RESUMO
A novel kind of potent HIV-1 protease inhibitors, containing diverse hydroxyphenylacetic acids as the P2-ligands and 4-substituted phenyl sulfonamides as the P2' ligands, were designed, synthesized and evaluated in this work. Majority of the target compounds exhibited good to excellent activity against HIV-1 protease with IC50 values below 200 nM. In particular, compound 18d with a 2-(3,4-dihydroxyphenyl) acetamide as the P2 ligand and a 4- methoxybenzene sulfonamide P2' ligand exhibited inhibitory activity IC50 value of 0.54 nM, which was better than that of the positive control darunavir (DRV). More importantly, no significant decline of the potency against HIV-1DRVRS (DRV-resistant mutation) and HIV-1NL4_3 variant (wild type) for 18d was detected. The molecular docking study of 18d with HIV-1 protease (PDB-ID: 1T3R, www.rcsb.org) revealed possible binding mode with the HIV-1 protease. These results suggested the validity of introducing phenol-derived moieties into the P2 ligand and deserve further optimization which was of great value for future discovery of novel HIV-1 protease.
Assuntos
Benzenoacetamidas , Inibidores da Protease de HIV , HIV-1 , Darunavir/metabolismo , Darunavir/farmacologia , HIV-1/genética , Simulação de Acoplamento Molecular , Ligantes , Protease de HIV/metabolismo , Sulfonamidas/química , Desenho de Fármacos , Cristalografia por Raios X , Relação Estrutura-AtividadeRESUMO
A novel benzene sulfonamide compound named IMB16-4 exhibits excellent anti-hepatic fibrosis activity in a recent study. To develop potential anti-hepatic fibrosis agents, a series of benzene sulfonamide derivatives were designed and synthesized based on the scaffold of the lead compound IMB16-4. As it turned out, most of the derivatives displayed potential anti-hepatic fibrosis activity, among which, compounds 11a, 11b, 11d, 13a, 36b, and 47b exhibited inhibition rates of 42.3%, 48.7%, 42.4%, 40.0%, 39.4%, and 49.3%, respectively, which were equivalent to the control IMB16-4 with an inhibition rate of 35.9%, Costunolide with an inhibition rate of 45.4%, and much more potent than that of Epigallocatechin gallate (EGCG) with an inhibition rate of 25.3%. Especially, compounds 46a, 46b, and 46c exhibited excellent anti-hepatic fibrosis activity with inhibition rates of 61.7%, 54.8%, and 60.7%, which were almost 1.5-fold inhibition rates of IMB16-4. In addition, compounds 46a, 46b, and 46c exhibited remarkable inhibitory activity in the gene expression of COL1A1, MMP-2, and the protein expression of COL1A1, FN, α-SMA, and TIMP-1 by inhibiting the JAK1-STAT1/3 pathway. These findings furnished valuable inspiration for the further development of anti-hepatic fibrosis agents.
Assuntos
Antifibróticos , Benzeno , Humanos , Derivados de Benzeno , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Sulfonamidas/farmacologia , Relação Estrutura-AtividadeRESUMO
Subplenones A-J (1-10), 10 new xanthone dimers, have been isolated and characterized from the endophytic fungus Subplenodomus sp. CPCC 401465, which resides within the Chinese medicinal plant Gentiana straminea. The isolation process was guided by antibacterial assays and molecular-networking-based analyses. The chemical structures of these compounds were elucidated through the interpretation of nuclear magnetic resonance (NMR) and high-resolution electrospray ionization mass spectrometry (HRESIMS) data. Furthermore, the relative configuration of the compounds was determined using NMR and single-crystal X-ray diffraction analyses, and the absolute configuration was established using electronic circular dichroism calculations. All of the isolated compounds exhibited significant inhibitory activity against Gram-positive bacteria. Notably, compounds 1, 5, and 7 displayed remarkable inhibitory activity against methicillin-resistant Staphylococcus aureus (MRSA) ATCC 700698, with a minimum inhibitory concentration (MIC) of 0.25 µg/mL, and against vancomycin-resistant Enterococcus faecium (VRE) ATCC 700221, with MIC values ranging from 0.5 to 1.0 µg/mL.
Assuntos
Ascomicetos , Staphylococcus aureus Resistente à Meticilina , Plantas Medicinais , Xantonas , Antibacterianos/química , Testes de Sensibilidade Microbiana , Xantonas/farmacologia , Xantonas/química , Estrutura MolecularRESUMO
We designed and synthesized 18 substituted indole derivatives containing a triazole scaffold as novel anti-influenza A virus candidates using a bio-isosteric and scaffold-hopping strategy from the lead compound 4-32-2. Most of the target compounds (eg: 6, 7a, 7d, 7f-j, 7l, 7m, 7o, 7q) exhibited potent anti-influenza A virus activity and low cytotoxicity in vitro. In particular, 7a exhibited the most potent anti-IAV activity (IC50: 1.34 ± 0.13 µM) with low cytotoxicity (CC50: > 100 µM), and high selectivity index (SI: > 74.63), which provides a new chemical scaffold for the development of novel anti-IAV drug.
Assuntos
Vírus da Influenza A , Triazóis , Antivirais/química , Desenho de Fármacos , Indóis/farmacologia , Relação Estrutura-Atividade , Triazóis/farmacologiaRESUMO
Based upon the preliminary design of enhancing genetic barrier to drug-resistant viral mutants by maximizing hydrogen-bonding or other van der Waals contacts, we have designed, synthesized and biologically evaluated a new class of HIV-1 protease inhibitors with phenol derived P2 ligands and nitro or halogens in P2' ligands. Results indicate that a majority of inhibitors exhibit robust enzyme inhibitory with IC50 values in picomolar or single digit nanomolar ranges. Among which, compound 17d displays potency with IC50 value of 21 pM and high protease selectivity. Of note, 17d exhibits greater antiviral activity against the DRV-resistant variant than the efficacy against the wild type virus. Furthermore, the molecular modeling studies demonstrate important interactions between 17d and the active sites of both the wild-type and DRV-resistant HIV-1 protease, as well as furnish insights for further optimization of new inhibitors.
Assuntos
Inibidores da Protease de HIV , HIV-1 , Cristalografia por Raios X , Protease de HIV/química , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacologia , Ligantes , Fenóis/farmacologiaRESUMO
With the increasing prevalence of drug-resistant variants, novel potent HIV-1 protease inhibitors with broad-spectrum antiviral activity against multidrug-resistant causative viruses are urgently needed. Herein, we designed and synthesized a new series of HIV-1 protease inhibitors with phenols or polyphenols as the P2 ligands and a variety of sulfonamide analogs as the P2' ligands. A number of these new inhibitors showed superb enzymatic inhibitory activity and antiviral activity. In particular, inhibitors 15d and 15f exhibited potent enzymatic inhibitory activity in the low picomolar range, and the latter showed excellent activity against the Darunavir-resistant HIV-1 variant. Furthermore, the molecular modeling studies provided insight into the ligand-binding site interactions between inhibitors and the enzyme cavity, and they sparked inspiration for the further optimization of potent inhibitors.
Assuntos
Inibidores da Protease de HIV , HIV-1 , Ligantes , Polifenóis/farmacologia , Fenóis/farmacologia , Inibidores da Protease de HIV/farmacologia , Inibidores da Protease de HIV/químicaRESUMO
Infections caused by antibiotic resistant bacteria are a major health concern throughout the world. It is well known that PFK-158 can enhance the antibacterial effect of polymyxin, but its own anti-bactericidal effect is rarely discussed. In order to investigate the anti-bactericidal effect of PFK-158 and its derivatives, PFK-158 and 35 derivatives were designed, synthesized, and evaluated for their antibacterial activities. Compounds A1, A3, A14, A15 and B6 exhibited potent antibacterial effect against both clinical drug sensitive and resistant Gram-positive bacteria, and they are 2-8 folds more potent than levofloxacin against Methicillin-resistant staphylococcus epidermidis (MRSE). A significant synergistic effect of these compounds and polymyxin against drug-resistant Gram-negative bacteria, which is similar to PFK-158 was also observed. The result can provided a new and broader prospect for the development of new medicine against drug-resistant bacteria.
Assuntos
Antibacterianos/farmacologia , Enterococcus/efeitos dos fármacos , Resistência a Meticilina/efeitos dos fármacos , Piridinas/farmacologia , Quinolinas/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Resistência a Vancomicina/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Quinolinas/síntese química , Quinolinas/química , Relação Estrutura-AtividadeRESUMO
Liver fibrosis is one of the most common pathological consequences of chronic liver diseases (CLD). To develop effective antifibrotic strategies, a novel class of 1-(substituted phenyl)-1,8-naphthalidine-3-carboxamide derivatives were designed and synthesized. By means of the collagen type I α 1 (COL1A1)-based screening and cytotoxicity assay in human hepatic stellate cell (HSC) line LX-2, seven compounds were screened out from total 60 derivatives with high inhibitory effect and relatively low cytotoxicity for further COL1A1 mRNA expression analysis. It was found that compound 17f and 19g dose-dependently inhibited the expression of fibrogenic markers, including α-smooth muscle actin (α-SMA), matrix metalloprotein 2 (MMP-2), connective tissue growth factor (CTGF) and transforming growth factor ß1 (TGFß1) on both mRNA and protein levels. Further mechanism studies indicated that they might suppress the hepatic fibrogenesis via inhibiting both PI3K/AKT/Smad and non-Smad JAK2/STAT3 signaling pathways. Furthermore, 19g administration attenuated hepatic histopathological injury and collagen accumulation, and reduced fibrogenesis-associated protein expression in liver tissues of bile duct ligation (BDL) rats, showing significant antifibrotic effect in vivo. These findings identified 1,8-naphthalidine derivatives as potent anti-hepatic fibrosis agents, and provided valuable information for further structure optimization.
Assuntos
1-Naftilamina/farmacologia , Descoberta de Drogas , Cirrose Hepática/tratamento farmacológico , 1-Naftilamina/síntese química , 1-Naftilamina/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/metabolismo , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Estrutura Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Proteínas Smad/antagonistas & inibidores , Proteínas Smad/metabolismo , Relação Estrutura-AtividadeRESUMO
Four 2,4-disubstituted quinazoline series containing various amide moieties were designed and synthesized as new anti-influenza A virus agents using the strategies of bio-isosterism and scaffold hopping. Many of them exhibit potent in vitro anti-influenza A virus activity and low cytotoxicity (CC50: >100 µM). Particularly, compounds 10a5 and 17a show better activity (IC50: 3.70-4.19 µM) and higher selective index (SI: >27.03, >23.87, respectively) against influenza A/WSN/33 virus (H1N1), opening a new direction for quinazoline derivatives in anti-influenza A virus field.
Assuntos
Antivirais/síntese química , Desenho de Fármacos , Quinazolinas/química , Antivirais/química , Antivirais/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células HEK293 , Humanos , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Quinazolinas/síntese química , Quinazolinas/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of novel HIV-1 protease inhibitors has been designed and synthesized, which contained morpholine derivatives as the P2 ligands and hydrophobic cyclopropyl as the P1' ligand at the meantime in this study, with the aim of improving the interactions between the active sites of HIV-1 protease and the inhibitors. Twenty-eight compounds were synthesized and assessed, among which inhibitors m18 and m1 exhibited excellent inhibitory effect on the activity of HIV-1 protease with IC50 value of 47 nM and 53 nM, respectively. The molecular modeling of m1 revealed possible hydrogen bondings or van der Waals between the inhibitor and the protease, worthy of in-depth study.
Assuntos
Inibidores da Protease de HIV/química , Protease de HIV/metabolismo , Morfolinas/química , Domínio Catalítico , Desenho de Fármacos , Ensaios Enzimáticos , Protease de HIV/química , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/metabolismo , HIV-1/enzimologia , Ligação de Hidrogênio , Simulação de Acoplamento Molecular , Morfolinas/síntese química , Morfolinas/metabolismo , Ligação Proteica , Eletricidade EstáticaRESUMO
In this work, according to the 'me-too me-better' design strategy, a peculiar side chain different from lefamulin at C14 position of pleuromutilin was introduced. A series of novel thioether pleuromutilin derivatives containing cyclohexane in the C14 chain was synthesized by ten-step synthesis reaction. All derivatives were characterized by Nuclear Magnetic Resonance (NMR) and High Resolution Mass Spectrometer (HRMS). Furthermore, majority of derivatives displayed moderate antibacterial activity in vitro. However, the compound 2C and 2J exhibited comparable or superior antibacterial activity to lefamulin. The summarized structure-activity relationship not only made the variety of pleuromutilin derivatives more diverse, but also provided new ideas for its design and development.
Assuntos
Antibacterianos/farmacologia , Diterpenos/farmacologia , Compostos Policíclicos/farmacologia , Antibacterianos/síntese química , Diterpenos/síntese química , Desenho de Fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Compostos Policíclicos/síntese química , Staphylococcus epidermidis/efeitos dos fármacos , Relação Estrutura-Atividade , PleuromutilinasRESUMO
Newly designed HIV-1 protease inhibitors that maximize interactions with the protein backbone, especially in the form of hydrogen bonds, may enhance the antiviral potency of these compounds and minimize acquisition of drug-resistant mutations. Herein, we described a series of new HIV-1 PIs containing phenols as the P2 ligands and chiral isopropanol as the P1' ligands, in combination with 4-trifluoromethylphenylsulfonamide or 4-nitrophenylsulfonamide as the P2' ligands. And most of these compounds exhibited nanomolar inhibitory potency. In particular, inhibitors 13c and 13e with 4-trifluoromethylphenylsulfonamide as the P2' ligand and (R) - isopropanol as the P1' ligand, exhibited antiviral IC50 values of 1.64 nM and 2.33 nM, respectively. Furthermore, they also showed remarkable activity against wild-type and DRV-resistant HIV-1 variants that raised the prospect of designing more effective PIs further.
Assuntos
Desenho de Fármacos , Inibidores da Protease de HIV/química , Inibidores da Protease de HIV/farmacologia , Protease de HIV/metabolismo , HIV-1/efeitos dos fármacos , 2-Propanol/química , 2-Propanol/farmacologia , Células HEK293 , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Protease de HIV/química , HIV-1/enzimologia , Humanos , Ligantes , Fenóis/química , Fenóis/farmacologiaRESUMO
Chronic tissue injury with fibrosis results in the disruption of tissue architecture, organ dysfunction, and eventual organ failure. Therefore, the development of effective antifibrotic drugs is urgently required. IMB-S7 is novel biphenyl compound derived from bifendate (biphenyldicarboxylate) that is used for the treatment of chronic hepatitis in China. In the current study we investigated the potential of IMB-S7 as an antihepatic fibrosis agent. In bile duct ligation (BDL) rat model, oral administration of IMB-S7 (400 mg· kg-1· d-1, for 14 days) significantly ameliorated BDL-induced liver necrosis, bile duct proliferation, and collagen accumulation. We then showed that IMB-S7 treatment markedly suppressed the TGF-ß/Smad pathway in human hepatic stellate cell line LX2 and mouse primary HSCs, as well as in liver samples of BDL rats, thus inhibiting the transcription of most fibrogenesis-associated genes, including TGF-ß1, COL1A1, and ACTA2. Furthermore, IMB-S7 treatment significantly suppressed the expression of integrin αv at the mRNA and protein levels in TGF-ß-treated LX2 cells and liver samples of BDL rats. Using integrin αv overexpression and silencing, we demonstrated that integrin αv activity correlated positively with the activation of TGF-ß/Smad pathway. Based on dual luciferase assay and DNA affinity precipitation assay, we revealed that IMB-S7 inactivated integrin αv through competitively inhibiting the binding of Sp1, a transcription factor, to the integrin αv (ITGAV) promoter (-173/-163 bp). These results suggest that IMB-S7 inhibits HSCs activation and liver fibrosis through Sp1-integrin αv signaling, and IMB-S7 may be a promising candidate to combat hepatic fibrosis in the future.
Assuntos
Compostos de Bifenilo/farmacologia , Integrina alfaV/genética , Cirrose Hepática/tratamento farmacológico , Fator de Transcrição Sp1/antagonistas & inibidores , Animais , Ductos Biliares/cirurgia , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Células Cultivadas , Relação Dose-Resposta a Droga , Humanos , Integrina alfaV/metabolismo , Cirrose Hepática/metabolismo , Cirrose Hepática/cirurgia , Estrutura Molecular , Ratos , Fator de Transcrição Sp1/metabolismo , Relação Estrutura-AtividadeRESUMO
Introducing purine bases to P2-ligands might enhance the potency of Human Immunodeficiency Virus-1 (HIV-1) protease inhibitory because of the carbonyl and NH groups promoting the formation of extensive H-bonding interactions. In this work, thirty-three compounds are synthesized and evaluated, among which inhibitors 16a, 16f and 16j containing N-2-(6-substituted-9H-purin-9-yl)acetamide as the P2-ligands along with 4-methoxylphenylsulfonamide as the P2'-ligand, display potent inhibitory effect on the activity of HIV-1 protease with IC50 43â¯nM, 42â¯nM and 68â¯nM in vitro, respectively.
Assuntos
Inibidores da Protease de HIV/uso terapêutico , Ligantes , Purinas/metabolismo , Inibidores da Protease de HIV/farmacologia , Humanos , Estrutura MolecularRESUMO
The design, synthesis and SAR study of a new series of HIV-1 protease inhibitors with pentacyclic triterpenoids as P2 ligands and phenylsulfonamide as P2' ligands were discussed. These compounds exhibited micromolar inhibitory potency, among which compound T1c displayed HIV-1 protease inhibition with IC50 values of 0.12⯵M, which was 67 times the inhibitory activity of its raw material Ursolic acid (8.0⯵M).
Assuntos
Fármacos Anti-HIV/farmacologia , Desenho de Fármacos , Inibidores da Protease de HIV/farmacologia , Protease de HIV/metabolismo , Triterpenos Pentacíclicos/farmacologia , Sulfonamidas/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Dose-Resposta a Droga , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/química , HIV-1/efeitos dos fármacos , Humanos , Ligantes , Testes de Sensibilidade Microbiana , Estrutura Molecular , Triterpenos Pentacíclicos/síntese química , Triterpenos Pentacíclicos/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/químicaRESUMO
A series of novel (E)-4-oxo-2-crotonamide derivatives were designed and synthesized to find potent antituberculosis agents. All the target compounds were evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv(MTB). Results reveal that 4-phenyl moiety at part A and short methyl group at part C were found to be favorable. Most of the derivatives displayed promising activity against MTB with MIC ranging from 0.125 to 4⯵g/mL. Especially, compound IIIa16 was found to have the best activity with MIC of 0.125⯵g/mL against MTB and with MIC in the range of 0.05-0.48⯵g/mL against drug-resistant clinical MTB isolates.
Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Crotonatos/farmacologia , Desenho de Fármacos , Amidas/química , Antituberculosos/síntese química , Crotonatos/química , Avaliação Pré-Clínica de Medicamentos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
The manipulation of bile acid (BA) homeostasis by blocking the ileal apical Na+-dependent bile salt transporter (ASBT/SLC10A2) may have therapeutic effects in nonalcoholic fatty liver disease. We developed a novel ASBT inhibitor, an N-(3,4-o-dichlorophenyl)-2-(3-trifluoromethoxy) benzamide derivative referred to as IMB17-15, and investigated its therapeutic effects and the molecular mechanisms underlying the effects. Syrian golden hamsters were challenged with high-fat diet (HFD) to induce NAFLD and were subsequently administered 400 mg/kg IMB17-15 by gavage daily for 21 days. Serum, liver, and fecal samples were collected for further analysis. Plasma concentration-time profiles of IMB17-15 were also constructed. The human hepatocyte cell line HL-7702 was treated with Oleic acid (OA) with or without IMB17-15. Western blotting and real-time PCR were used to study the molecular mechanisms of IMB17-15. We found that IMB17-15 inhibited ASBT and subsequently suppressed ileal farnesoid X receptor (FXR) and FXR-activated fibroblast growth factor15/19 (FGF15/19) expression, which reduced the hepatic phosphorylated extracellular regulated protein kinase (ERK) and c-Jun N-terminal kinase (JNK) levels and upregulated the cholesterol 7α-hydroxylase (CYP7A1) activity. Additionally, IMB17-15 stimulated adenosine monophosphate (AMP)-activated protein kinase (AMPKα) phosphorylation and enhanced peroxisome proliferator activated receptor α (PPARα) expression and thus promoted triglyceride (TG) oxidation and high-density lipoprotein cholesterol (HDL-c) metabolism through an ASBT-independent mechanism. In conclusion, a novel ASBT inhibitor known as IMB17-15 protected hamsters against HFD-induced NFALD by manipulating BA and lipid homeostasis. IMB17-15 also reduced lipid deposition in human hepatic cell lines, indicating that it may be useful as a therapy for NAFLD patients.
Assuntos
Benzamidas/uso terapêutico , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Sulfonamidas/uso terapêutico , Simportadores/antagonistas & inibidores , Animais , Benzamidas/farmacocinética , Benzamidas/toxicidade , Linhagem Celular , Citocinas/metabolismo , Dieta Hiperlipídica , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Fígado/patologia , Masculino , Mesocricetus , Camundongos , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Sulfonamidas/farmacocinética , Sulfonamidas/toxicidadeRESUMO
A new series of (sulfonamido)propanamides (6a1-6a13, 6b1-6b15, 7c1-7c5, 6d1-6d5, 6e1-6e6) was designed and synthesized. All the synthesized compounds were characterized by NMR and mass spectrometry. The target compounds were evaluated for their inâ vitro cytotoxic activity against hepatocellular carcinoma (HepG2), fibrosarcoma (HT-1080), mouth epidermal carcinoma (KB), and breast adenocarcinoma (MCF-7) cell lines with the sulforhodamine B (SRB) assay, with gemcitabine and mitomycin C as positive controls. Most of these compounds exhibit a more potent cytotoxic effect than the positive control group on various cancer cell lines and the most potent compound, 6a7, shows the IC50 values of 29.78±0.516â µm, 30.70±0.61â µm, and 64.89±3.09â µm in HepG2, HT-1080, KB, and MCF-7â cell lines, respectively. Thus, these compounds with potent cytotoxic activity have potential for development as new chemotherapy agents.
Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Propionatos/farmacologia , Sulfonamidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Propionatos/síntese química , Propionatos/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/químicaRESUMO
Influenza A virus (IAV), a highly pathogenic virus to human beings, is most susceptible to mutation and thus causes rapid, severe global pandemics resulting in millions of fatalities worldwide. Since resistance to the existing anti-influenza drugs is developing, innovative inhibitors with a different mode of action are urgently needed. The lead compound 6092B-E5 has proven to be an effective antiviral reagent in our previous work. Using the principles of substitution and bioisosterism of the indole ring, six series of novel anti-IAV target products were designed, synthesized and evaluated for their antiviral effect in this work. Compounds D1 , D3 , D9 , G1 , G3 , G12 and G23 were identified as promising anti-IAV candidates with excellent anti-IAV efficacy (IC50 values of 3.06-5.77â µm) and low cytotoxicity (CC50 values up to and beyond 100â µm). This work represents a successful application of the substitution and bioisosteric replacement strategy for the discovery of novel antiviral molecules that can be used for further structural optimization.
Assuntos
Antivirais/química , Indóis/química , Vírus da Influenza A/efeitos dos fármacos , Antivirais/farmacologia , Desenho de Fármacos , Humanos , Indóis/síntese química , Indóis/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of novel thioether or sulfoxide-type pleuromutilin derivatives containing heteroaromatic substituents at the end of C14 side chain were designed and synthesized. All of the derivatives were evaluated for their inâ vitro antibacterial activity. Some of them showed good to excellent antibacterial activity comparable to retapamulin and azamulin in most of the tested Gram-positive pathogens. In this work, a five-membered heterocyclic moiety, a pyrimidine-heterocyclic moiety, or a benzoheterocyclic moiety was introduced in the C14 side chain to increase the structural diversity of the pleuromutilin derivatives. The antibacterial results reveal that the thioether-containing pleuromutilin derivatives exert a more potency activity than the sulfoxide-type derivatives against Gram-positive pathogens. The structure-activity relationship summarized in this work may provide with some interesting clues as to which functionalities are beneficial for high antimicrobial activity of the pleuromutilin derivatives.