Synthesis and antimycobacterial activity of disubstituted benzyltriazoles

AbstractThe increasing prevalence of multidrug-resistant strains ofMycobacterium tuberculosis (Mtb), the pathogen of human tuberculosis (TB), serves as a strong incentive for the discovery and development of new agents for the treatment of this plight. In search for such drugs, we investigated a series of benzyltriazole derivatives. We herein report the design, synthesis and biological activity of disubstituted benzyltriazoles against the human virulent H37Rv strain ofMtb as well as the toxicity on human embryonic kidney (HEK-293) cells. The derivative21 featuring trifluoromethyl substituent inpara position on the phenyl ring andn-butyl chain in position 4 on the triazole ring was the most active with MIC90 and MIC99 values of 1.73 and 3.2  µM, respectively, in the albumin-free medium. It also displays high selectivity towards bacteria growth inhibition (SI >  58), thus stands as a better hit for further investigation, including lead optimization, DMPK parameters determination and assessment of its activity in animal models.
Source: Medicinal Chemistry Research - Category: Chemistry Source Type: research

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Conclusions: AEs were common, but not more frequent or severe among MDR-TB/HIV co-infected participants receiving concurrent antiretroviral therapy. Given the favorable treatment outcomes associated with concurrent treatment, antiretroviral therapy initiation should not be delayed in MDR-TB patients with HIV-coinfection.
Source: JAIDS Journal of Acquired Immune Deficiency Syndromes - Category: Infectious Diseases Tags: Clinical Science Source Type: research
ConclusionsOur study provides the first insight into molecular epidemiology of MDR-TB in Kuwait and identified several potential clusters of local transmission of MDR-TB involving 2 –6 subjects which had escaped detection by routine surveillance studies. Prospective detection of resistance-conferring mutations can identify possible cases of local transmission of MDR-TB in low MDR-TB settings.
Source: European Journal of Medical Research - Category: Research Source Type: research
Despite all our efforts, the disease burden of tuberculosis (TB) is not falling fast enough to reach the 2030 milestone of the End TB strategy [1]. Multidrug-resistant tuberculosis (MDR-TB) remains a public health crisis, with low treatment success rates [1]. The repurposed drug linezolid has emerged as a core drug in MDR-TB treatment regimens [2, 3], despite its toxicity, e.g. anaemia, peripheral neuropathy and gastrointestinal disorders, optic neuritis, and thrombocytopenia [4, 5]. Currently, linezolid is used off-label, as part of Group A "Medicines to be prioritised" of the World Health Organization (WHO) MDR...
Source: European Respiratory Journal - Category: Respiratory Medicine Authors: Tags: Original Articles: Research letters Source Type: research
ConclusionOur results show strong bactericidal potential of CHP against M.tuberculosis that warrant its immediate mechanistic, pharmacokinetic and pharmacodynamic studies.Graphical abstract
Source: Journal of Global Antimicrobial Resistance - Category: Infectious Diseases Source Type: research
CYCLOSERINE ENANTIOMERS ARE REVERSIBLE INHIBITORS OF HUMAN ALANINE:GLYOXYLATE AMINOTRANSFERASE: IMPLICATIONS FOR PRIMARY HYPEROXALURIA TYPE 1. Biochem J. 2019 Dec 03;: Authors: Dindo M, Grottelli S, Annunziato G, Giardina G, Pieroni M, Pampalone G, Faccini A, Cutruzzolà F, Laurino P, Costantino G, Cellini B Abstract Peroxisomal alanine:glyoxylate aminotransferase (AGT) is responsible for glyoxylate detoxification in human liver and utilizes pyridoxal 5'-phosphate (PLP) as coenzyme. The deficit of AGT leads to Primary Hyperoxaluria Type I (PH1), a rare disease characterized by calcium oxalate st...
Source: The Biochemical Journal - Category: Biochemistry Authors: Tags: Biochem J Source Type: research
ConclusionWGS ofM. tuberculosis isolates allows the detection of drug resistance to all drugs in a single test and also provides insight into the evolution and drug-resistant TB.
Source: Journal of Global Antimicrobial Resistance - Category: Infectious Diseases Source Type: research
Sandra Gemma Tuberculosis (TB) is one of the top 10 causes of death worldwide. This scenario is further complicated by the insurgence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. The identification of appropriate drugs with multi-target affinity profiles is considered to be a widely accepted strategy to overcome the rapid development of resistance. The aim of this study was to discover Food and Drug Administration (FDA)-approved drugs possessing antimycobacterial activity, potentially coupled to an effective multi-target profile. An integrated screening platform was implemented based on comput...
Source: Molecules - Category: Chemistry Authors: Tags: Article Source Type: research
This study is the first to identify specific metabolome variations related to the addition of Tween 80 to the growth media during M. tuberculosis culturing. The consideration of these results during the method development and data interpretation phases of future metabolomics investigations will improve the quality of the analyses as well as the credibility of potential research outcomes. These results will also assist in the interpretation of research questions specifically aimed at aspects of mycobacterial metabolism, even when using other methodologies such as transcriptomics or fluxomics.
Source: Journal of Microbiological Methods - Category: Microbiology Source Type: research
Conditions:   Tuberculosis, Pulmonary;   Tuberculosis, Multidrug-Resistant;   Tuberculosis, MDR;   Tuberculosis;   Drug-Resistant Tuberculosis Intervention:   Drug: Pretomanid Sponsor:   Global Alliance for TB Drug Development Not yet recruiting
Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
In conclusion, this work represents the first comprehensive molecular epidemiological description of TB in Latvia, highlighting the high genetic diversity of MTB strains circulating in Riga and Riga region. In combination with detailed epidemiological data this approach was helpful for the in-depth understanding of epidemiological processes in settings where the Next-Gen sequencing is not available as a routine method. PMID: 31783188 [PubMed - as supplied by publisher]
Source: Infection, Genetics and Evolution - Category: Genetics & Stem Cells Authors: Tags: Infect Genet Evol Source Type: research
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