Aerosol Infection Model of Tuberculosis in Wistar Rats

We explored suitability of a rat tuberculosis aerosol infection model for investigating the pharmacodynamics of new antimycobacterial agents. Infection of rats via the aerosol route led to a reproducible course of M. tuberculosis infection in the lungs. The pulmonary bacterial load increased logarithmically during the first six weeks, thereafter, the infection stabilized for the next 12 weeks. We observed macroscopically visible granulomas in the lungs with demonstrable acid-fast bacilli and associated histopathology. Rifampicin (RIF) at a dose range of 30 to 270 mg/kg exhibited a sharp dose response while isoniazid (INH) at a dose range of 10 to 90 mg/kg and ethambutol (EMB) at 100 to 1000 mg/kg showed shallow dose responses. Pyrazinamide (PZA) had no dose response between 300 and 1000 mg/kg dose range. In a separate time kill study at fixed drug doses (RIF 90 mg/kg, INH 30 mg/kg, EMB 300 mg/kg, and PZA 300 mg/kg) the bactericidal effect of all the four drugs increased with longer duration of treatment from two weeks to four weeks. The observed infection profile and therapeutic outcomes in this rat model suggest that it can be used as an additional, pharmacologically relevant efficacy model to develop novel antitubercular compounds at the interface of discovery and development

Aerosol Infection Model of Tuberculosis in Wistar Rats

We explored suitability of a rat tuberculosis aerosol infection model for investigating the pharmacodynamics of new antimycobacterial agents. Infection of rats via the aerosol route led to a reproducible course of M. tuberculosis infection in the lungs. The pulmonary bacterial load increased logarithmically during the first six weeks, thereafter, the infection stabilized for the next 12 weeks. We observed macroscopically visible granulomas in the lungs with demonstrable acid-fast bacilli and associated histopathology. Rifampicin (RIF) at a dose range of 30 to 270 mg/kg exhibited a sharp dose response while isoniazid (INH) at a dose range of 10 to 90 mg/kg and ethambutol (EMB) at 100 to 1000 mg/kg showed shallow dose responses. Pyrazinamide (PZA) had no dose response between 300 and 1000 mg/kg dose range. In a separate time kill study at fixed drug doses (RIF 90 mg/kg, INH 30 mg/kg, EMB 300 mg/kg, and PZA 300 mg/kg) the bactericidal effect of all the four drugs increased with longer duration of treatment from two weeks to four weeks. The observed infection profile and therapeutic outcomes in this rat model suggest that it can be used as an additional, pharmacologically relevant efficacy model to develop novel antitubercular compounds at the interface of discovery and development

Synthesis and in vitro anticancer activity of 6-chloro-7-methyl-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one derivatives: molecular docking and interaction with bovine serum albumin

A novel series of 6-chloro-7-methyl-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one derivatives were synthesized. Structure of the newly synthesized compounds was established by their analytical and spectroscopic data. The title compounds were evaluated for their anticancer activity against human breast cancer (T-47D) and lung cancer (NCI-H226) cell lines. Effects of compounds on the cell morphology of these cell lines were studied. Among the series of compounds tested, 6-chloro-7-methyl-2-(4-((2-(piperidin-1-yl)ethylamino)methyl) phenyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one [MTDP4(9)] exhibited good anticancer activity against both cell lines. Further, the binding interaction of [MTDP4(9)] with bovine serum albumin has been investigated by UV, fluorescence and molecular docking studies

In silico binding affinity studies of N-9 substituted 6-(4-(4-propoxyphenyl)piperazin-1-yl)-9H-purine derivatives-Target for P70-S6K1 & PI3K-δ kinases

P70-S6K1 & PI3K-δ kinases are identified to be involved in many physiological processes associated with cancer, therefore many of the inhibitors being designed to target these kinases are in clinical trials. In the current study we have exploited the N-9 substituted 6-(4-(4-propoxyphenyl) piperazin-1-yl)-9H-purine derivatives for their inhibitory properties with the above kinases. We have used an in silico docking study with seventeen purine derivatives for their binding affinity calculations. The binding affinities of these small molecules with P70-S6K1 & PI3K-δ were performed using AutoDock Vina. Among all the compounds, PP16 showed highest binding affinity of −14.7 kcal/mol with P70-S6K1 kinase & −17.2 kcal/mol with PI3K-δ kinases as compared to the molecules under clinical trials (PF-4708671 & IC-87114). Docking studies revealed that N-9 coumarine substituted purine derivative could be one of the potential ligands for the inhibition of P70-S6K1 & PI3K-δ kinases. Hence, this compound can be further investigated by in vitro and in vivo experiments for further validation

Isoniazid Pharmacokinetics-Pharmacodynamics in an Aerosol Infection Model of Tuberculosis

Limited data exist on the pharmacokinetic-pharmacodynamic (PK-PD) parameters of the bactericidal activities of the available antimycobacterial drugs. We report on the PK-PD relationships for isoniazid. Isoniazid exhibited concentration (C)-dependent killing of Mycobacterium tuberculosis H37Rv in vitro, with a maximum reduction of 4 log(10) CFU/ml. In these studies, 50% of the maximum effect was achieved at a C/MIC ratio of 0.5, and the maximum effect did not increase with exposure times of up to 21 days. Conversely, isoniazid produced less than a 0.5-log(10) CFU/ml reduction in two different intracellular infection models (J774A.1 murine macrophages and whole human blood). In a murine model of aerosol infection, isoniazid therapy for 6 days produced a reduction of 1.4 log(10) CFU/lung. Dose fractionation studies demonstrated that the 24-h area under the concentration-time curve/MIC (r(2) = 0.83) correlated best with the bactericidal efficacy, followed by the maximum concentration of drug in serum/MIC (r(2) = 0.73)

Synthesis and <i>in vitro</i> anticancer activity of 6-chloro-7-methyl-5<i>H</i>-[1,3,4]thiadiazolo[3,2-<i>a</i>]pyrimidin-5-one derivatives: molecular docking and interaction with bovine serum albumin

<p>A novel series of 6-chloro-7-methyl-5<i>H</i>-[1,3,4]thiadiazolo[3,2-<i>a</i>]pyrimidin-5-one derivatives were synthesized. Structure of the newly synthesized compounds was established by their analytical and spectroscopic data. The title compounds were evaluated for their anticancer activity against human breast cancer (T-47D) and lung cancer (NCI-H226) cell lines. Effects of compounds on the cell morphology of these cell lines were studied. Among the series of compounds tested, 6-chloro-7-methyl-2-(4-((2-(piperidin-1-yl)ethylamino)methyl) phenyl)-[1,3,4]thiadiazolo[3,2-<i>a</i>]pyrimidin-5-one [MTDP4(9)] exhibited good anticancer activity against both cell lines. Further, the binding interaction of [MTDP4(9)] with bovine serum albumin has been investigated by UV, fluorescence and molecular docking studies.</p