1,720,982 research outputs found
COX inhibitors: a patent review (2011 - 2014)
No full textThe COX enzymes play a central role in the biosynthetic pathway of important biological mediators called prostanoids. Differences in regulation of gene expression, stability of transcripts and proteins determine the different biological functions of COX-1 and COX-2. While the COX-1 gene has been considered to be a ‘housekeeping’ gene expressed in many tissues and cells, COX-2 gene is upregulated during inflammation, hypoxia and in many cancers
MmpL3 inhibitors: diverse chemical scaffolds inhibit the same target
No full textMmpL3 belongs to the Resistance, Nodulation and Division (RND) superfamily whose role in mycobacteria is the formation of the outer membrane. Indeed, it has been shown that MmpL3 is associated with the export of mycolic acids in the form of trehalose monomycolates (TMM) to the periplasmic space or the outer membrane. In the last few years several whole cell-based screenings of compound libraries brought by a number of diverse chemical scaffolds active against M. tuberculosis (Mtb) that surprisingly share MmpL3 as target. The diverse identified pharmacophores owe important differences among each other, in fact while some of them display inhibitory activity against pathogens that are devoid of mycolic acids and are active against non-replicating Mtb bacilli, some others specifically target mycobacteria and do not kill non-replicating bacilli. The scope of this review is to provide the recent advances in MmpL3 inhibitor discovery with a special focus on structure activity relationship (SAR) studies in order to provide information that could help in developing novel membrane-active anti- TB agents. Moreover, this review will provide the most recent insights into the modes of action of the MmpL3 inhibitors
Novel inhibitors of Mycobacterium tuberculosis tryptophan biosynthetic pathway to treat tuberculosis
No full textSAR analysis of new anti-TB drugs currently in pre-clinical and clinical development
No full textDespite enormous efforts have been made in the hunt for new drugs, tuberculosis (TB) still remains the first bacterial cause of mortality worldwide, causing an estimated 8.6 million new cases and 1.3 million deaths in 2012. Multi-drug resistant-TB strains no longer respond to first-line drugs and are inexorably spreading with an estimated 650 000 cases as well as extensively-drug resistant-TB strains, which are resistant to any fluoroquinolone and at least one of the second-line drugs, with 60 000 cases. Thus the discovery and development of new medicines is a major keystone for tuberculosis treatment and control. After decades of dormancy in the field of TB drug development, recent efforts from various groups have generated a promising TB drug pipeline. Several new therapeutic agents are concurrently studied in clinical trials together with much activity in the hittolead and lead optimization stages. In this article we will review the recent advances in TB drug discovery with a special focus on structure activity relationship studies of the most advanced compound classe
Development of MmpL3 inhibitors for tuberculosis treatment
No full textTuberculosis (TB) is the leading cause of death worldwide from a single infectious agent, with an estimated 10 million new cases of active TB and approximately 1.3 million deaths in 2017. Despite several new or repurposed drugs being in advanced stages of clinical trials, low treatment success rates for MDR- and XDR-TB and HIV co-infections demonstrate the necessity for development of new anti-tubercular drugs as well as the discovery and characterization of novel druggable targets.
In this book chapter we describe one of our medicinal chemistry projects on the development of a class of 1,5-diphenyl pyrroles active against the causative agent Mycobacterium tuberculosis (Mtb) to outline our experience in developing new anti-mycobacterials. We have identified an initial “soft-hit” (BM212) by the more reliable whole-cell screening assay; BM212 underwent chemical modifications that brought by several active hits. Next, the hit-to-lead program provided an improved lead BM635, active against both replicating and non-replicating bacilli, and efficacious in a murine model of tuberculosis infection. Further medicinal chemistry efforts included diverse strategies for improving the lead-like properties of this class of compounds. Meanwhile, we have elucidated target and mode of action of this class of compounds
1,5-Diarylpyrroles as potent antitubercular and anti-inflammatory agents
No full textThis minireview surveys the work of our research group directed toward finding novel antimycobacterial and anti-inflammatory drugs. Many active compounds were found with a common 1,5-diarylpyrrole skeleton. Some of the synthesized compounds, designed on the basis of structure–activity relationship studies, showed very interesting activities and proved to be effective in vivo, thus providing evidence of their attractiveness for lead optimization
New Pyrrole Derivatives as Anti-inflammatory and Analgesic Agents: Design, Synthesis and Biological Evaluation
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Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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