Molecular design and evaluation of aza-polycyclic carbamoyl pyridones as HIV-1 integrase strand transfer inhibitors.

Integrase strand transfer inhibitors (INSTIs) are the most prescribed anchor drug in antiretroviral therapy. Today, there is an increasing need for long-acting treatment of HIV-1 infection. Improving drug pharmacokinetics and anti-HIV-1 activity are key to developing more robust inhibitors suitable for long-acting formulations, but 2nd-generation INSTIs have chiral centers, making it difficult to conduct further exploration. In this study, we designed aza-tricyclic and aza-bicyclic carbamoyl pyridone scaffolds which are devoid of the problematic hemiaminal stereocenter present in dolutegravir (DTG). This scaffold hopping made it easy to introduce several substituents, and evolving structure-activity studies using these scaffolds resulted in several leads with promising properties.

Synthetic Methods for Azaheterocyclic Phosphonates and Their Biological Activity: An Update 2004-2024.

The increasing importance of azaheterocyclic phosphonates in the agrochemical, synthetic, and medicinal field has provoked an intense search in the development of synthetic routes for obtaining novel members of this family of compounds. This updated review covers methodologies established since 2004, focusing on the synthesis of azaheterocyclic phosphonates, of which the phosphonate moiety is directly substituted onto to the azaheterocyclic structure. Emphasizing recent advances, this review classifies newly developed synthetic approaches according to the ring size and providing information on biological activities whenever available. Furthermore, this review summarizes information on various methods for the formation of C-P bonds, examining sustainable approaches such as the Michaelis-Arbuzov reaction, the Michaelis-Becker reaction, the Pudovik reaction, the Hirao coupling, and the Kabachnik-Fields reaction. After analyzing the biological activities and applications of azaheterocyclic phosphonates investigated in recent years, a predominant focus on the evaluation of these compounds as anticancer agents is evident. Furthermore, emerging applications underline the versatility and potential of these compounds, highlighting the need for continued research on synthetic methods to expand this interesting family.

Discovery of Novel Azaindoles as Potent and Selective PI3Kδ Inhibitors for Treatment of Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system and the unmet need for MS treatment demands new therapeutic development. Particularly, PI3Kδ is a high-value target for autoimmune disease, while the investigation of PI3Kδ inhibitors for MS therapy is relatively scarce. Herein, we report a novel class of azaindoles as PI3Kδ inhibitors for MS treatment. Compound 31, designed via nitrogen bioisosterism, displayed excellent PI3Kδ inhibitory activity and selectivity. In vitro assay showed that 31 exhibited superior activity on T lymphocytes to inhibit the proliferation of CD4+, CD8+, and CD3+ T cells. In the experimental autoimmune encephalomyelitis (EAE) model, 31 showed a comparable therapeutical efficacy with Dexamethasone to significantly ameliorate EAE symptoms. Mechanistic studies showed that compound 31 could significantly inhibit the PI3K/AKT/mTOR signaling pathway and inhibited T-cell proliferation and differentiation. Overall, this work provides a new structural PI3Kδ inhibitor and a new vision for MS therapy.

Coumarin-azasugar-benzyl conjugates as non-neurotoxic dual inhibitors of butyrylcholinesterase and cancer cell growth.

We have applied the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction to prepare a library of ten coumarin-azasugar-benzyl conjugates and two phthalimide-azasugar-benzyl conjugates with potential anti-Alzheimer and anti-cancer properties. The compounds were evaluated as cholinesterase inhibitors, demonstrating a general preference, of up to 676-fold, for the inhibition of butyrylcholinesterase (BuChE) over acetylcholinesterase (AChE). Nine of the compounds behaved as stronger BuChE inhibitors than galantamine, one of the few drugs in clinical use against Alzheimer's disease. The most potent BuChE inhibitor (IC50 = 74 nM) was found to exhibit dual activities, as it also showed high activity (GI50 = 5.6 ± 1.1 µM) for inhibiting the growth of WiDr (colon cancer cells). In vitro studies on this dual-activity compound on Cerebellar Granule Neurons (CGNs) demonstrated that it displays no neurotoxicity.

Streptococcus pneumoniae: sensibilidade a penicilina e moxifloxacina / Streptococcus pneumoniae: susceptibility to penicillin and moxifloxacin

OBJETIVO: Determinar a concentração inibitória mínima (CIM) de penicilina parenteral e moxifloxacina contra cepas de Streptococcus pneumoniae isoladas em um centro hospitalar. Métodos: Estudo in vitro prospectivo de 100 isolados de S. pneumoniae coletados de pacientes tratados entre outubro de 2008 e julho de 2010 no complexo do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, em São Paulo (SP). Os isolados foram obtidos de culturas do trato respiratório e de amostras de sangue não relacionadas a infecções meníngeas e foram testados quanto à suscetibilidade a penicilina e moxifloxacina por E test. As interpretações categóricas de CIM foram baseadas em padrões atualizados. RESULTADOS: Todos os isolados foram suscetíveis a penicilina parenteral (CIM < 2 µg/mL) e, consequentemente, eram também suscetíveis a amoxicilina, ampicilina, cefalosporinas de terceira e quarta geração e ertapenem. Quanto à moxifloxacina, 99 por cento das cepas de S. pneumoniae também foram suscetíveis, e somente uma teve CIM = 1,5 µg/mL (intermediário). Conclusões: Nossos resultados mostraram altas taxas de sensibilidade a penicilina parenteral e moxifloxacin nos isolados de S. pneumoniae não relacionados a meningite, o que difere de relatos internacionais. Relatos sobre resistência a penicilina devem ser baseados em pontos de corte atualizados para isolados não relacionados a meningite a fim de guiar a escolha terapêutica antimicrobiana e melhorar a predição dos desfechos clínicos.

OBJECTIVE: To determine the minimum inhibitory concentrations (MICs) of parenteral penicillin and moxifloxacin against Streptococcus pneumoniae strains isolated at a hospital center. METHODS: In-vitro, prospective study involving 100 S. pneumoniae isolates collected from patients who had been treated, between October of 2008 and July of 2010, at the Hospital das Clínicas complex of the University of São Paulo School of Medicine, located in the city of São Paulo, Brazil. The isolates were obtained from respiratory tract cultures or blood samples unrelated to meningeal infections, and they were tested for penicillin and moxifloxacin susceptibility by E-test. The MIC category interpretations were based on updated standards. RESULTS: All isolates were fully susceptible to parenteral penicillin (MIC < 2 µg/mL), and, consequently, they were also susceptible to amoxicillin, ampicillin, third/fourth generation cephalosporins, and ertapenem. Of the S. pneumoniae strains, 99 percent were also susceptible to moxifloxacin, and only one strain showed an MIC = 1.5 µg/mL (intermediate). CONCLUSIONS: Our results showed high susceptibility rates to parenteral penicillin and moxifloxacin among S. pneumoniae isolates unrelated to meningitis, which differs from international reports. Reports on penicillin resistance should be based on updated breakpoints for non-meningitis isolates in order to guide the selection of an antimicrobial therapy and to improve the prediction of the clinical outcomes.

Fluoroquinolone susceptibilities to methicillin-resistant and susceptible coagulase-negative Staphylococcus isolated from eye infection

PURPOSE: To evaluate the fluoroquinolone susceptibilities of ocular isolate coagulase-negative staphylococci (CoNS), identified at the Microbiology Laboratory - UNIFESP. DESIGN: Experimental laboratory investigation. METHODS: The minimum inhibitory concentrations (MICs) of 21 strains of methicillin-resistant coagulase-negative staphylococci (MRCoNS) and 22 methicillin-sensitive coagulase-negative staphylococci (MSCoNS) to ciprofloxacin, ofloxacin, gatifloxacin and moxifloxacin were determined, using the E-test method standardized by the Clinical and Laboratory Standards Institute (CLSI/NCCLS). RESULTS: The MIC90s (µg/ml) for the second generation of tested fluoroquinolones were higher than the fourth generation, especially for the methicillin-resistant coagulase-negative staphylococci group. CONCLUSION: Our results indicate that methicillin-sensitive coagulase-negative staphylococci are more susceptible to quinolones than are methicillin-resistant coagulase-negative staphylococci and that fourth generation fluoroquinolones appear to be more potent, affecting even coagulase-negative staphylococcal strains resistant to second generation fluoroquinolones.

OBJETIVOS: Avaliar a suscetibilidade a fluorquinolonas dos Staphylococcus coagulase-negativo (SCoN) identificados no Laboratório de Microbiologia Ocular da Unifesp. MÉTODOS: Foi determinada a concentração inibitória mínima de 21 cepas de SCoN meticilina-resistentes e 22 meticilina-sensíveis para ciprofloxacina, ofloxacina, gatifloxacina e moxifloxacina, utilizando o E-test estandartizado pelo CLSI/NCCLS. RESULTADOS: Os MIC90 (µg/ml) de 43 SCoN isolados para fluorquinolonas de segunda geração foram maiores do que os de quarta geração, principalmente para o grupo dos meticilina-resistentes. CONCLUSÃO: Nossos resultados indicam que Staphylococcus coagulase-negativo meticilina-sensíveis são mais suscetíveis às quinolonas do que os Staphylococcus coagulase-negativo meticilina-resistentes, fluorquinolonas de quarta geração parecem ser mais potentes, cobrindo inclusive cepas de Staphylococcus coagulase-negativo resistentes à segunda geração de fluorquinolonas.

In vitro activity of fluoroquinolones against common respiratory pathogens / La actividad in vitro de las fluorquinolonas contra los patógenos respiratorios

The treatment of respiratory infections is often empiric, necessitating the use of agents with a broad range of antimicrobial activity. The fluoroquinolones, having activity against common respiratory pathogens, fit this description. New fluoroquinolones have been developed in an attempt to improve the in vitro activity against a wide variety of respiratory tract pathogens. The objective of the study is to compare in vitro activity of newest fluoroquinolones, gatifloxacin and moxifloxacin, with levofloxacin and ciprofloxacin using three major respiratory pathogens, Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. Minimum inhibitory concentrations (MICs) of four fluoroquinolones were tested against 93 S pneumoniae, 62 H influenzae and 60 M catarrhalis, ie 215 isolates by the E-test method. National Committee for Clinical Laboratory Standards (NCCLS)-approved interpretive criteria were used throughout. All isolates were susceptible to the tested fluoro-quinolones. Ninety per cent of S pneumoniae strains were inhibited by ciprofloxacin at concentrations of 2 mg/L. The gatifloxacin and moxifloxacin MICs were lower than the ciprofloxacin and levofloxacin MICs against S pneumoniae. In contrast to S pneumoniae, in vitro activities of gatifloxacin and moxifloxacin offered no apparent advantages over ciprofloxacin and levofloxacin for H influenzae and M catarrhalis.

La terapia de las infecciones respiratorias es a menudo empírica, y exige por ende el uso de agentes con un amplio espectro de actividad antimicrobiana. Por su actividad contra los patógenos respiratorios comunes, las fluorquinolonas se ajustan a esta descripción. Nuevas fluorquinolonas han sido desarrolladas, en un intento por mejorar la actividad in vitro contra una variedad de patógenos de las vías respiratorias. El objetivo de este estudio es comparar la actividad in vitro de las fluorquinolonas más recientes – la gatifloxacina y la moxifloxacina – con la levofloxacina y la ciprofloxacina, usando tres de los más importantes patógenos respiratorios: Streptococcus pneumoniae, Haemophilus influenzae y Moraxella catarrhalis. Las concentraciones inhibitorias mínimas (CIMs) de las cuatro fluorquinolonas fueron sometidas a prueba contra 93 S pneumoniae, 62 H influenzae y 60 M catarrhalis, para un total de 215 aislados mediante el método de E-test. En todos los casos se aplicaron criterios interpretativos aprobados por el Comité Nacional para Normas del Laboratorio Clínico (NCCLS). Todos los aislados resultaron sensibles a las fluorquinolonas ensayadas. El noventa por ciento de las cepas de S pneumoniae fueron inhibidas por la ciprofloxacina a concentrationes of 2 mg/L. Las CIMs de la gatifloxacina y la moxifloxacina fueron más bajas que las CIMs de la ciprofloxacina y la levofloxacina contra S pneumoniae. En contraste con S pneumoniae, la actividad in vitro de la gatifloxacina y la moxifloxacina no ofrecieron ventajas aparentes por encima de la ciprofloxacina y la levofloxacina frente a H influenzae y M catarrhalis.

Actividad de las fluoroquinolonas en aislamientos clínicos de Streptococcus pneumoniae con diferente susceptibilidad a la penicilina: Estudio epidemiológico en cinco ciudades de la República Mexicana / Flouroquinolone activity in clinical isolates of Streptococcus pneumoniae with different susceptibility to penicilline: An epidemiological study in five cities of Mexico

Objetivo: Determinar el grado de sensibilidad a cinco fluoroquinolonas, y la resistencia cruzada, en aislados clínicos de neumococo con diferente susceptibilidad a la penicilina Diseño: Estudio transversal Lugar: Los aislamientos de Streptococcus pneumoniae (Sp) se obtuvieron en cinco centros de atención médica y en un laboratorio de referencia de cinco ciudades de la República Mexicana, durante febrero de 1999 a mayo del 2000. Material: 231 aislamientos de Sp obtenidos de muestras de secreción de la vía aérea o sangre, de 231 pacientes con infección respiratoria aguda o bacteriemia adquiridas en la comunidad. Mediciones: Se midió la susceptibilidad in vitro a penicilina (PEN), ciprofloxacina (CIP), levofloxacina (LEV), gatifloxacina (GAT), moxifloxacina (MOX) y gemifloxacina (GEM) mediante la determinación de la concentración mínima inhibitoria (CMI) con la prueba E. Resultados: 42% de los aislamientos mostraron susceptibilidad disminuida a la PEN. La mínima concentración del antibiótico que logró inhibir al 90% de los aislamientos fue de 3 µg/ml (para la CIP), 1 Hg/ml (para la LEV), 0.25ng/ml (para la GAT), 0.125 µg/ml (para la MOX) y 0.032 µg/ml (para la GEM). La mediana de la CMI para la LEV (GAT, MOX y GEM) se incrementó proporcionalmente a la disminución de la sensibilidad del neumococo a la CIP. La susceptibilidad a la CIP fue semejante entre los aislamientos sensibles y resistentes a la PEN. Conclusión: las fluoroquinolonas de tercera y cuarta generación mostraron tener buena actividad inhibitoria del neumococo, incluyendo a las cepas resistentes a la PEN, siendo mayor que la de CIP. Se documentó resistencia cruzada entre las fluoroquinolonas.

Objective: Determine the susceptibility to five fluoroquinolones and cross resistance of pneumococcus clinical isolates with different penicillin susceptibilities gathered in a community based study . Design: Cross sectional survey. Materials: Two hundred and thirty one (231) isolates were obtained from respiratory secretions or blood specimensfrom 231 patients with acquired acute respiratory infection or bacteremia. Outcome measures: In vitro susceptibility to penicillin (PEN), ciprofloxacin (CIP), levofloxacin (LEV), gatifloxacin (GAT), moxifloxacin (MOX) and gemifloxacin (GEM) was determined with minimal inhibitory concentration (MIC) using the E test. Results: 42% of the isolates showed decreased susceptibility to PEN. The lowest antibiotic concentration that inhibited 90% of the isolates was 3 Hg/ml (for CIP), 1 µg/ml (forLEV), 0.25 µg/ml (for GAT), 0.125 µg/ml (for MOX) and 0.032 µg/ml (for GEM). Median MIC for LEV, GAT, MOX and GEM increased with decreasing susceptibility to CIP. Susceptibility to CIP was similar between penicillin susceptible and penicillin resistant pneumococci. Conclusion: Third and fourth generation fluoroquinolones showed very high inhibitory activity, higher than that for CIP, for both penicillin susceptible and penicillin resistant pneumococci. We noted cross resistance among fluoroquinolones.