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Cytochrome bdoxidase (Cyt-bd) is an attractive drug target in Mycobacterium tuberculosis, especially in the context of developing a drug combination targeting energy metabolism. However, currently few synthetically assessable scaffolds target Cyt-bd. Herein, we report that thieno[3,2-d]pyrimidin-4-amines inhibit Cyt-bd, and report an initial structure–activity-relationship (SAR) of 13 compounds in three mycobacterial strains: Mycobacterium bovisBCG, Mycobacterium tuberculosisH37Rv and Mycobacterium tuberculosisclinical isolate N0145 in an established ATP depletion assay with or without the cytochrome bcc : aa3(QcrB) inhibitor Q203. All compounds displayed activity against M. bovisBCG and the M. tuberculosisclinical isolate strain N0145 with ATP IC50values from 6 to 54 μM in the presence of Q203 only, as expected from a Cyt-bdinhibitor. All derivatives were much less potent against M. tuberculosisH37Rv compared to N0145 (IC50's from 24 to >100 μM and 9–52 μM, respectively), an observation that may be attributed to the higher expression of the Cyt-bd-encoding genes in the laboratory-adapted M. tuberculosisH37Rv strain. N-(4-(tert-butyl)phenethyl)thieno[3,2-d]pyrimidin-4-amine (19) was the most active compound with ATP IC50values from 6 to 18 μM against all strains in the presence of Q203, making it a good chemical probe for interrogation the function of the mycobacterial Cyt-bdunder various physiological conditions.

The formation efficiency of hydride-induced Meisenheimer complexes of nitroaromatic compounds is consistent with their anti-TB activities exemplied by MDL860 and benzothiazol N-oxide (BTO) analogs. Herein we report that nitro cyano phenoxybenzenes (MDL860 and analogs) reacted slowly and incompletely which reflected their moderate anti-TB activity, in contrast to the instantaneous reaction of BTO derivatives to quantitatively generate Meisenheimer complexes which corresponded to their enhanced anti-TB activity. These results were corroborated by mycobacterial and radiolabelling studies that confirmed inhibition of the DprE1 enzyme by BTO derivatives but not MDL860 analogs.

ABSTRACTA panel of six imidazo[1,2-a]pyridine-3-carboxamides (IAPs) were shown to have low-micromolar activity against Mycobacterium aviumstrains. Compound ND-10885 (compound 2) showed significant activity in the lung, spleen, and liver in a mouse M. aviuminfection model. A combined regimen consisting of ND-10885 (compound 2) and rifampin was additive in its anti-M. aviumactivity in the lung. Our data indicate that IAPs represent a new class of antibiotics that are active against M. aviumand could potentially serve as an effective addition to a combined treatment regimen.

The executive–legislative framework employed in the republic of Udmurtia throughout the 1990s distinguished it from other regions in Russia, making it a crucial case for analysis. While Udmurtia's parliamentary executive should have dampened incumbency rates in the republic, the number of incumbent legislators winning re-election has increased significantly over time. At the same time, the proportion of business and industrial interests in parliament has also increased. With this set of politicians representing broader societal interests in the republic, these findings provide some hope for the rise of minimally responsive, increasingly professionalized regional legislatures in Russia, as opposed to government by apparatchiks. In this context, Putin's decision to appoint governors should spur political conflict in Russia as regional elites with personal stakes in their regional economies and vested interests in democratic institutions confront an encroaching federal government.

As part of a fast-paced oncology program, quinolinone 1 was discovered and developed as a potent inhibitor of farnesyl transferase for the treatment of cancer. The initial synthesis, which suffered from a lengthy linear sequence and a late-stage chromatographic resolution, was deemed not amenable to large-scale production. While investigating alternate routes to address these issues, the original synthesis was successively improved and streamlined. This enabled route supplied the timely production of drug substance required to support early toxicological and clinical studies. Several iterations of the process were made, and as a result of these improvements, an efficient four-step sequence was developed for the synthesis of quinolinone d-tartrate 2 starting from readily available outsourced intermediate 5 in 26% overall yield, including a classical resolution. The key features of the synthesis include a Castro−Stevens coupling, an imidazole Grignard addition, and a concomitant classical resolution/final salt formation with d-(−)-tartaric acid.

This study examines the pattern and regulatory properties of cyclic nucleotide phosphodiesterases in a human lymphoblastoid B-cell line (RPMI 8392) established from a patient with acute lymphocytic leukaemia. In this cell line, phosphodiesterase activity measured at 0.25 microM-cyclic AMP is approx. 7-fold greater than that in isolated human peripheral-blood lymphocytes, and 16% of the phosphodiesterase activity in RPMI 8392 cells is associated with particulate fractions. Phosphodiesterase activity in crude fractions of this cell line is reproducibly stimulated by about 60-80% by Ca2+-calmodulin. In the presence of 20 nM-calmodulin, half-maximal stimulation occurs at 0.7 microM-Ca2+. The cytosolic phosphodiesterase activity of RPMI 8392 cells is separated into two forms by DEAE-Sephacel chromatography. The first form is eluted at approx. 0.2 M-sodium acetate, catalyses the hydrolysis of both cyclic AMP and cyclic GMP, and is stimulated 3-fold by Ca2+-calmodulin. This form exhibits non-linear kinetics for cyclic AMP in the absence of calmodulin, with extrapolated Km values of 0.8 and 4 microM, and non-linear kinetics in the presence of calmodulin, with extrapolated Km values of 0.5 and 1 microM. The Vmax. values are increased approx. 3-fold by calmodulin. The second form is eluted at approx. 0.6 M-sodium acetate, is specific for cyclic AMP, and insensitive to stimulation by Ca2+-calmodulin. The Ca2+-calmodulin-sensitive phosphodiesterase from the DEAE-Sephacel column can be adsorbed to a calmodulin-Sepharose affinity column and eluted with EGTA. This enzymic activity can also be immunoprecipitated by a monoclonal antibody directed against a calmodulin-bovine heart phosphodiesterase complex. This study documents the existence of Ca2+-calmodulin-sensitive phosphodiesterase in a cultured lymphoblastoid cell line derived from a leukaemic patient.

Immunomodulators are those extrinsic or intrinsic substances which regulate or alter the scope, type, duration or competency of the immune response. This paper presents an overview of the mechanisms of immunomodulation, and discusses selected chemical and biologic substances which are capable of modifying the immune or biologic response of the organism. The immunopharmacology, including in vivoand in vitroassays, of a novel acridine immunomodulator is discussed. This low molecular weight compound is an immunomodulator and anti-cancer adjuvant, which has been shown to induce high levels of circulating interferon in mice, protect mice against lethal viral infection, stimulate macrophage and NK cell cytotoxicity for tumor cells, partially restore humoral and cellular immune responses in tumor bearing immunosuppressed mice, and augment the cytotoxic T-lymphocyte response to syngeneic tumor cells. Tissue changes, consisting of presence of drug bound to lysosomal membranes, perivascular infiltrates in mouse liver, glomerular hyalinization in mouse kidney, and focal myocardial changes in mice are described. The compound persists intracellularly for extended periods of time in cells with high lysosomal activity. The tissue changes are interpreted to be a result of overloading of cellular mechanisms for elimination from the cells involved.

Ninety-six patients with chest pain were studied to determine the relation between left ventricular function and severity of coronary artery disease in patients with and without a history of myocardial infarction. Coronary arteriography was performed obtaining cineangiograms (60 frames/sec) and large roll film angiograms (2 to 6 frames/sec) for precise definition of the coronary anatomy. The criteria for diagnosis of myocardial infarction were a typical history, a rise and fall in serum glutamic oxaloacetic transaminase levels and evolutionary S-T segment changes associated with Q waves of at least 0.03 second. Left ventricular function was assessed by measurement of left ventricular end-diastolic pressure and volume, and left ventricular ejection fraction, mass and compliance. Fifteen patients had normal findings; 81 were classified according to number of diseased vessels and presence or absence of myocardial infarction. There were no group differences in age or heart rate. Left ventricular end-diastolic pressure was abnormally increased in patients with three vessel disease and myocardial infarction. Left ventricular end-diastolic volume was increased and the ejection fraction was reduced in patients in each vessel disease group with myocardial infarction. Although ejection fraction was reduced in patients with three vessel disease without myocardial infarction, it was further reduced when infarction occurred. Left ventricular mass increased in patients with three vessel disease with or without myocardial infarction. Values for ventricular compliance were reduced in all patients with myocardial infarction and were lower in those with two and three vessel disease and infarction than in those with two and three vessel disease without infarction. These findings suggest that a previous history of myocardial infarction needs to be considered together with anatomic abnormalities of the coronary arteries in assessing cardiac performance in patients with ischemic heart disease. In patients with one, two or three vessel coronary artery disease, a previous myocardial infarction significantly alters left ventricular performance; the ejection fraction is a more sensitive measurement of left ventricular function than left ventricular end-diastolic pressure or volume.

Hyperplasia was produced in the kidneys of rats maintained on a hypertensive-inducing regimen of DCA and saline. The hyperplasia in these intact animals was similar to the hyperplasia observed in uninephrectomized rats even to the extent of having a peak mitotic activity on the 2nd day and a lesser one on the 8th day. The long duration of treatment appears to be unnecessary because there was no cumulative effect and the highest peak occurs after only the first injection of DCA. In fact, the long treatment may have an inhibitory effect on the maximum mitotic activity possible with this technique.

ABSTRACTThe imidazopyridines are a promising new class of antitubercular agents with potent activity in vitroand in vivo. We isolated mutants of Mycobacterium tuberculosisresistant to a representative imidazopyridine; the mutants had large shifts (>20-fold) in MIC. Whole-genome sequencing revealed mutations in Rv1339, a hypothetical protein of unknown function. We isolated mutants resistant to three further compounds from the series; resistant mutants isolated from two of the compounds had single nucleotide polymorphisms in Rv1339 and resistant mutants isolated from the third compound had single nucleotide polymorphisms in QcrB, the proposed target for the series. All the strains were resistant to two compounds, regardless of the mutation, and a strain carrying the QcrB T313I mutation was resistant to all of the imidazopyridine derivatives tested, confirming cross-resistance. By monitoring pH homeostasis and ATP generation, we confirmed that compounds from the series were targeting QcrB; imidazopyridines disrupted pH homeostasis and depleted ATP, providing further evidence of an effect on the electron transport chain. A representative compound was bacteriostatic against replicating bacteria, consistent with a mode of action against QcrB. The series had a narrow inhibitory spectrum, with no activity against other bacterial species. No synergy or antagonism was seen with other antituberculosis drugs under development. In conclusion, our data support the hypothesis that the imidazopyridine series functions by reducing ATP generation via inhibition of QcrB.

Five title compounds are prepared and tested for their antibacterial activities.

A three‐step process enables access to aryl oxazoles via formation of β‐hydroxy amides (III), cyclization to oxazolines (IV), and dehydration to provide oxazoles (V).