RESUMEN
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.
Asunto(s)
Bencenoacetamidas , Inhibidores de la Proteasa del VIH , VIH-1 , Darunavir/metabolismo , Darunavir/farmacología , VIH-1/genética , Simulación del Acoplamiento Molecular , Ligandos , Proteasa del VIH/metabolismo , Sulfonamidas/química , Diseño de Fármacos , Cristalografía por Rayos X , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Ascomicetos , Staphylococcus aureus Resistente a Meticilina , Plantas Medicinales , Xantonas , Antibacterianos/química , Pruebas de Sensibilidad Microbiana , Xantonas/farmacología , Xantonas/química , Estructura MolecularRESUMEN
There are six new phthalide derivatives Verbalide A ~ F (1-6) together with another known derivative (7) isolated from the endophytic fungus Preussia sp. CPCC 400972. Their structures were established by comprehensive spectroscopic analyses, including NMR and HRESIMS. In addition, compounds 1-7 exhibited excellent inhibitory effect against influenza A virus.
Asunto(s)
Ascomicetos , Benzofuranos , Estructura Molecular , Ascomicetos/química , Benzofuranos/farmacología , Benzofuranos/química , Espectroscopía de Resonancia MagnéticaRESUMEN
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.
Asunto(s)
Antifibróticos , Benceno , Humanos , Derivados del Benceno , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/metabolismo , Sulfonamidas/farmacología , Relación Estructura-ActividadRESUMEN
The design, synthesis, and biological evaluation of a novel series of HIV-1 protease inhibitors containing pyrrolidines with diverse linkers as the P2 ligands and various aromatic derivatives as the P2' ligands were described. A number of inhibitors demonstrated potent efficacy in both enzyme and cellular assays, as well as relatively low cytotoxicity. In particular, inhibitor 34b with a (R)-pyrrolidine-3-carboxamide P2 ligand and a 4-hydroxyphenyl P2' ligand displayed exceptional enzyme inhibitory activity with an IC50 value of 0.32 nM. Furthermore, 34b also exhibited robust antiviral activity against both wild-type HIV-1 and drug-resistant variant with low micromolar EC50 values. In addition, the molecular modelling studies revealed the extensive interactions between inhibitor 34b and the backbone residues of both wild-type and drug-resistant HIV-1 protease. These results suggested the feasibility of utilizing pyrrolidine derivatives as the P2 ligands and provided valuable information for further design and optimization of highly potent HIV-1 protease inhibitors.
Asunto(s)
Inhibidores de la Proteasa del VIH , VIH-1 , Relación Estructura-Actividad , Ligandos , Cristalografía por Rayos X , Pirrolidinas/farmacología , Proteasa del VIH/metabolismo , Diseño de FármacosRESUMEN
The development of dual inhibitors of HIV-1 protease and reverse transcriptase is an attractive strategy for multi-target therapeutic of AIDS, which may be privileged in delaying the occurrence of drug resistance. We herein designed a novel kind of dual inhibitors with benzofuran or indole cores. Biological results showed that a number of inhibitors displayed significant activity against both HIV-1 protease and reverse transcriptase. Among which, inhibitor 10f exhibited a good correlation with an approximate ratio of 1: 2 between the two enzymes. Furthermore, the dual inhibitors illustrated similar potency against both the wild-type virus and drug-resistant mutant. In addition, the molecular dynamic simulation studies verified the dual actions of such inhibitors.
Asunto(s)
Fármacos Anti-VIH , Inhibidores de la Proteasa del VIH , Inhibidores de la Transcriptasa Inversa/farmacología , Inhibidores de la Transcriptasa Inversa/química , Fármacos Anti-VIH/farmacología , Proteasa del VIH , ADN Polimerasa Dirigida por ARN , Transcriptasa Inversa del VIH , Inhibidores de la Proteasa del VIH/farmacología , Inhibidores de la Proteasa del VIH/químicaRESUMEN
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.
Asunto(s)
Inhibidores de la Proteasa del VIH , VIH-1 , Ligandos , Polifenoles/farmacología , Fenoles/farmacología , Inhibidores de la Proteasa del VIH/farmacología , Inhibidores de la Proteasa del VIH/químicaRESUMEN
By harnessing the payload DM1 and a monoclonal antibody LR004 through a noncleavable linker succinimidyl-4-(N-maleimidomethyl)-cyclohexane-1-carboxylate, we designed and evaluated an antibody-drug conjugate LR-DM1 with an appropriate drug-antibody ratio of 3.6. LR-DM1, which was targeted toward the epidermal growth factor receptor for pancreatic cancer, exhibited potent antiproliferation activity in vitro with a half-maximal inhibitory concentration value of 7.03 nM for Capan-2 cells. Particularly, it displayed prominent tumor growth inhibition in vivo under 20 mg/kg LR-DM1 dosage in a single administration or multiple administrations without apparent abnormality of pathological observation. Moreover, LR-DM1 possessed a relatively broad therapeutic index with a half-lethal dose above 300 mg/kg, which was over 15-fold higher than the highest administration dosage of 20 mg/kg. This initial study on LR-DM1 holds promise for further development of a new antibody drug conjugate that is transformative for treatment of patients concerned.
Asunto(s)
Neoplasias de la Mama , Inmunoconjugados , Maitansina , Neoplasias Pancreáticas , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Receptores ErbB/metabolismo , Femenino , Humanos , Inmunoconjugados/farmacología , Inmunoconjugados/uso terapéutico , Maitansina/farmacología , Maitansina/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Receptor ErbB-2 , Trastuzumab , Neoplasias PancreáticasRESUMEN
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.
Asunto(s)
Inhibidores de la Proteasa del VIH , VIH-1 , Cristalografía por Rayos X , Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/farmacología , Ligandos , Fenoles/farmacologíaRESUMEN
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.
Asunto(s)
Virus de la Influenza A , Triazoles , Antivirales/química , Diseño de Fármacos , Indoles/farmacología , Relación Estructura-Actividad , Triazoles/farmacologíaRESUMEN
By following up on the design vector of optimizing amine-based HIV-1 protease inhibitors, we have designed and biologically evaluated a novel class of inhibitors with the free nitrogen or sulphone in morpholine cores as P2 ligands in combination with diverse substituted phenylsulfonamide P2' ligands. As it turns out, a majority of these inhibitors exhibit prominent enzymatic inhibitory activity in low nanomolar ranges with relatively low cytotoxicity. Particularly, inhibitor 1e containing a morpholine carboxamide P2 ligand and a 4-hydroxyphenylsulfonamide P2' ligand illustrates a robust enzyme inhibitory IC50 value of 90 pM. Furthermore, 1e demonstrates impressive in vivo antiviral activity with EC50 value of 89 nM and a degree of inhibitory potency against the DRV-resistant variant. More importantly, 1e exhibits remarkable activity with EC50 values of 13.59 nM and 8.23 nM against subtype C HIV-1 strains ZM246 and Indie, respectively. Furthermore, the in silico studies provide molecular insights into binding features of inhibitors with HIV-1 protease, and furnish a valuable forecast on further process.
Asunto(s)
Inhibidores de la Proteasa del VIH , VIH-1 , Cristalografía por Rayos X , Diseño de Fármacos , Proteasa del VIH/metabolismo , Ligandos , Morfolinas , Relación Estructura-ActividadRESUMEN
BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder diagnosed during adolescence and adulthood. Assessment of the long-term risks of the current drugs for ADHD treatment has been insufficient, and little is known concerning the long-term therapeutic effects of psychostimulants. Commercially available traditional Chinese medicine compound oral preparations [e.g., Dimu Ningshen (DMNS)] have been widely used in the clinical treatment of ADHD, but their influence on the interaction between gut microbes and potential metabolomes remains inconclusive. METHODS: We used a series of behavioral experiments to evaluate the behavioral effects of DMNS on adolescent and adult ADHD rats and used 16S rDNA sequencing of gut microbes and nontarget metabolomics to evaluate the potential pathogenesis of ADHD and explore the biological mechanism of DMNS in ADHD treatment. RESULTS: For the first time, DMNS was shown to reduce the excessive activity of adult and adolescent ADHD rats and improve the attention deficit of adult ADHD rats. DMNS improved the structural composition of the ADHD gut microbiota and reduced the abundance of Ruminococcaceae_NK4A214_group, Ruminococcus_2, and Eubacterium_nodatum_group. Simultaneously, DMNS increased the circulating levels of peripheral monoamine neurotransmitter precursors (e.g., phenylalanine) and reduced the circulating levels of peripheral fatty acid amides (e.g., oleamide). Finally, the changes in the ADHD serum metabolites were strongly correlated with the gut microbiota. CONCLUSION: DMNS has a good effect in treating ADHD, and it may exert this effect by regulating the gut microbiota and affecting metabolites in the peripheral circulation.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Animales , Modelos Animales de Enfermedad , Medicamentos Herbarios Chinos/uso terapéutico , Microbioma Gastrointestinal/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Metabolómica , Fitoterapia , Distribución Aleatoria , Ratas , Ratas Endogámicas SHR , Ratas Sprague-Dawley , Organismos Libres de Patógenos EspecíficosRESUMEN
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.
Asunto(s)
1-Naftilamina/farmacología , Descubrimiento de Drogas , Cirrosis Hepática/tratamiento farmacológico , 1-Naftilamina/síntesis química , 1-Naftilamina/química , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Humanos , Janus Quinasa 2/antagonistas & inhibidores , Janus Quinasa 2/metabolismo , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Estructura Molecular , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/metabolismo , Proteínas Smad/antagonistas & inhibidores , Proteínas Smad/metabolismo , Relación Estructura-ActividadRESUMEN
The emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the global pandemic coronavirus disease (COVID-19), but no specific antiviral drug has been proven effective for controlling this pandemic to date. In this study, several 2-((indol-3-yl)thio)-N-benzyl-acetamides were identified as SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) inhibitors. After a two-round optimization, a new series of 2-((indol-3-yl)thio)-N-benzyl-acetamides was designed, synthesized, and evaluated for SARS-CoV-2 RdRp inhibitory effect. Compounds 6b2, 6b5, 6c9, 6d2, and 6d5 were identified as potent inhibitors with IC50 values of 3.35 ± 0.21 µM, 4.55 ± 0.2 µM, 1.65 ± 0.05 µM, 3.76 ± 0.79 µM, and 1.11 ± 0.05 µM, respectively; the IC50 of remdesivir (control) was measured as 1.19 ± 0.36 µM. All of the compounds inhibited RNA synthesis by SARS-CoV-2 RdRp. The most potent compound 6d5, which showed a stronger inhibitory activity against the human coronavirus HCoV-OC43 than remdesivir, is a promising candidate for further investigation.
Asunto(s)
Acetamidas/síntesis química , Antivirales/síntesis química , Tratamiento Farmacológico de COVID-19 , Inhibidores Enzimáticos/síntesis química , ARN Viral/antagonistas & inhibidores , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , SARS-CoV-2/efectos de los fármacos , Acetamidas/farmacología , Adenosina Monofosfato/análogos & derivados , Adenosina Monofosfato/farmacología , Adenosina Monofosfato/normas , Alanina/análogos & derivados , Alanina/farmacología , Alanina/normas , Antivirales/farmacología , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Simulación del Acoplamiento Molecular , Estructura Molecular , Unión Proteica , SARS-CoV-2/genética , Relación Estructura-ActividadRESUMEN
Upon the basis of both possible ligand-binding site interactions and the uniformity of key residues in active sites, a novel class of HIV-1 PR/RT dual inhibitors was designed and evaluated. Cinnamic acids or phenylpropionic acids with more flexible chain and smaller steric hindrance were introduced into the inhibitors, giving rise to significant improvement in HIV-1 RT inhibitory activity by one or two orders of magnitude, with comparable or even improved potency against PR at the same time, compared with coumarin anologues in our previous studies. Among these inhibitors, 38d displayed a 19-fold improvement in anti-PR activity with IC50 value of 0.081 nM compared to the control DRV. In addition, inhibitor 38c exhibited an excellent anti-RT IC50 value of 0.43 µM, only a 4.7-fold less potent activity than the control EFV. More significantly, the disparate ratio between HIV-1 PR and RT inhibition became more reasonable with ratio of 1: 10.4, just as 37b. Furthermore, the assays on HIV-1 late stage and early stage supported the rationality of designing dual inhibitors. The SAR data as well as molecular modeling studies provided new insight for further optimization of more potent HIV-1 PR/RT dual inhibitors.
Asunto(s)
Amidas/farmacología , Fármacos Anti-VIH/farmacología , Cinamatos/farmacología , Inhibidores de la Proteasa del VIH/farmacología , Fenilpropionatos/farmacología , Inhibidores de la Transcriptasa Inversa/farmacología , Amidas/síntesis química , Amidas/química , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Cinamatos/síntesis química , Cinamatos/química , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Proteasa del VIH/metabolismo , Inhibidores de la Proteasa del VIH/síntesis química , Inhibidores de la Proteasa del VIH/química , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Transcriptasa Inversa del VIH/metabolismo , VIH-1/efectos de los fármacos , VIH-1/enzimología , Pruebas de Sensibilidad Microbiana , Modelos Moleculares , Estructura Molecular , Fenilpropionatos/síntesis química , Fenilpropionatos/química , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/química , Relación Estructura-ActividadRESUMEN
A novel class of HIV-1 protease inhibitors with flexible piperidine as the P2 ligand was designed with the aim of improving extensive interactions with the active subsites. Many inhibitors exhibited good to excellent inhibitory effect on enzymatic activity and viral infectivity. In particular, inhibitor 3a with (R)-piperidine-3-carboxamide as the P2 ligand and 4-methoxybenzenesulfonamide as the P2' ligand showed an enzyme Ki value of 29 pM and antiviral IC50 value of 0.13 nM, more than six-fold enhancement of activity compared to DRV. Furthermore, there was no significant change in potency against DRV-resistant mutations and HIV-1NL4-3 variant for 3a. Besides, inhibitor 3a exhibited potent antiviral activity against subtype C variants with low nanomole EC50 values. In addition, the molecular modeling revealed important hydrogen bonds and other favorable van der Waals interactions with the backbone atoms of the protease and provided insight for designing and optimizing more potent HIV-1 protease inhibitors.
Asunto(s)
Fármacos Anti-VIH/farmacología , Diseño de Fármacos , Inhibidores de la Proteasa del VIH/farmacología , Proteasa del VIH/metabolismo , VIH-1/efectos de los fármacos , Piperidinas/farmacología , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Darunavir/farmacología , Relación Dosis-Respuesta a Droga , Farmacorresistencia Viral/efectos de los fármacos , Inhibidores de la Proteasa del VIH/síntesis química , Inhibidores de la Proteasa del VIH/química , VIH-1/enzimología , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antibacterianos/farmacología , Enterococcus/efectos de los fármacos , Resistencia a la Meticilina/efectos de los fármacos , Piridinas/farmacología , Quinolinas/farmacología , Staphylococcus aureus/efectos de los fármacos , Resistencia a la Vancomicina/efectos de los fármacos , Antibacterianos/síntesis química , Antibacterianos/química , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Piridinas/síntesis química , Piridinas/química , Quinolinas/síntesis química , Quinolinas/química , Relación Estructura-ActividadRESUMEN
We report herein the synthesis of a series of novel quinoline derivatives, based on the lead compound 1a, identified from a rRSV-mGFP high-throughput screening assay. Our results revealed that target compounds 1b, 1g-h, 1af and 1ah (IC50 = 3.10-6.93 µM) had good in vitro activity against RSV, which were better than 1a and ribavirin. In addition, we found that compound 1g displayed the lower cytotoxicity (CC50: 2490.33 µM) and the highest selective index (SI = 673.06), suggesting its promising potential as a candidate for further development. On the other hand, compounds 1a, 1m, 1v, 1ad-1af and 1ah-1ai (IC50s: 1.87-14.28 µM) were more active against IAV than or comparable to ribavirin (IC50: 15.36 ± 0.93 µM). Particularly, the most active compound 1ae (IC50: 1.87 ± 0.58 µM) was found to be 8.2-fold more potent than the reference drug, which could inhibit the virus transcription and replication cycle at an early stage.
Asunto(s)
Antivirales/farmacología , Virus de la Influenza A/efectos de los fármacos , Quinolinas/farmacología , Virus Sincitiales Respiratorios/efectos de los fármacos , Antivirales/síntesis química , Antivirales/química , Línea Celular , Relación Dosis-Respuesta a Droga , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Quinolinas/síntesis química , Quinolinas/química , Relación Estructura-ActividadRESUMEN
It is an urgent need to develop more effective anti-influenza agents due to the emergence of highly pathogenic and drug-resistant influenza viruses. Herein, a series of 2,4-disubstituted quinazoline derivatives were designed, synthesized and their antiviral activities against influenza A virus were evaluated. Nine compounds (10a2, 16a, 16e, 16i, 16j, 16n, 16o, 16p and 16r) showed potent activity against influenza A virus (IAV) with IC50 at the low-micromole level (1.29-9.04 µM). Particularly, 16e and 16r possess good anti-IAV activity (IC50: 1.29 µM and 3.43 µM, respectively) and acceptable cytotoxicity, and inhibit the transcription and replication of viral RNA. Together with reasonable PK profiles of 16e, these results suggest their promising potential as candidates for further investigation.
Asunto(s)
Acetamidas/química , Antivirales/síntesis química , Antivirales/farmacología , Diseño de Fármacos , Virus de la Influenza A/efectos de los fármacos , Quinazolinas/síntesis química , Quinazolinas/farmacología , Antivirales/química , Técnicas de Química Sintética , Farmacorresistencia Viral/efectos de los fármacos , Virus de la Influenza A/genética , Virus de la Influenza A/fisiología , Quinazolinas/química , ARN Viral/genética , Transcripción Genética/efectos de los fármacos , Replicación Viral/efectos de los fármacosRESUMEN
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.