 15 showed strong potency (IC50 values of 0.81-31.19 nM) against five different cancer cells including multidrug-resistant MCF7/ADR cells. Compound 15 displayed a high cancer cell selectivity (IC50(L02)/average IC50: SI = 7.7). The l-valine prodrug 7a and the phosphate prodrug 15a exerted rohust in vivo antitumor efficacies and accepted safety prolifes. Further mechanism studies revealed that 7 and 15 directly bind to the colchicine site in tubulin to block tubulin polymerization, promote microtubule fragmentation at the cellular level, and induce apoptosis with G2/M cell cycle arrest. These compounds also inhibit HEMC-1 cells migration and vascular tube formation. Additionally, compound 7 displayed a selective inhibition of Topo I. Collectively, these studies suggest that 7 and 15 represents a promising new generation of tubulin inhibitors for cancer treatment.
Assuntos
Antineoplásicos , Apoptose , Carbazóis , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Sulfonamidas , Moduladores de Tubulina , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Carbazóis/farmacologia , Carbazóis/química , Carbazóis/síntese química , Relação Estrutura-Atividade , Sulfonamidas/farmacologia , Sulfonamidas/química , Sulfonamidas/síntese química , Proliferação de Células/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Estrutura Molecular , Moduladores de Tubulina/farmacologia , Moduladores de Tubulina/química , Moduladores de Tubulina/síntese química , Tubulina (Proteína)/metabolismo , Relação Dose-Resposta a Droga , Linhagem Celular Tumoral , Animais , Movimento Celular/efeitos dos fármacos , CamundongosRESUMO
Dicationic 2,6-diphenylpyrazines, aza-analogues and prodrugs were synthesized; evaluated for DNA affinity, activity against Trypanosoma brucei rhodesiense (T. b. r.) and Plasmodium falciparum (P. f.) in vitro, efficacy in T. b. r. STIB900 acute and T. b. brucei GVR35 CNS mouse models. Most diamidines gave poly(dA-dT)2 ΔTm values greater than pentamidine, IC50 values: T. b. r. (4.8-37nM) and P. f. (10-52nM). Most diamidines and prodrugs gave cures for STIB900 model (11, 19a and 24b 4/4 cures); 12 3/4 cures for GVR35 model. Metabolic stability half-life values for O-methylamidoxime prodrugs did not correlate with STIB900 results.
Assuntos
Antiprotozoários/síntese química , Compostos Aza/química , Pentamidina/química , Pró-Fármacos/síntese química , Pirazinas/química , Animais , Antiprotozoários/uso terapêutico , Antiprotozoários/toxicidade , Cátions/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Camundongos , Mioblastos/citologia , Testes de Sensibilidade Parasitária , Pentamidina/uso terapêutico , Pentamidina/toxicidade , Plasmodium falciparum/efeitos dos fármacos , Poli dA-dT/química , Poli dA-dT/metabolismo , Pró-Fármacos/uso terapêutico , Pró-Fármacos/toxicidade , Ratos , Relação Estrutura-Atividade , Temperatura de Transição , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológicoRESUMO
In the title compound, C20H19N3O4S, a novel tubulin ligand active against human cancer, the dihedral angle between the pyridine ring and the carbazole ring system is 42.87â (10)°. In the crystal, the mol-ecules are held together by N-Hâ¯O and C-Hâ¯O hydrogen bonds into layers, which are assembled into a three-dimensional network via π-π stacking inter-actions between inversion-related pyridine rings, with centroid-centroid distances of 3.5101â (12)â Å.
RESUMO
A series of novel biaryl amide derivatives were synthesized and evaluated for anti-HCV virus activity. Some significant SARs were uncovered. The intensive structural modifications led to fifteen novel compounds with more potent inhibitory activity compared to the hit compounds IMB 26 and IMB1f. Among them, compound 80 was the most active, with EC50 values almost equivalent to the clinical drug telaprevir (EC50 = 15 nM). Furthermore, it also had a good safety and in vitro and oral pharmacokinetic (oral bioavailability in rats: 34%) profile, suggesting a highly drug-like nature. Compound 80represents a more promising scaffold for anti-HCV virus activity for further study.
Assuntos
Amidas/farmacologia , Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Amidas/síntese química , Amidas/química , Antivirais/síntese química , Antivirais/química , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The present study aimed to determine the in vitro biological efficacy and selectivity of 7 novel AIAs upon bloodstream trypomastigotes and intracellular amastigotes of Trypanosoma cruzi. The biological activity of these aromatic compounds was assayed for 48 and 24 h against intracellular parasites and bloodstream forms of T. cruzi (Y strain), respectively. Additional assays were also performed to determine their potential use in blood banks by treating the bloodstream parasites with the compounds diluted in mouse blood for 24 h at 4°C. Toxicity against mammalian cells was evaluated using primary cultures of cardiac cells incubated for 24 and 48 h with the AIAs and then cellular death rates were determined by MTT colorimetric assays. Our data demonstrated the outstanding trypanocidal effect of AIAs against T. cruzi, especially DB1853, DB1862, DB1867 and DB1868, giving IC50 values ranging between 16 and 70 nanomolar against both parasite forms. All AIAs presented superior efficacy to benznidazole and some, such as DB1868, also demonstrated promising activity as a candidate agent for blood prophylaxis. The excellent anti-trypanosomal efficacy of these novel AIAs against T. cruzi stimulates further in vivo studies and justifies the screening of new analogues with the goal of establishing a useful alternative therapy for Chagas disease.
Assuntos
Amidas/farmacologia , Doença de Chagas/tratamento farmacológico , Tripanossomicidas/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Amidas/química , Amidas/isolamento & purificação , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Doença de Chagas/parasitologia , Concentração Inibidora 50 , Camundongos , Miócitos Cardíacos , Nitroimidazóis/farmacologia , Testes de Sensibilidade Parasitária , Tripanossomicidas/química , Tripanossomicidas/isolamento & purificaçãoRESUMO
Here, we formulated and investigated the structure-activity relationships of novel N-substituted carbazole sulfonamide derivatives with improved physicochemical properties. Most of these new compounds displayed good aqueous solubility. Certain molecules presented strong in vitro antiproliferative and in vivo antitumor activity. Relative to the control, 50 mg/kg compound 3v substantially reduced human HepG2 xenograft mouse tumor growth by 54.5% and its efficacy was comparable to that of CA-4P. Compound 3h demonstrated anticancer efficacy in both subcutaneous and orthotopic HepG2 xenograft mouse models. We also developed a novel synthetic method for 7-hydroxy-substituted carbazole sulfonamides. Compared with the control, 25 mg/kg compound 4c inhibited human HepG2 xenograft mouse tumor growth by 71.7% and was more potent than 50 mg/kg CA-4P with only 50% tumor shrinkage efficacy. Among the three water-soluble carbazole sulfonamide derivatives formulated in the present study, compound 4c displayed the most effective tumor growth inhibition in vivo and merit further investigation as potential antitumor agents for cancer therapy.
Assuntos
Antineoplásicos/farmacologia , Carbazóis/farmacologia , Sulfonamidas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Carbazóis/síntese química , Carbazóis/química , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Ratos , Solubilidade , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Células Tumorais Cultivadas , Água/químicaRESUMO
A new class of novel bis-benzimidazole diamidine compounds have been synthesized and evaluated for in vitro antibacterial activities, including drug-resistant bacterial strains. Anti-MRSA and anti-VRE activities of the most potent compound 1 were more active than Vancomycin. The mechanism of action for this class of compounds appears to be different from existing antibiotics. Bis-benzimidazole diamidine compounds have potential for further investigation as a new class of potent anti-MRSA and anti-VRE agents.
Assuntos
Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Enterococcus faecium/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Antibacterianos/química , Antibacterianos/classificação , Antibacterianos/farmacologia , Benzimidazóis/classificação , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Resistência a Meticilina/efeitos dos fármacos , Relação Estrutura-Atividade , Resistência a Vancomicina/efeitos dos fármacosRESUMO
A series of dicationic diaryl ethers have been synthesized and evaluated for in vitro antibacterial activities, including drug resistant bacterial strains. Most of these compounds have shown potent antibacterial activities. Several compounds, such as piperidinyl and thiomorpholinyl compounds 9e and 9l, improved the antimicrobial selectivity and kept potent anti-MRSA and anti-VRE activity. The most potent bis-indole diphenyl ether 19 exhibited anti-MRSA MIC value of 0.06 microg/mL and enhanced antimicrobial selectivity.
Assuntos
Antibacterianos/síntese química , Benzimidazóis/síntese química , Enterococcus/efeitos dos fármacos , Éteres/síntese química , Indóis/síntese química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Pentamidina/síntese química , Éteres Fenílicos/síntese química , Resistência a Vancomicina , Antibacterianos/química , Antibacterianos/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacologia , Éteres/química , Éteres/farmacologia , Indóis/química , Indóis/farmacologia , Testes de Sensibilidade Microbiana , Pentamidina/química , Pentamidina/farmacologia , Éteres Fenílicos/química , Éteres Fenílicos/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of bis-benzimidazole diamidine compounds containing different central linkers has been synthesized and evaluated for in vitro antibacterial activities, including drug-resistant bacterial strains. Seven compounds have shown potent antibacterial activities. The anti-MRSA and anti-VRE activities of compound 1h were more potent than that of the lead compound 1a and vancomycin.
Assuntos
Antibacterianos/síntese química , Benzimidazóis/química , Benzimidazóis/síntese química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Pentamidina/análogos & derivados , Resistência a Vancomicina/efeitos dos fármacos , Antibacterianos/química , Antibacterianos/farmacologia , Benzimidazóis/farmacologia , Cátions/química , Testes de Sensibilidade Microbiana , Pentamidina/síntese química , Pentamidina/química , Pentamidina/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of azaterphenyl diamidines has been synthesized and evaluated for in vitro antiprotozoal activity against both Trypanosoma brucei rhodesiense (T. b. r.) and Plasmodium falciparum (P. f.) and in vivo efficacy in the STIB900 acute mouse model for T. b. r. Six of the 13 compounds showed IC(50) values less than 7 nM against T. b. r. Twelve of those exhibited IC(50) values less than 6 nM against P. f. and six of those showed IC(50) values 0.6 nM, which are more than 25-fold as potent as furamidine. Moreover, two of them showed more than 40-fold selectivity for P. f. versus T. b. r. Three compounds 15b, 19d and 19e exhibited in vivo efficacy against T. b. r. much superior to furamidine, and equivalent to or better than azafuramidine. The antiparasitic activity of these diamidines depends on the ring nitrogen atom(s) location relative to the amidine groups and generally correlates with DNA binding affinity.
Assuntos
Antiprotozoários/química , Antiprotozoários/uso terapêutico , Pentamidina/análogos & derivados , Pentamidina/uso terapêutico , Plasmodium falciparum/efeitos dos fármacos , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Animais , Antiprotozoários/farmacologia , Concentração Inibidora 50 , Malária Falciparum/tratamento farmacológico , Camundongos , Testes de Sensibilidade Parasitária , Pentamidina/farmacologia , Relação Estrutura-Atividade , Tripanossomíase Africana/tratamento farmacológicoRESUMO
PURPOSE: We have synthesized a new tubulin ligand N-(2,6-dimethoxypyridine-3-yl)-9-methylcarbazole-3-sulfonamide (IG-105). This work investigates its anticancer effect and mechanism. EXPERIMENTAL DESIGN: Anticancer efficacy was evaluated at the molecular target, cancer cells and nude mice. The mechanism was explored at submolecular, molecular, and cellular levels. RESULTS: IG-105 showed a potent activity against human leukemia and solid tumors in breast, liver, prostate, lung, skin, colon, and pancreas with IC(50) values between 0.012 and 0.298 mumol/L. It was also active in drug-resistant tumor cells and not a P-glycoprotein substrate. It inhibited microtubule assembly followed by M-phase arrest, Bcl-2 inactivation, and then apoptosis through caspase pathways. The colchicine pocket on tubulin is the binding site of IG-105. Nude mice experiments showed that IG-105 monotherapy at 100 mg/kg i.p. (q2d) yielded 81% inhibition of Bel-7402 hepatoma growth and at 275 mg/kg i.p. (q2d) completely inhibited the tumor growth. MCF-7 breast cancer in nude mice showed a similar therapeutic response to IG-105. Acute toxicity of IG-105 was not found even at 1,000 mg/kg i.p. In combination with oxaliplatin or doxorubicin, IG-105 converted each of these subcurative compounds into a curative treatment with complete inhibition for tumor growth in the hepatoma-bearing nude mice. The combination was more active than either drug. In no experiment was toxicity increased by combination chemotherapy. CONCLUSIONS: IG-105 inhibits microtubule assembly by binding at colchicine pocket. It shows a potent anticancer activity in vitro and in vivo and has good safety in mice. We consider IG-105 merits further investigation.
Assuntos
Carbazóis/farmacologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Sulfonamidas/química , Tubulina (Proteína)/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Antineoplásicos/farmacologia , Carbazóis/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Concentração Inibidora 50 , Ligantes , Camundongos , Camundongos Nus , Microtúbulos/metabolismo , Transplante de Neoplasias , Sulfonamidas/farmacologia , Moduladores de Tubulina/metabolismoRESUMO
Eighteen diamidino azaterphenyls and analogues were evaluated as anti-leishmanials; nine of the compounds gave IC50 values less than 1 microM, five exhibited values less than 0.40 microM, and two gave values less than 0.10 microM in a Leishmania donovani axenic amastigote assay. The activity of the diamidines strongly depends on the ring N-atom location relative to the amidine groups and correlates with DNA affinity. Transmission electron microscopy studies showed a dramatic dilation of the mitochondrion and evidence of disintegration of the kinetoplast of the amastigotes.
Assuntos
Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Leishmania donovani/efeitos dos fármacos , Compostos de Terfenil/síntese química , Compostos de Terfenil/farmacologia , Animais , Antiprotozoários/química , Compostos Aza/síntese química , Compostos Aza/química , Compostos Aza/farmacologia , Benzamidinas/síntese química , Benzamidinas/química , Benzamidinas/farmacologia , DNA de Protozoário/metabolismo , Leishmania donovani/genética , Leishmania donovani/ultraestrutura , Ratos , Relação Estrutura-Atividade , Compostos de Terfenil/químicaRESUMO
A series of novel diamidines with N-substituents on an amidine N-atom were synthesized and evaluated for their cytotoxicity and in vitro antibacterial activity against a range of Gram-positive and Gram-negative bacterial strains. Based on structure-activity relationship, N-substituents with a branched chain and a shorter carbon chain on the amidine N-atom exhibited more promising activity against Gram-negative and MDR-Gram-positive bacteria; compounds 5c and 5i were the most powerful candidate compounds. Compound 5c showed greater efficacy than levofloxacin against most drug-resistant Gram-positive bacteria and exhibited broad-spectrum antibacterial activity against Gram-negative bacteria, with MIC values in the range of 2-16⯵g/mL. Slightly more potent antibacterial activity against Klebsiella pneumoniae, Acinetobacter calcoaceticus, Enterobacter cloacae, and Proteus mirabilis was observed for 5i in comparison with 5c. Compound 5i also showed remarkable antibacterial activity against NDM-1-producing Gram-negative bacteria, with MIC values in the range of 2-4⯵g/mL, and was superior to the reference drugs meropenem and levofloxacin. Effective antibacterial activity of 5i was also shown in vivo in a mouse model of Staphylococcus aureus MRSA strain, with an ED50values of 2.62â¯mg/kg.
Assuntos
Amidinas/farmacologia , Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Indóis/farmacologia , Amidinas/síntese química , Amidinas/química , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Indóis/síntese química , Indóis/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Human APOBEC3G (hA3G) is a restriction factor that inhibits human immunodeficiency 1 virus (HIV-1) replication. The virally encoded protein Vif binds to hA3G and induces its degradation, thereby counteracting the antiviral activity of hA3G. Vif-mediated hA3G degradation clearly represents a potential target for anti-HIV drug development. Herein, we have performed virtual screening to discover small molecule inhibitors that target the binding interface of the Vif/hA3G complex. Subsequent biochemical studies have led to the identification of a small molecule inhibitor, IMB-301 that binds to hA3G, interrupts the hA3G-Vif interaction and inhibits Vif-mediated degradation of hA3G. As a result, IMB-301 strongly inhibits HIV-1 replication in a hA3G-dependent manner. Our study further demonstrates the feasibility of inhibiting HIV replication by abrogating the Vif-hA3G interaction with small molecules.
Assuntos
Desaminase APOBEC-3G/metabolismo , Fármacos Anti-HIV/farmacologia , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Produtos do Gene vif do Vírus da Imunodeficiência Humana/metabolismo , Desaminase APOBEC-3G/química , Desaminase APOBEC-3G/genética , Infecções por HIV/metabolismo , Infecções por HIV/virologia , Ensaios de Triagem em Larga Escala , Humanos , Conformação Proteica , Replicação Viral/efeitos dos fármacos , Produtos do Gene vif do Vírus da Imunodeficiência Humana/química , Produtos do Gene vif do Vírus da Imunodeficiência Humana/genéticaRESUMO
Androgen receptor (AR) plays a critical role in the development and progression of prostate cancer (PCa). Current antiandrogen therapies induce resistant mutations at the hormone binding pocket (HBP) that convert the activity of these agents from antagonist to agonist. Thus, there is a high unmet medical need for the development of novel antiandrogens which circumvent mutation-based resistance. Herein, through the analysis of AR structures with ligands binding to the activation function-2 (AF2) site, we built a combined pharmacophore model. In silico screening and the subsequent biological evaluation lead to the discovery of the novel lead compound IMB-A6 that binds to the AF2 site, which inhibits the activity of either wild-type (WT) or resistance mutated ARs. Our work demonstrates structure-based drug design is an efficient strategy to discover new antiandrogens, and provides a new class of small molecular antiandrogens for the development of novel treatment agents against PCa.