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Antitubercular agent

Galina Karabanovich, Jan Němeček, Lenka Valášková, Alejandro Carazo, Klára Konečná, Jiřina Stolaříková, Alexandr Hrabálek, Oto Pavliš, Petr Pávek, Kateřina Vávrová, Jaroslav Roh, Věra Klimešová
Two new classes of antitubercular agents, namely 5-alkylsulfanyl-1-(3,5-dinitrophenyl)-1H-tetrazoles and 2-alkylsulfanyl-5-(3,5-dinitrophenyl)-1,3,4-oxadiazoles, and their structure-activity relationships are described. These compounds possessed excellent activity against Mycobacterium tuberculosis, including the clinically isolated multidrug (MDR) and extensively drug-resistant (XDR) strains, with no cross resistance with first or second-line anti-TB drugs. The minimum inhibitory concentration (MIC) values of the most promising compounds reached 0...
November 21, 2016: European Journal of Medicinal Chemistry
Neduri V Balaji, Bollikolla Hari Babu, Gottumukkala V Subbaraju, Kurre Purna Nagasree, Muthyala Murali Krishna Kumar
A series of 20 hispolons/dihydrohispolons were synthesized and characterized by spectral data. These compounds were subjected to in vitro antitubercular activity screening against Mycobacterium tuberculosis (H37Rv) strain. The synthesized compounds showed varied antitubercular activity ranging from 100 to 1.6μg/mL. Among the screened compounds, four compounds (H1, H2, H3 and H15) have shown moderate activity with MIC 25μg/mL. Potent activities were observed for the dihydrohispolon derivative H14 (MIC 1.6μg/mL) followed by H13 (6...
November 18, 2016: Bioorganic & Medicinal Chemistry Letters
Kinjal Prajapati, Mira Desai, Samidh Shah, Jigar Panchal, Jigar Kapadia, Ramkumar Dikshit
OBJECTIVE: The objective of this study was to analyze the various aspects of serious adverse drug reactions (serious ADRs) such as clinical presentation, causality, severity, and preventability occurring in a hospital setting. MATERIALS AND METHODS: All serious ADRs reported from January 2010 to May 2015 at ADR Monitoring Centre, Department of Pharmacology, B. J. Medical College and Civil Hospital, Ahmedabad, were selected as per the World health Organization -Uppsala Monitoring Center (WHO-UMC) criteria...
October 2016: Perspectives in Clinical Research
Raquel S Amim, Cláudia Pessoa, Maria C S Lourenço, Marcus V N de Souza, Josane A Lessa
BACKGROUND: Schiff bases have been greatly studied in biological field due to their wide range of pharmacological activities, such as antitubercular and antitumour. In the search of novel antitubercular agents, several compounds containing pharmacophoric group of ethambutol have been synthesized and evaluated against mycobacteria species causing tuberculosis. In this work, we investigate whether ethylenediamine, Schiff base as well as nitro group together could contribute to the formation of novel molecules with dual biological activities: antitubercular and anticancer...
November 4, 2016: Medicinal Chemistry
Ziqiang Li, Xiaoguang Bai, Qi Deng, Guoning Zhang, Lei Zhou, Yishuang Liu, Juxian Wang, Yucheng Wang
Following up the SAR study of triazolothiadiazoles for their antitubercular activities targeting Mt SD in our previous study, on the principle of scaffold hopping, the C3 and C6 positions of triazolothiadiazine were examined systematically to define a preliminary structure-activity relationship (SAR) with respect to biological activity. This study herein highlights the potential of two highly potent advanced leads 6c-3, 6g-3 and several other compounds with comparable potencies as promising new candidates for the treatment of TB (6c-3, MIC-H37Rv=0...
October 21, 2016: Bioorganic & Medicinal Chemistry
Bharathkumar Inturi, Gurubasavaraj V Pujar, Madhusudhan N Purohit
Mycobacterium tuberculosis enoyl-ACP reductase (InhA) has been validated as a promising target for antitubercular agents. Isoniazid (INH), the most prescribed drug to treat tuberculosis (TB), inhibits a NADH-dependent InhA that provides precursors of mycolic acids, which are components of the mycobacterial cell wall. It is a pro-drug that needs activation to form the inhibitory INH-NAD adduct by KatG coding for catalase-peroxidase. The INH resistance of M. tuberculosis is caused by mutations in KatG, which may lead to multidrug-resistant TB (MDR-TB)...
October 24, 2016: Archiv der Pharmazie
Eleni Pitta, Olga Balabon, Maciej K Rogacki, Jesús Gómez, Fraser Cunningham, Jurgen Joosens, Koen Augustyns, Pieter van der Veken, Robert Bates
During the construction of bioactive molecules, regioselective alkylation of heterocyclic, N/O ambident nucleophiles is a frequently encountered synthetic transformation. In this framework, specific attention is required to unambiguously determine the structures of obtained reaction products. As part of our project on quinoloxyacetamide based antimycobacterial agents, a series of N- or O- alkylated quinolin-4-ol, 1,5-naphthyridin-4-ol and quinazolin-4-ol derivatives were prepared during the course of which we observed unexpected selectivity issues...
October 11, 2016: European Journal of Medicinal Chemistry
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 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)...
December 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
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