Journal ArticleDOI
Identification of antitubercular benzothiazinone compounds by ligand-based design
Tomislav Karoli,Bernd Becker,Johannes Zuegg,Ute Möllmann,Soumya Ramu,Johnny X. Huang,Mark E. Cooper +6 more
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TLDR
Several of the BTZ compounds showed improved activity against MDR-TB while retaining low toxicity with higher microsomal, metabolic, and plasma stability and were tested against a panel of mycobacterial strains.Abstract:
1,3-Benzothiazin-4-ones (BTZs) are a novel class of TB drug candidates with potent activity against M. tuberculosis. An in silico ligand-based model based on structure–activity data from 170 BTZ compounds was used to design a new series. Compounds were tested against a panel of mycobacterial strains and were profiled for cytotoxicity, stability, and antiproliferative effects. Several of the compounds showed improved activity against MDR-TB while retaining low toxicity with higher microsomal, metabolic, and plasma stability.read more
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Nitro-Group-Containing Drugs
TL;DR: The current Perspective covers various aspects of agents that contain nitro groups, their bioreductive activation mechanisms, their toxicities, and approaches to combat their toxicity issues.
Journal ArticleDOI
Thiolates Chemically Induce Redox Activation of BTZ043 and Related Potent Nitroaromatic Anti-Tuberculosis Agents
Rohit Tiwari,Garrett C. Moraski,Viktor Krchňák,Patricia A. Miller,Mariangelli Colon-Martinez,Eliza Herrero,Allen G. Oliver,Marvin J. Miller +7 more
TL;DR: Chemical studies offer an alternate hypothesis for the mechanism of action of nitroaromatic anti-TB agents, in that the cysteine thiol(ate) or a hydride source at the active site of DprE1 may trigger the reduction of the nitro groups in a manner similar to the von Richter reaction to theNitroso intermediates, to initiate the inhibition of DPRE1.
Journal ArticleDOI
The 8-Pyrrole-Benzothiazinones Are Noncovalent Inhibitors of DprE1 from Mycobacterium tuberculosis
Vadim Makarov,João Neres,Ruben C. Hartkoorn,O. B. Ryabova,Elena Kazakova,Michal Šarkan,Stanislav Huszár,Jérémie Piton,Gaëlle S. Kolly,Anthony Vocat,Trent M. Conroy,Katarína Mikušová,Stewart T. Cole +12 more
TL;DR: The most promising compound, PyrBTZ01, did not show efficacy in a mouse model of acute tuberculosis, suggesting that BTZ-mediated killing through DprE1 inhibition requires a combination of both covalent bond formation and compound potency.
Journal ArticleDOI
Synthesis and structure-activity relationships evaluation of benzothiazinone derivatives as potential anti-tubercular agents.
Chao Gao,Tinghong Ye,Ningyu Wang,Xiu-Xiu Zeng,Lidan Zhang,Ying Xiong,Xin-Yu You,Yong Xia,Ying Xu,Cui-Ting Peng,Weiqiong Zuo,Yuquan Wei,Luoting Yu +12 more
TL;DR: Results suggested that the volume and lipophilicity of the substituents were important in maintaining activity, and compound 8o was nontoxic to Vero cells and orally bioavailable in a preliminary pharmacokinetics study.
Journal ArticleDOI
Identification of Better Pharmacokinetic Benzothiazinone Derivatives as New Antitubercular Agents.
Kai Lv,Xuefu You,Bin Wang,Zengquan Wei,Yun Chai,Bo Wang,Apeng Wang,Guocheng Huang,Mingliang Liu,Yu Lu +9 more
TL;DR: A series of new 8-nitro-6-(trifluoromethyl)-1,3-benzothiazin-4-one(BTZ) derivatives containing a C-2 nitrogen spiro-heterocycle moiety based on the structures of BTZ candidates BTZ043 and PBTZ169 have promising potential to be lead compounds for future antitubercular drug discovery.
References
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Journal ArticleDOI
Benzothiazinones Kill Mycobacterium tuberculosis by Blocking Arabinan Synthesis
Vadim Makarov,Giulia Manina,Katarína Mikušová,Ute Möllmann,O. B. Ryabova,Brigitte Saint-Joanis,Neeraj Dhar,Maria Rosalia Pasca,Silvia Buroni,Anna Paola Lucarelli,Anna Milano,Edda De Rossi,Martina Belanova,Adela Bobovská,Petronela Dianišková,Jana Korduláková,Claudia Sala,Elizabeth Fullam,Patricia Schneider,John D. McKinney,Priscille Brodin,Thierry Christophe,Simon J. Waddell,Philip D. Butcher,Jakob Albrethsen,Ida Rosenkrands,Roland Brosch,Vrinda Nandi,Sowmya Bharath,Sheshagiri Gaonkar,Radha Shandil,V. Balasubramanian,Tanjore S. Balganesh,Sandeep Tyagi,Jacques H. Grosset,Giovanna Riccardi,Stewart T. Cole +36 more
TL;DR: The synthesis and characterization of 1,3-benzothiazin-4-ones (BTZs), a new class of antimycobacterial agents that kill Mycobacterium tuberculosis in vitro, ex vivo, and in mouse models of TB are described.
Journal ArticleDOI
A facile procedure for acetalization under aprotic conditions
TL;DR: Carbonyl compounds are readily acetalized by alkoxysilanes in the presence of trimethylsilyl trifluoromethanesulfonate catalyst.
Journal ArticleDOI
Global tuberculosis drug development pipeline: the need and the reality
TL;DR: To eliminate tuberculosis as a public health concern by 2050, all responsible parties need to work together to strengthen the global antituberculosis drug pipeline and support the development of new antituber tuberculosis drug regimens.
Journal ArticleDOI
High throughput solubility measurement in drug discovery and development
Jochem Alsenz,Manfred Kansy +1 more
TL;DR: Future needs and trends in solubility assay development designed to overcome current bottlenecks and trade-offs between speed and quality/quantity of measurements are addressed.
Journal ArticleDOI
A High-Throughput Screening Method for the Determination of Aqueous Drug Solubility Using Laser Nephelometry in Microtiter Plates
TL;DR: A fast method based on laser nephelometry that can determine the solubility of potential drug candidates supplied as dimethyl sulfoxide (DMSO) solutions in 96-well plates is described.
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