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Antitubercular agent

Géraldine San Jose, Emily R Jackson, Amanda Haymond, Chinchu Johny, Rachel L Edwards, Xu Wang, R Carl Brothers, Emma K Edelstein, Audrey R Odom, Helena I Boshoff, Robin D Couch, Cynthia S Dowd
Despite continued research efforts, the threat of drug resistance from a variety of bacteria continues to plague clinical communities. Discovery and validation of novel biochemical targets will facilitate development of new drugs to combat these organisms. The methylerythritol phosphate (MEP) pathway to make isoprene units is a biosynthetic pathway essential to many bacteria. We and others have explored inhibitors of the MEP pathway as novel antibacterial agents. Mycobacterium tuberculosis, the causative agent of tuberculosis, and Yersinia pestis, resulting in the plague or "black death", both rely on the MEP pathway for isoprene production...
October 12, 2016: ACS Infectious Diseases
Saurabh Garg, Neeraj Shakya, Naveen C Srivastav, Babita Agrawal, Dennis Y Kunimoto, Rakesh Kumar
The resurgence of mycobacterial infections and the emergence of drug-resistant strains urgently require a new class of agents that are distinct than current therapies. A group of 5-ethynyl (6-10), 5-(2-propynyloxy) (16, 18, 20, 22, 24), 5-(2-propynyloxy)-3-N-(2-propynyl) (17, 19, 21, 23, 25) and 5-hydroxymethyl-3-N-(2-propynyl) (30-33) derivatives of pyrimidine nucleosides were synthesized and evaluated against mycobacteria [Mycobacterium tuberculosis (Mtb), Mycobacterium bovis (BCG) and Mycobacterium avium], gram-positive bacteria (Staphylococcus aureus and Enterococcus faecalis) and gram-negative bacteria (Escherichia coli, Salmonella typhimurium and Pseudomonas aeruginosa) alone and in combination with existing drugs in in vitro assays...
November 1, 2016: Bioorganic & Medicinal Chemistry
Vinayak Singh, Valerie Mizrahi
Tuberculosis (TB) is a global epidemic associated increasingly with resistance to first- and second-line antitubercular drugs. The magnitude of this global health threat underscores the urgent need to discover new antimycobacterial agents that have novel mechanisms of action (MOA). In this short review, we highlight some of the key advances that have enabled the strengths of target-led and phenotypic approaches to TB drug discovery to be harnessed both independently and in combination. Critically, these promise to fuel the front-end of the TB drug pipeline with new, pharmacologically validated drug targets together with lead compounds that act on these targets...
September 17, 2016: Drug Discovery Today
Giorgia Mori, Laurent Roberto Chiarelli, Giovanna Riccardi, Maria Rosalia Pasca
The term 'prodrug' was first introduced by Albert in 1958. Generally, prodrugs can be utilized for improving active drug solubility and bioavailability, increasing drug permeability and absorption, modifying the distribution profile, preventing fast metabolism and excretion, and reducing toxicity. Previously, the prodrug approach was a final resort during the drug discovery process only after all other approaches had been exhausted. However, this strategy is now considered during the early stages of the drug development process...
September 17, 2016: Drug Discovery Today
Peter M Njogu, Eric M Guantai, Elumalai Pavadai, Kelly Chibale
Despite the tremendous improvement in overall global health heralded by the adoption of the Millennium Declaration in the year 2000, tropical infections remain a major health problem in the developing world. Recent estimates indicate that the major tropical infectious diseases, namely, malaria, tuberculosis, trypanosomiasis, and leishmaniasis, account for more than 2.2 million deaths and a loss of approximately 85 million disability-adjusted life years annually. The crucial role of chemotherapy in curtailing the deleterious health and economic impacts of these infections has invigorated the search for new drugs against tropical infectious diseases...
January 8, 2016: ACS Infectious Diseases
Gisele S S Firmino, Marcus V N de Souza, Claudia Pessoa, Maria C S Lourenco, Jackson A L C Resende, Josane A Lessa
In this study, the N,N,O metal chelator 2-pyridinecarboxaldehydeisonicotinoyl hydrazone (HPCIH, 1) and its derivatives 2-acetylpyridine-(HAPIH 2), 2-pyridineformamide-(HPAmIH, 3) and pyrazineformamide-(HPzAmIH, 4) were employed in the synthesis of four copper(II) complexes, [Cu(HPCIH)Cl2]·0.4H2O (5), [Cu(HAPIH)Cl2]·1.25H2O (6), [Cu(HPAmIH)Cl2]·H2O (7) and [Cu(HPzAmIH)Cl2]·1.25H2O (8). The compounds were assayed for their action toward Mycobacterium tuberculosis H37Rv ATCC 27294 strain and the human tumor cell lines OVCAR-8 (ovarian cancer), SF-295 (glioblastoma multiforme) and HCT-116 (colon adenocarcinoma)...
September 3, 2016: Biometals: An International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine
Gisela C Muscia, Silvia E Asis, Graciela Y Buldain
BACKGROUND: Many 2-substituted quinolines and especially 2-arylvinyl derivatives isolated from plants or prepared by synthesis have been designed from ethnopharmacological studies. OBJECTIVE: In order to explore new aspects of the structure-antituberculosis activity relationship, a series of styrylquinoline derivatives was prepared Method: A series of styrylquinoline derivatives was prepared from quinaldic acid and a variety of arylbenzaldehydes under eco-friendly conditions via Knoevenagel reaction and trifluoroacetic acid (TFA) as catalyst...
September 1, 2016: Medicinal Chemistry
Behnoush Hajian, Eric Scocchera, Santosh Keshipeddy, Narendran G-Dayanandan, Carolyn Shoen, Jolanta Krucinska, Stephanie Reeve, Michael Cynamon, Amy C Anderson, Dennis L Wright
Mycobacterium tuberculosis continues to cause widespread, life-threatening disease. In the last decade, this threat has grown dramatically as multi- and extensively-drug resistant (MDR and XDR) bacteria have spread globally and the number of agents that effectively treat these infections is significantly reduced. We have been developing the propargyl-linked antifolates (PLAs) as potent inhibitors of the essential enzyme dihydrofolate reductase (DHFR) from bacteria and recently found that charged PLAs with partial zwitterionic character showed improved mycobacterial cell permeability...
2016: PloS One
Kavita Chaudhari, Sanjay Surana, Pritam Jain, Harun M Patel
New classes of drugs are needed to treat tuberculosis (TB) in order to combat the emergence of resistance (MDR and XDR) to existing agents and shorten the duration of therapy. Mycobacterial DNA gyrase B subunit has been identified to be one of the potentially under exploited drug targets in the field of antitubercular drug discovery. In the present review, we discussed the synthesis, structural optimization and docking study of effective potent DNA gyrase inhibitor against M. tuberculosis, with improved properties such as enhanced activity against MDR strains, reduced toxicity...
August 20, 2016: European Journal of Medicinal Chemistry
Georgios Daletos, Elena Ancheeva, Chaidir Chaidir, Rainer Kalscheuer, Peter Proksch
Marine organisms play an important role in natural product-based drug research due to accumulation of structurally unique and bioactive metabolites. The exploration of marine-derived compounds may significantly extend the scientific knowledge of potential scaffolds for antibiotic drug discovery. Development of novel antitubercular agents is especially significant as the emergence of drug-resistant Mycobacterium tuberculosis strains remains threateningly high. Marine invertebrates (i.e., sponges, corals, gorgonians) as a source of new chemical entities are the center of research for several scientific groups, and the wide spectrum of biological activities of marine-derived compounds encourages scientists to carry out investigations in the field of antibiotic research, including tuberculosis treatment...
October 2016: Archiv der Pharmazie
Tatsuya Yuba, Mayumi Hatsuse, Mai Kodama, Sayaka Uda, Akihiro Yoshimura, Naoko Kurisu
A 79-year-old man with a history of tuberculosis was found to have chronic empyema in the right lung and was diagnosed with malignant diffuse large-cell lymphoma (Ann Arbor stage IIE). After completion of one course of rituximab plus cyclophosphamide, pirarubicin, vincristine, and prednisolone (R-CHOP) chemotherapy, the patient developed lung abscess and sepsis caused by Streptococcus intermedius. This condition was treated with antimicrobial agents, and chemotherapy was resumed. After the second course, the chemotherapy regimen was continued without prednisolone, and after administration of the third course, a chest wall mass was found in the right lung...
April 2016: Kekkaku: [Tuberculosis]
Á Ábrahám, Zs Baranyai, G Gyulai, E Pári, K Horváti, Sz Bősze, É Kiss
Novel peptide conjugates of two antitubercular drug candidates were synthesised and characterised using new tuftsin peptide derivative (OT14) as carrier moiety. As antitubercular drug candidates two pyridopyrimidine derivatives, TB803 (2-allylamino-4-oxopyrido[1,2-a]pyrimidine-3-carbaldehyde) and TB820 (4-oxo-2-(pyrrolidin-1-yl)-pyrido[1,2-a]pyrimidin-3-carbaldehyde) inhibiting vital enzyme of Mycobacterium tuberculosis were applied. Membrane affinity of the compounds TB803 and TB820 and their peptide conjugates was evaluated using experimental lipid mono- and bilayer models...
November 1, 2016: Colloids and Surfaces. B, Biointerfaces
Rupesh Agrawal, Dinesh V Gunasekeran, Julio J Gonzalez-Lopez, Joao Cardoso, Bhaskar Gupta, Peter K F Addison, Mark Westcott, Carlos E Pavesio
PURPOSE: Describe the clinical features and outcomes of patients with peripheral retinal vasculitis (RV) and describe clinical characteristics of presumed tubercular RV in a nonendemic setting. METHODS: Retrospective cohort study of 110 consecutive patients with peripheral RV at a tertiary referral eye care center in the United Kingdom. Retinal vasculitis was defined as RV with vitritis associated with peripheral retinal ischemia. Patients who also had positive Quantiferon Gold in Tube test, positive tuberculin skin test, and/or other evidence of systemic tuberculosis such as biopsy were labeled with presumed tubercular RV...
August 2, 2016: Retina
Sidhartha S Kar, Varadaraj Bhat G, Praveen Pn Rao, Vishnu P Shenoy, Indira Bairy, G Gautham Shenoy
A series of triclosan mimic diphenyl ether derivatives have been synthesized and evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv. The binding mode of the compounds at the active site of enoyl-acyl carrier protein reductase of M. tuberculosis has been explored. Among them, compound 10b was found to possess antitubercular activity (minimum inhibitory concentration =12.5 µg/mL) comparable to triclosan. All the synthesized compounds exhibited low levels of cytotoxicity against Vero and HepG2 cell lines, and three compounds 10a, 10b, and 10c had a selectivity index more than 10...
2016: Drug Design, Development and Therapy
Remya Ramesh, Rahul D Shingare, Vinod Kumar, Amitesh Anand, Swetha B, Sridhar Veeraraghavan, Srikant Viswanadha, Ramesh Ummanni, Rajesh Gokhale, D Srinivasa Reddy
The structural similarity between an MmpL3 inhibitor BM212, and a cannabinoid receptor modulator rimonabant, prompted us to investigate the anti-tubercular activity of rimonabant and its analogues. Further optimization, particularly through incorporation of silicon into the scaffold, resulted in new compounds with significant improvement in anti-tubercular activity against Mycobacterium tuberculosis (H37Rv). The sila analogue 18a was found to be the most potent antimycobacterial compound (MIC, 31 ng/mL) from this series with an excellent selectivity index...
October 21, 2016: European Journal of Medicinal Chemistry
María Martínez-Hoyos, Esther Perez-Herran, Gulcin Gulten, Lourdes Encinas, Daniel Álvarez-Gómez, Emilio Alvarez, Santiago Ferrer-Bazaga, Adolfo García-Pérez, Fátima Ortega, Iñigo Angulo-Barturen, Joaquin Rullas-Trincado, Delia Blanco Ruano, Pedro Torres, Pablo Castañeda, Sophie Huss, Raquel Fernández Menéndez, Silvia González Del Valle, Lluis Ballell, David Barros, Sundip Modha, Neeraj Dhar, François Signorino-Gelo, John D McKinney, Jose Francisco García-Bustos, Jose Luis Lavandera, James C Sacchettini, M Soledad Jimenez, Nuria Martín-Casabona, Julia Castro-Pichel, Alfonso Mendoza-Losana
Despite being one of the first antitubercular agents identified, isoniazid (INH) is still the most prescribed drug for prophylaxis and tuberculosis (TB) treatment and, together with rifampicin, the pillars of current chemotherapy. A high percentage of isoniazid resistance is linked to mutations in the pro-drug activating enzyme KatG, so the discovery of direct inhibitors (DI) of the enoyl-ACP reductase (InhA) has been pursued by many groups leading to the identification of different enzyme inhibitors, active against Mycobacterium tuberculosis (Mtb), but with poor physicochemical properties to be considered as preclinical candidates...
June 2016: EBioMedicine
Pradip K Gadekar, Abhijit Roychowdhury, Prashant S Kharkar, Vijay M Khedkar, Manisha Arkile, Hardik Manek, Dhiman Sarkar, Rajiv Sharma, V Vijayakumar, S Sarveswari
The design, synthesis and antimicrobial evaluation of a novel series of azaspiro analogues of linezolid (1) have been described. Linezolid comprises of a morpholine ring which is known for its metabolism-related liabilities. Therefore, the key modification made in the linezolid structure was the replacement of morpholine moiety with its bioisostere, 2-oxa-6-azaspiro[3.3]heptane. Furthermore, the replacement of N-acetyl terminal of 1 with various aromatic or aliphatic functionalities was carried out. The title compounds were evaluated against a panel of Gram-positive and Gram-negative bacteria and Mycobacterium tuberculosis...
October 21, 2016: European Journal of Medicinal Chemistry
Chao Gao, Cuiting Peng, Yaojie Shi, Xinyu You, Kai Ran, Lu Xiong, Ting-Hong Ye, Lidan Zhang, Ningyu Wang, Yongxia Zhu, Kun Liu, Weiqiong Zuo, Luoting Yu, Yuquan Wei
New chemotherapeutic compounds are needed to combat multidrug-resistant Mycobacterium tuberculosis (Mtb), which remains a serious public-health challenge. Decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1 enzyme) has been characterized as an attractive therapeutic target to address this urgent demand. Herein, we have identified a new class of DprE1 inhibitors benzothiazinethiones as antitubercular agents. Benzothiazinethione analogue SKLB-TB1001 exhibited excellent activity against Mtb in the Microplate Alamar blue assay and intracellular model, meanwhile SKLB-TB1001 was also highly potent against multi-drug resistant extensively and drug resistant clinical isolates...
2016: Scientific Reports
Gabriel A Gutiérrez-Rebolledo, A Georgina Siordia-Reyes, Mariana Meckes-Fischer, Adelina Jiménez-Arellanes
OBJECTIVE: To estimate to what extent the mixture of ursolic acid and oleanolic acid, in addition to the antitubercular standard regime, affects the hepatotoxicity profile. METHODS: Liver injury was induced in male BALB/c mice by administering, per os and daily for 11 weeks, a combination of anti-Tubercular (anti-TB) agents Rifampicin (10 mg/kg), Isoniazid (10 mg/kg), and Pyrazinamide (30 mg/kg). The ursolic acid and oleanolic acid mixture at doses of 100 or 200 μg/mouse/day was subcutaneously injected throughout the entire study period (11 weeks)...
July 2016: Asian Pacific Journal of Tropical Medicine
Hiroyuki Sasabe, Yoshihiko Shimokawa, Masakazu Shibata, Kenta Hashizume, Yusuke Hamasako, Yoshihiro Ohzone, Eiji Kashiyama, Ken Umehara
No abstract text is available yet for this article.
July 2016: Antimicrobial Agents and Chemotherapy
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