Mycobacterium tuberculosis is a causative agent for the world threatening infectious disease known as tuberculosis. M. tuberculosis is also referred as Koch's bacillus as it was first defined by Robert Koch in 1821. In the entire history of M. tuberculosis infection, several different targets were identified and explored with a hope of effective therapeutic treatment against tuberculosis. Drug-resistant tuberculosis is the major obstacle for researchers and letting them fail continuously to discover new drug candidates. Among the numerous antitubercular targets, Decaprenyl-phosphoryl-β-D-ribose-2'-epimerase (DprE1) is novel target identified in the year 2009. The present article portrays insights of DprE1 enzyme in all the aspects i.e., identification, structural elucidation to designing strategies and synthesis of potential drug candidates to combat resistant strains. Along with the synthesis and biological activity of novel compounds, structure-activity relationship (SAR) data is given to help medicinal chemists and researchers working in this area for the development of new inhibitors to fight against M. tuberculosis. DprE1 is new ray of hope for antitubercular treatment. No single drug candidate (DprE1 inhibitor) has passed clinical trial yet and hence it nullifies the risk of development of resistance or mutations at specific residues. Researchers working in this area have to design and come up with new potent candidates with less dose, no toxicity to combat this deadly infection. This review emphasized on year wise systematic development and progress of DprE1 inhibitors.
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http://dx.doi.org/10.1016/j.ijtb.2021.09.003 | DOI Listing |
Lancet Microbe
December 2024
Institute of Infectious Diseases and Tropical Medicine, LMU University Hospital, LMU Munich, Germany; German Center for Infection Research, Munich Partner Site, Munich, Germany; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology, Infection, and Pandemic Research, Munich, Germany; Unit Global Health, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. Electronic address:
Background: The broad use of bedaquiline and pretomanid as the mainstay of new regimens to combat tuberculosis is a risk due to increasing bedaquiline resistance. We aimed to assess the safety, bactericidal activity, and pharmacokinetics of BTZ-043, a first-in-class DprE1 inhibitor with strong bactericidal activity in murine models.
Methods: This open-label, dose-expansion, randomised, controlled, phase 1b/2a trial was conducted in two specialised tuberculosis sites in Cape Town, South Africa.
Antimicrob Agents Chemother
November 2024
Resistell AG, Muttenz, Switzerland.
Novel drugs and improved diagnostics for (MTB) are urgently needed and go hand in hand. We evaluated the activity of two benzothiazinone drug candidates (MCZ, PBTZ169; BTZ043) and their main metabolites against MTB using advanced nanomotion technology. The results demonstrated significant reductions in MTB viability within 7 h, indicating the potential for rapid, precise antibiotic susceptibility testing based on a phenotypic read-out in real time.
View Article and Find Full Text PDFPLoS One
November 2024
Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany.
Mycobacterium tuberculosis is a lethal human pathogen, with the key flavoenzyme for catalyzing bacterial cell-wall biosynthesis, decaprenylphosphoryl-D-ribose oxidase (DprE1), considered an Achilles heal for tuberculosis (TB) progression. Inhibition of DprE1 blocks cell wall biosynthesis and is a highly promising antitubercular target. Macozinone (PBTZ169, a benzothiazinone (BTZ) derivative) is an irreversible DprE1 inhibitor that has attracted considerable attention because it exhibits an additive activity when combined with other anti-TB drugs.
View Article and Find Full Text PDFJ Biomol Struct Dyn
November 2024
Organic and Medicinal Chemistry Laboratory, Department of Chemistry, National Institute of Technology Karnataka, Mangalore, Karnataka, India.
In this study, we present a novel series of 4-oxo-1,4-dihydroquinazolinylpyrazine-2-carboxamide derivatives, which exert their inhibitory effect on decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1) the establishment of non-covalent interactions with the pivotal Cys387 residue located within the enzyme's active site. These compounds underwent scrutiny for their efficacy in combatting the H37Rv strain, and compounds T8 and T13 exhibited promising antitubercular activity, boasting a minimal inhibitory concentration (MIC) of 7.99 and 8.
View Article and Find Full Text PDFFuture Med Chem
December 2024
Department of Natural Products & Medicinal Chemistry, CSIR - Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500 007, India.
We designed and synthesized a series of compounds with a 3,5-disubstituted pyridine moiety and evaluated them against (Mtb) and drug-resistant Mtb clinical isolates. A library of 3,5-disubstituted pyridine was synthesized. The compounds were screened for activity against H37Rv.
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