N-methylisatin-beta-thiosemicarbazone derivative (SCH 16) is an inhibitor of Japanese encephalitis virus infection in vitro and in vivo

<p>Abstract</p> <p>Background</p> <p>During the early and mid part of 20^thcentury, several reports described the therapeutic effects of N-methylisatin-β-Thiosemicarbazone (MIBT) against pox viruses, Maloney leukemia viruses and recently against HIV. However, their ability to inhibit flavivirus replication has not been investigated. Hence the present study was designed to evaluate the antiviral activity of 14 MIBT derivatives against Flaviviruses that are prevalent in India such as Japanese Encephalitis Virus (JEV), Dengue-2 (Den-2) and West Nile viruses (WNV).</p> <p>Results</p> <p>Amongst the fourteen Mannich bases of MIBT derivatives tested one compound – SCH 16 was able to completely inhibit <it>in vitro </it>Japanese encephalitis virus (JEV) and West Nile virus (WNV) replication. However no antiviral activity of SCH 16 was noted against Den-2 virus replication. This compound was able to inhibit 50% of the plaques (IC₅₀) produced by JEV and WNV at a concentration of 16 μgm/ml (0.000025 μM) and 4 μgm/ml (0.000006 μM) respectively. Furthermore, SCH 16 at a concentration of 500 mg/kg body weight administered by oral route twice daily was able to completely (100%) prevent mortality in mice challenged with 50LD₅₀JEV by the peripheral route. Our experiments to understand the mechanism of action suggest that SCH 16 inhibited JEV replication at the level of early protein translation.</p> <p>Conclusion</p> <p>Only one of the 14 isatin derivatives -SCH 16 exhibited antiviral action on JEV and WNV virus infection <it>in vitro</it>. SCH 16 was also found to completely inhibit JEV replication <it>in vivo </it>in a mouse model challenged peripherally with 50LD₅₀of the virus. These results warrant further research and development on SCH 16 as a possible therapeutic agent.</p

Synthesis and antitubercular evaluation of 2-iminothiazolidine-4-ones

In the present manuscript, we report synthesis of new 3 and 5 substituted 2-imino thiazolidine-4-ones by three step synthetic protocols from 3-trifluormethyl aniline or 2-amino heterocycle. The compounds were evaluated for in vitro activities against Mycobacterium tuberculosis (MTB) in presence and absence of efflux pump inhibitor, cytotoxicity against RAW 264.7 cells. Among the thirty six compounds, 2-imino-3-(5-nitrothiazol-2-yl)-5-(3,4,5-trimethoxybenzylidene)thiazolidin-4-one (5g) was found to be the most active compound in vitro with MICs of 3.31 µM against log-phase culture of MTB and also non-toxic up to 100 µM. Compound 5g showed minimum inhibitory concentration (MIC) of 0.82 µM against MTB in presence of efflux pump inhibitor verapamil

Salicylanilide Diethyl Phosphates as Potential Inhibitors of Some Mycobacterial Enzymes

Antimycobacterially active salicylanilide diethyl phosphates were evaluated to identify their potential drug target(s) for the inhibition of several mycobacterial enzymes, including isocitrate lyase, L-alanine dehydrogenase (MtAlaDH), lysine ε-aminotransferase, chorismate mutase, and pantothenate synthetase. The enzymes are related to the nongrowing state of Mycobacterium tuberculosis. Salicylanilide diethyl phosphates represent new candidates with significant inhibitory activity especially against L-alanine dehydrogenase. The most active MtAlaDH inhibitor, 5-chloro-2-[(3-chlorophenyl)carbamoyl]phenyl diethyl phosphate, has an IC50 of 4.96 µM and the best docking results. Other mycobacterial enzymes were mostly inhibited by some derivatives but at higher concentrations; isocitrate lyase showed the highest resistance to salicylanilide diethyl phosphates

Depletion of M. tuberculosis GlmU from infected murine lungs effects the clearance of the pathogen

M. tuberculosis N-acetyl-glucosamine-1-phosphate uridyltransferase (GlmUMtb) is a bi-functional enzyme engaged in the synthesis of two metabolic intermediates N-acetylglucosamine-1-phosphate (GlcNAc-1-P) and UDP-GlcNAc, catalyzed by the C- and N-terminal domains respectively. UDP-GlcNAc is a key metabolite essential for the synthesis of peptidoglycan, disaccharide linker, arabinogalactan and mycothiols. While GlmUMtb was predicted to be an essential gene, till date the role of GlmUMtb in modulating the in vitro growth of Mtb or its role in survival of pathogen ex vivo / in vivo have not been deciphered. Here we present the results of a comprehensive study dissecting the role of GlmUMtb in arbitrating the survival of the pathogen both in vitro and in vivo. We find that absence of GlmUMtb leads to extensive perturbation of bacterial morphology and substantial reduction in cell wall thickness under normoxic as well as hypoxic conditions. Complementation studies show that the acetyl- and uridyl- transferase activities of GlmUMtb are independently essential for bacterial survival in vitro and GlmUMtb is also found to be essential for mycobacterial survival in THP-1 cells as well as in guinea pigs. Depletion of GlmUMtb from infected murine lungs, four weeks post infection, led to significant reduction in the bacillary load. The administration of Oxa33, a novel oxazolidine derivative that specifically inhibits GlmUMtb, to infected mice resulted in significant decrease in the bacillary load. Thus our study establishes GlmUMtb as a strong candidate for intervention measures against established tuberculosis infections

Efficacy and safety of once-daily nevirapine- or efavirenz-based antiretroviral therapy in HIV-associated tuberculosis: a randomized clinical trial

Background: Nevirapine (NVP) can be safely and effectively administered once-daily but has not been assessed in human immunodeficiency virus (HIV)–infected patients with tuberculosis (TB). We studied the safety and efficacy of once-daily NVP, compared with efavirenz (EFV; standard therapy); both drugs were administered in combination with 2 nucleoside reverse-transcriptase inhibitors. Methods: An open-label, noninferiority, randomized controlled clinical trial was conducted at 3 sites in southern India. HIV-infected patients with TB were treated with a standard short-course anti-TB regimen (2EHRZ3/4RH3; [2 months of Ethambutol, Isoniazid, Rifampicin, Pyrazinamide/4 months of Isoniazid and Rifampicin] thrice weekly) and randomized to receive once-daily EFV at a dose of 600 mg or NVP at a dose of 400 mg (after 14 days of 200 mg administered once daily) with didanosine 250/400 mg and lamivudine 300 mg after 2 months. Sputum smears and mycobacterial cultures were performed every month. CD4+ cell count, viral load, and liver function test results were monitored periodically. Primary outcome was a composite of death, virological failure, default, or serious adverse event (SAE) at 24 weeks. Both intent-to-treat and per protocol analyses were done, and planned interim analyses were performed. Results: A total of 116 patients (75% [87 patients] of whom had pulmonary TB), with a mean age of 36 years, a median CD4+ cell count of 84 cells/mm3, and a median viral load of 310?000 copies/mL, were randomized. At 24 weeks, 50 of 59 patients in the EFV group and 37 of 57 patients in the NVP group had virological suppression (P = .024). There were no deaths, 1 SAE, and 5 treatment failures in the EFV arm, compared with 5 deaths, 2 SAEs, and 10 treatment failures in the NVP arm. The trial was halted by the data and safety monitoring board at the second interim analysis. Favorable TB treatment outcomes were observed in 93% of the patients in the EFV arm and 84% of the patients in the NVP arm (P = .058). Conclusions: Compared with a regimen of didanosine, lamivudine, and EFV, a regimen of once-daily didanosine, lamivudine, and NVP was inferior and was associated with more frequent virologic failure and death

Sinteza N4-(2,4-dimetilfenil) semikarbazona kao inhibitori 4-aminobutirat aminotransferaze

Several 2,4-dimethylphenyl substituted semicarbazones were synthesized in three steps involving aryl urea and aryl semicarbazide formations. The structures were confirmed by spectral and elemental analyses. All the compounds were evaluated for anticonvulsant activity by using a series of test models including maximal electroshock seizure (MES), subcutaneous pentylenetetrazole (scPTZ) and subcutaneous strychnine (scSTY) seizure threshold tests. The compounds were also evaluated for behavioural impairement and depression activity. In the neurochemical investigation, potent compounds were evaluated for their effects on rat brain -aminobutyric acid levels and in vitro -aminobutyrate transaminase (Pseudomonas fluorescens) activity. Preliminary studies suggest these compounds to exhibit anticonvulsant activity via GABA-mediated mechanism.Sintetizirano je nekoliko 2,4-dimetilfenil supstituiranih semikarbazona u tri sintetska koraka koji uključuju aril uree i aril semikarbazide. Strukture spojeva su potvrđene spektroskopskim metoda i elementarnom analizom. Ispitano je antikonvulzivno djelovanje novih spojeva nakon izazivanja konvulzija elektrošokom te supkutanom primjenom pentilentetrazola ili strihnina. Osim toga, testirano je antidepresivno djelovanje te učinak tih spojeva na ponašanje štakora. Praćen je njihov utjecaj na koncentraciju gama-aminomaslačne kiseline (GABA) u mozgu štakora te in vitro na aktivnost gama-aminobutirat transaminaze (Pseudomonas fluorescens). Preliminarni pokusi ukazuju da antikonvulzivno djelovanje ovih spojeva uključuje GABA-ergički sustav

Sinteza N4-(2,4-dimetilfenil) semikarbazona kao inhibitori 4-aminobutirat aminotransferaze

Several 2,4-dimethylphenyl substituted semicarbazones were synthesized in three steps involving aryl urea and aryl semicarbazide formations. The structures were confirmed by spectral and elemental analyses. All the compounds were evaluated for anticonvulsant activity by using a series of test models including maximal electroshock seizure (MES), subcutaneous pentylenetetrazole (scPTZ) and subcutaneous strychnine (scSTY) seizure threshold tests. The compounds were also evaluated for behavioural impairement and depression activity. In the neurochemical investigation, potent compounds were evaluated for their effects on rat brain -aminobutyric acid levels and in vitro -aminobutyrate transaminase (Pseudomonas fluorescens) activity. Preliminary studies suggest these compounds to exhibit anticonvulsant activity via GABA-mediated mechanism.Sintetizirano je nekoliko 2,4-dimetilfenil supstituiranih semikarbazona u tri sintetska koraka koji uključuju aril uree i aril semikarbazide. Strukture spojeva su potvrđene spektroskopskim metoda i elementarnom analizom. Ispitano je antikonvulzivno djelovanje novih spojeva nakon izazivanja konvulzija elektrošokom te supkutanom primjenom pentilentetrazola ili strihnina. Osim toga, testirano je antidepresivno djelovanje te učinak tih spojeva na ponašanje štakora. Praćen je njihov utjecaj na koncentraciju gama-aminomaslačne kiseline (GABA) u mozgu štakora te in vitro na aktivnost gama-aminobutirat transaminaze (Pseudomonas fluorescens). Preliminarni pokusi ukazuju da antikonvulzivno djelovanje ovih spojeva uključuje GABA-ergički sustav

Novel Thiazolidinone-Azole Hybrids: Design, Synthesis and Antimycobacterial Activity Studies

Abstract To develop novel antimycobacterial agents, a new series of thiazolidinone-azole hybrids 4a-b, 5a-b and 6-13 were designed and synthesized. Thiazolidin-4-ones (4a-b and 5a-b) were obtained by the reaction of Schiff bases and hydrazones (2a-b and 3a-b) with mercaptoacetic acid. 5-Benzylidene derivatives (6-13) were gained by treatment of 5a-b with appropriate benzaldehydes according to Knoevenagel condensation. To evaluate their structures 1 H NMR, IR, mass spectrometry and elemental analysis data were used. The target compounds were screened for their antimycobacterial activity against M. tuberculosis H37Rv strain using the microplate alamar blue assay method. Among them, 6, 10 and 12 (MIC: 14.27-14.74 μM) were found as most active compounds in the series. It was seen that both phenylamino and benzylidene substitutions on thiazolidin-4-one ring caused an improvement in the antimycobacterial activity

Implementación de la estrategia de segmentación de clientes para el incremento en el uso de la tarjeta de crédito de una entidad bancaria

RESUMEN La tesis en la modalidad de suficiencia profesional denominada “Implementación de la estrategia de segmentación de clientes para el incremento en el uso de la tarjeta de crédito de una entidad bancaria” presenta el problema general: ¿Cómo la implementación de la estrategia de segmentación de los clientes incrementará el uso de la tarjeta de crédito de una entidad bancaria?, del cual se plantea el objetivo general: Implementar la estrategia de segmentación de clientes para incrementar el uso de la tarjeta de crédito de una entidad bancaria. Se desarrolla un caso de éxito en una entidad bancaria que se sustenta en los aportes teóricos acerca de la Segmentación de Clientes desde el punto de vista del Marketing, el CRM y la Estadística; también se presenta las bases de la teoría de administración aplicada a la Gestión de Campañas. En el desarrollo del caso se realizó dos segmentaciones: por nivel de consumo (Heavy, Medium, Light Transactor) y por consumo en giros comerciales (Viajeros, Retail, Buen comer, etc) lo que impactó positivamente en el conocimiento del cliente y en la formulación de estrategias comerciales innovadoras que originó buenos resultados en el incremento de uso de la tarjeta de crédito. PALABRAS CLAVE: segmentación, tarjeta de crédito, entidad bancaria, marketing, CRM, gestión de campañas, conocimiento del cliente.ABSTRACT The thesis in the modality of professional sufficiency denominated "Implementation of the strategy of the customer segmentation for the increase in the use of the credit card of a bank" presents the general problem: How the implementation of the strategy of customer segmentation will increase the use of the credit card of a bank?, which propose the general objective: Implement the strategy of customer segmentation to increase the use of the credit card of a bank. It developed a success case in a bank that is based on theoretical contributions on the Customer Segmentation from the point of view of Marketing, CRM and Statistics; it also presents the bases of management theory applied to Campaign Management. In the development of the case, there were two segmentations: by level of consumption (Heavy, Medium, Light Transactor) and by commercial spins consumption (Travellers, Retail, God eating, et cetera.) which positively impacted the customer knowledge and formulation of innovative commercial strategies that resulted in good results for the increase of credit card use. KEYWORDS: segmentation, credit card, banking, CRM, campaign management, customer knowledge

Design and development of novel inhibitors for the treatment of latent tuberculosis

Objective/background: “The captain of all these men of death”, is the apt sobriquet for the age-old disease tuberculosis (TB). Despite the availability of many drugs, cases of increasing resistance in the forms of multi-drug and extensively drug-resistant TB and persistence [characteristic of Mycobacterium tuberculosis (MTB)] make the eradication of TB a nightmare. Approval of bedaquiline by the Food and Drug Administration focused attention on quinoline scaffolds for development of new anti-TB agents. Lysine ɛ-aminotransferase (LAT) in MTB plays a pivotal role in regulating amino acid synthesis, which in turn affects mycobacterial persistence. Here, developed quinoline inhibitors that targeted LAT with an objective to eliminate dormant forms of mycobacterium. Methods: Using e-pharmacophore approaches, quinolone (PBD: 2CJD) leads were found to inhibit lysine binding to LAT. To investigate structural activity relationships, 21 analogues were synthesized and characterized based on the identified lead molecules. Results: Among the derivatives, N-(pyridin-2-yl methyl)-2-(4-(quinolin-4-yl) piperazin-1-yl) acetamide was identified as a potent molecule, with an IC50 for LAT of 1.04 μM. In nutrient-starved and zebra fish models, this molecule exhibited logarithmic reductions of 2.1- and 2.2-fold, respectively, at a concentration of 10 μg/mL. The compound also exhibited good activity against persistent forms of mycobacteria (biofilm model), showing logarithmic reduction of 2.8-fold. Additionally, the hit molecule showed concentration-dependent kill kinetics against dormant forms of mycobacteria, and were devoid of cytotoxicity against RAW cell lines 264.7 at concentrations of 50 μM. Conclusion: Our results indicated that the hit molecule showed activity against both active and persistent forms of infection, which is ideal for new anti-TB agents. This molecule requires further pharmacokinetic and dynamic screening for development as new drug candidate