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Antitubercular agent

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https://www.readbyqxmd.com/read/28626525/identification-of-better-pharmacokinetic-benzothiazinone-derivatives-as-new-antitubercular-agents
#1
Kai Lv, Xuefu You, Bin Wang, Zengquan Wei, Yun Chai, Bo Wang, Apeng Wang, Guocheng Huang, Mingliang Liu, Yu Lu
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 were designed and synthesized as new antitubercular agents. Many of them were found to have excellent in vitro activity (MIC < 0.15 μM) against the drug susceptive Mycobacterium tuberculosis H37Rv strain and two clinically isolated multidrug-resistant strains. Compounds 11l and 11m display acceptable safety, greater aqueous solubility, and better pharmacokinetic profiles than PBTZ169, suggesting their promising potential to be lead compounds for future antitubercular drug discovery...
June 8, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28582669/qsar-driven-design-synthesis-and-discovery-of-potent-chalcone-derivatives-with-antitubercular-activity
#2
Marcelo N Gomes, Rodolpho C Braga, Edyta M Grzelak, Bruno J Neves, Eugene Muratov, Rui Ma, Larry L Klein, Sanghyun Cho, Guilherme R Oliveira, Scott G Franzblau, Carolina Horta Andrade
New anti-tuberculosis (anti-TB) drugs are urgently needed to battle drug-resistant Mycobacterium tuberculosis strains and to shorten the current 6-12-month treatment regimen. In this work, we have continued the efforts to develop chalcone-based anti-TB compounds by using an in silico design and QSAR-driven approach. Initially, we developed SAR rules and binary QSAR models using literature data for targeted design of new heteroaryl chalcone compounds with anti-TB activity. Using these models, we prioritized 33 compounds for synthesis and biological evaluation...
May 10, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28559262/metformin-adjunctive-therapy-does-not-improve-the-sterilizing-activity-of-the-first-line-antitubercular-regimen-in-mice
#3
Noton K Dutta, Michael L Pinn, Petros C Karakousis
Preliminary preclinical and observational studies suggest the potential utility of metformin as an adjunctive, host-directed agent for treatment of tuberculosis (TB). In this study, we sought to investigate the bactericidal and sterilizing activities of human-like exposures of metformin when given in combination with the first-line regimen against chronic tuberculosis in BALB/c mice. Mice receiving metformin adjunctive therapy had similar lung bacillary burdens with control mice during treatment and the proportion of mice with microbiological relapse was similar between the two groups...
May 30, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28555087/strategic-incorporation-of-fluorine-in-the-drug-discovery-of-new-generation-antitubercular-agents-targeting-bacterial-cell-division-protein-ftsz
#4
Iwao Ojima, Divya Awasthi, Longfei Wei, Krupanandan Haranahalli
This article presents an account of our research on the discovery and development of new-generation fluorine-containing antibacterial agents against drug-resistant tuberculosis, targeting FtsZ. FtsZ is an essential protein for bacterial cell division and a highly promising therapeutic target for antibacterial drug discovery. Through design, synthesis and semi-HTP screening of libraries of novel benzimidazoles, followed by SAR studies, we identified highly potent lead compounds. However, these lead compounds were found to lack sufficient metabolic and plasma stabilities...
April 2017: Journal of Fluorine Chemistry
https://www.readbyqxmd.com/read/28550767/antibiotics-and-mania-a-systematic-review
#5
REVIEW
Simon Lambrichts, Lukas Van Oudenhove, Pascal Sienaert
OBJECTIVES: Mania can occur secondary to a medical condition and can be elicited by various pharmacological treatments, both in patients with or without a history of affective disorder. Antibiotic-induced mania or antibiomania is suggested to be a rare phenomenon. We reviewed the literature in order to collect published reports of antibiomania and to summarize new insights about its mechanism and management. METHODS: We performed a MEDLINE-search and used manual cross-referencing for reports of antibiotic-induced mania and included cases in which a (hypo)manic episode was diagnosed in close temporal relationship with the prescription of an antibiotic...
May 20, 2017: Journal of Affective Disorders
https://www.readbyqxmd.com/read/28532916/spinal-intramedullary-tuberculosis-with-concurrent-supra-and-infratentorial-intracranial-disease-in-a-9-month-old-boy-case-report-and-review-of-the-literature
#6
REVIEW
Michael George Zaki Ghali, Visish M Srinivasan, C J Kim, Archana Malik
Tuberculous involvement of the spinal cord parenchyma is an exceedingly rare clinical entity; even more so is concurrent intracranial tuberculosis (TB). Spinal intramedullary TB presents with a characteristic subacute myelopathy, with slowly progressive paraplegia, sensory deficits, and/or bowel and bladder dysfunction. Diagnosis is strongly suspected with a clinical history of known TB in conjunction with characteristic findings on magnetic resonance imaging. Management involves multi-agent antitubercular chemotherapy without or with operative intervention...
May 19, 2017: World Neurosurgery
https://www.readbyqxmd.com/read/28527405/synthesis-and-structure-activity-relationships-of-novel-fused-ring-analogues-of-q203-as-antitubercular-agents
#7
Sunhee Kang, Young Mi Kim, Heekyung Jeon, Sejin Park, Min Jung Seo, Saeyeon Lee, Dongsik Park, Jiyeon Nam, Seokwoo Lee, Kiyean Nam, Sanghee Kim, Jaeseung Kim
A set of fused ring analogues of a new antitubercular agent, Q203, was designed and synthesized. To reduce the lipophilicity of Q203 caused by linearly extended side chains, shorter and heteroatoms containing fused rings were introduced into the side chain region. Antitubercular activity was tested against H37Rv-GFP replicating in liquid broth culture medium (extracellular) and within macrophages (intracellular). Many analogues showed potent extracellular activities as well as intracellular activities without cytotoxicity...
May 10, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28497493/natural-and-synthetic-flavonoids-as-potent-mycobacterium-tuberculosis-ugm-inhibitors
#8
Stephane Vincent, Sydney Villaume, Jian Fu, Inès N'Go, Huayong Lou, Hui Liang, Laurent Kremer, Weidong Pan
This study reports a novel class of inhibitors of UDP-galactopyranose mutase (UGM) derived from a screening of natural products. This enzyme is an essential biocatalyst involved in the cell wall biosynthesis of Mycobacterium tuberculosis. Flavonoids were found to be potent inhibitors of UGM. The synthesis of novel methylated flavonoids allowed to perform a structure-activity relationship analysis and to determine which functional groups and structural elements are required for UGM inhibition.The binding mode of one of the best inhibitor was found to be non-competitive...
May 11, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28462696/hybrid-docking-qsar-studies-of-1-4-dihydropyridine-3-5-dicarboxamides-as-potential-antitubercular-agents
#9
Yasaman Rasouli, Asghar Davood
BACKGROUND: Tuberculosis is one of the main medical problems that some people are suffering still from this infectious disease. 1, 4-dihydropyridines are a multi-target ligands that recently are recognized as an anti-tubercular agents. METHOD: In the current research we did computational studies of some synthesized 1, 4-dihydropyridine-3, 5-dicarboxamides in non-hydrolyzed and hydrolyzed forms to find the drug-receptor interactions profile. RESULTS: Among equations that obtained for non-hydrolyzed compounds, the model with better statistical parameters such as R2= 0...
April 26, 2017: Current Computer-aided Drug Design
https://www.readbyqxmd.com/read/28459575/7-substituted-2-nitro-5-6-dihydroimidazo-2-1-b-1-3-oxazines-novel-antitubercular-agents-lead-to-a-new-preclinical-candidate-for-visceral-leishmaniasis
#10
Andrew M Thompson, Patrick D O'Connor, Andrew J Marshall, Vanessa Yardley, Louis Maes, Suman Gupta, Delphine Launay, Stephanie Braillard, Eric Chatelain, Scott G Franzblau, Baojie Wan, Yuehong Wang, Zhenkun Ma, Christopher B Cooper, William A Denny
Within a backup program for the clinical investigational agent pretomanid (PA-824), scaffold hopping from delamanid inspired the discovery of a novel class of potent antitubercular agents that unexpectedly possessed notable utility against the kinetoplastid disease visceral leishmaniasis (VL). Following the identification of delamanid analogue DNDI-VL-2098 as a VL preclinical candidate, this structurally related 7-substituted 2-nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazine class was further explored, seeking efficacious backup compounds with improved solubility and safety...
May 25, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28446777/structural-investigations-on-orotate-phosphoribosyltransferase-from-mycobacterium-tuberculosis-a-key-enzyme-of-the-de-novo-pyrimidine-biosynthesis
#11
Stefano Donini, Davide M Ferraris, Riccardo Miggiano, Alberto Massarotti, Menico Rizzi
The Mycobacterium tuberculosis orotate phosphoribosyltransferase (MtOPRT) catalyses the conversion of α-D-5-phosphoribosyl-1-pyrophosphate (PRPP) and orotate (OA) in pyrophosphate and orotidine 5'-monophosphate (OMP), in presence of Mg(2+). This enzyme is the only responsible for the synthesis of orotidine 5'-monophosphate, a key precursor in the de novo pyrimidine biosynthesis pathway, making MtOPRT an attractive drug target for the development of antitubercular agents. We report the crystal structures of MtOPRT in complex with PRPP (2...
April 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28419153/biochemical-and-structural-investigations-on-phosphoribosylpyrophosphate-synthetase-from-mycobacterium-smegmatis
#12
Stefano Donini, Silvia Garavaglia, Davide M Ferraris, Riccardo Miggiano, Shigetarou Mori, Keigo Shibayama, Menico Rizzi
Mycobacterium smegmatis represents one model for studying the biology of its pathogenic relative Mycobacterium tuberculosis. The structural characterization of a M. tuberculosis ortholog protein can serve as a valid tool for the development of molecules active against the M. tuberculosis target. In this context, we report the biochemical and structural characterization of M. smegmatis phosphoribosylpyrophosphate synthetase (PrsA), the ortholog of M. tuberculosis PrsA, the unique enzyme responsible for the synthesis of phosphoribosylpyrophosphate (PRPP)...
2017: PloS One
https://www.readbyqxmd.com/read/28407303/rifampicin-reverses-nicardipine-effect-inducing-uncontrolled-essential-hypertension
#13
Elena-Mihaela Cordeanu, Sébastien Gaertner, Alix Faller, Corina Mirea, Jean-Marc Lessinger, Veronique Kemmel, Dominique Stephan
Dihydropyridine calcium-channel blockers are a known substrate for the cytochrome P450 isoform 3A4. Rifampicin, an antitubercular agent, is one of the most potent inducers of hepatic and intestinal CYP3A4 thus increasing dihydropyridine metabolism. We report a case of a 67-year-old hypertensive female treated with a 4-drug antihypertensive regimen including a dihydropyridine (nicardipine 50mg bid), who was admitted for septic arthritis of the knee requiring antibiotic treatment with teicoplanin 400mg od and rifampicin 600mg bid...
April 13, 2017: Fundamental & Clinical Pharmacology
https://www.readbyqxmd.com/read/28384546/in%C3%A2-vitro-biological-evaluation-of-new-antimycobacterial-salicylanilide-tuftsin-conjugates
#14
Zsuzsa Baranyai, Martin Krátký, Rudolf Vosátka, Eleonóra Szabó, Zsuzsanna Senoner, Sándor Dávid, Jiřina Stolaříková, Jarmila Vinšová, Szilvia Bősze
Tuberculosis is caused by Mycobacterium tuberculosis, an intracellular pathogen that can survive in host cells, mainly in macrophages. An increase of multidrug-resistant tuberculosis qualifies this infectious disease as a major public health problem worldwide. The cellular uptake of the antimycobacterial agents by infected host cells is limited. Our approach is to enhance the cellular uptake of the antituberculars by target cell-directed delivery using drug-peptide conjugates to achieve an increased intracellular efficacy...
March 24, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28372908/novel-quinoxalinyl-chalcone-hybrid-scaffolds-as-enoyl-acp-reductase-inhibitors-synthesis-molecular-docking-and-biological-evaluation
#15
Vidya Desai, Sulaksha Desai, Sonia Naik Gaonkar, Uddesh Palyekar, Shrinivas D Joshi, Sheshagiri K Dixit
We report herein, first ever synthesis of series of novel differently substituted quinoxalinyl chalcones using Claisen Schmidt condensation, its molecular docking studies, and potential to be good anti-microbial, anti-tubercular and anti-cancer agents. The antimicrobial studies were carried out against Staphylococcus aureus, Escherichia coli and Candida albicans using disc diffusion procedure. The selected chalcones were tested for anti-cancer and cytotoxicity activity against MCF-7 cancer cell line using MTT assay method...
March 24, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28279848/structure-activity-relationship-studies-on-3-5-dinitrophenyl-tetrazoles-as-antitubercular-agents
#16
Jan Němeček, Pavel Sychra, Miloslav Macháček, Markéta Benková, Galina Karabanovich, Klára Konečná, Věra Kavková, Jiřina Stolaříková, Alexandr Hrabálek, Kateřina Vávrová, Ondřej Soukup, Jaroslav Roh, Věra Klimešová
In this study, we described the structure-activity relationships of substituted 3,5-dinitrophenyl tetrazoles as potent antitubercular agents. These simple and readily accessible compounds possessed high in vitro antimycobacterial activities against Mycobacterium tuberculosis, including clinically isolated multidrug (MDR) and extensively drug-resistant (XDR) strains, with submicromolar minimum inhibitory concentrations (MICs). The most promising compounds showed low in vitro cytotoxicity and negligible antibacterial and antifungal activities, highlighting their highly selective antimycobacterial effects...
April 21, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28274627/three-component-one-pot-synthesis-of-anthranilamide-schiff-bases-bearing-4-aminoquinoline-moiety-as-mycobacterium-tuberculosis-gyrase-inhibitors
#17
Preeti S Salve, Shankar G Alegaon, Dharmarajan Sriram
An efficient three-component, one-pot protocol is described for the synthesis of biologically interesting 2-(benzylideneamino)-N-(7-chloroquinolin-4-yl)benzohydrazide derivatives from isatoic anhydride, 7-chloro-4-hydrazinylquinoline and aromatic and/or hetero aromatic aldehydes under catalyst free condensation by using water as reaction media. All synthesized compounds were evaluated for their antimycobacterial activity against Mycobacterium tuberculosis (MTB) and cytotoxicity activity against normal VERO cell lines...
February 17, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28260468/tuberculosis-after-renal-transplant
#18
Samia Barbouch, Meriam Hajji, Imed Helal, Mondher Ounissi, Mohammed Mongi Bacha, Fathi Ben Hamida, Ezzedine Abderrahim, Taieb Ben Abdallah
Tuberculosis is one of the leading infections after renal transplant, particularly in developing countries where the incidence and prevalence in the general population are high. Diagnosis requires bacteriologic and histologic confirmation. Interactions among the antitubercular drugs and the immunosuppressive agents have to be considered while prescribing, and surveillance for adverse effects is required. Although rare, case reports are available on extrapulmonary tuberculosis in allograft recipients. Here, we present a 25-year-old kidney transplant recipient who was diagnosed with lymph node tuberculosis under uncommon circumstances but who had a good outcome...
February 2017: Experimental and Clinical Transplantation
https://www.readbyqxmd.com/read/28196957/a-novel-small-molecule-inhibitor-of-the-mycobacterium-tuberculosis-demethylmenaquinone-methyltransferase-meng-is-bactericidal-to-both-growing-and-nutritionally-deprived-persister-cells
#19
Paridhi Sukheja, Pradeep Kumar, Nisha Mittal, Shao-Gang Li, Eric Singleton, Riccardo Russo, Alexander L Perryman, Riju Shrestha, Divya Awasthi, Seema Husain, Patricia Soteropoulos, Roman Brukh, Nancy Connell, Joel S Freundlich, David Alland
Active tuberculosis (TB) and latent Mycobacterium tuberculosis infection both require lengthy treatments to achieve durable cures. This problem has partly been attributable to the existence of nonreplicating M. tuberculosis "persisters" that are difficult to kill using conventional anti-TB treatments. Compounds that target the respiratory pathway have the potential to kill both replicating and persistent M. tuberculosis and shorten TB treatment, as this pathway is essential in both metabolic states. We developed a novel respiratory pathway-specific whole-cell screen to identify new respiration inhibitors...
February 14, 2017: MBio
https://www.readbyqxmd.com/read/28185538/synthesis-and-biological-evaluation-of-hybrid-1-5-and-2-5-disubstituted-indoles-as-potentially-new-antitubercular-agents
#20
Ana Soares, Mónica S Estevão, M Manuel B Marques, Vasily Kovalishyn, Diogo A R S Latino, João Aires-de-Sousa, Jorge Ramos, Miguel Viveiros, Filomena Martins
BACKGROUND: Tuberculosis (TB) is the second leading cause of mortality worldwide being a highly contagious and insidious illness caused by Mycobacterium tuberculosis, Mtb. Additionally, the emergence of multidrug-resistant and extensively drug-resistant strains of Mtb, together with significant levels of co-infection with HIV and TB (HIV/TB) makes the search for new antitubercular drugs urgent and challenging. METHODS: This work was based on the hypothesis that an active compound could be obtained if substituents present in some other active compounds were attached on a core of an important structure, in this case the indole scaffold, thus generating a hybrid compound...
February 9, 2017: Medicinal Chemistry
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