دورية أكاديمية
أعرض في EDS

Design, Synthesis, and Characterization of N-Oxide-Containing Heterocycles with in Vivo Sterilizing Antitubercular Activity.

التفاصيل البيبلوغرافية
العنوان: Design, Synthesis, and Characterization of N-Oxide-Containing Heterocycles with in Vivo Sterilizing Antitubercular Activity.
المؤلفون: Dos Santos Fernandes GF; São Paulo State University (UNESP) , Institute of Chemistry, Araraquara 14800060, Brazil.; São Paulo State University (UNESP) , School of Pharmaceutical Sciences, Araraquara 14800903, Brazil.; Universidad de Navarra , Department of Organic and Pharmaceutical Chemistry, Instituto de Salud Tropical, Pamplona 31008, Spain., de Souza PC; São Paulo State University (UNESP) , School of Pharmaceutical Sciences, Araraquara 14800903, Brazil.; Institute of Tuberculosis Research, University of Illinois at Chicago , Chicago, Illinois 60607, United States., Moreno-Viguri E; Universidad de Navarra , Department of Organic and Pharmaceutical Chemistry, Instituto de Salud Tropical, Pamplona 31008, Spain., Santivañez-Veliz M; Universidad de Navarra , Department of Organic and Pharmaceutical Chemistry, Instituto de Salud Tropical, Pamplona 31008, Spain., Paucar R; Universidad de Navarra , Department of Organic and Pharmaceutical Chemistry, Instituto de Salud Tropical, Pamplona 31008, Spain., Pérez-Silanes S; Universidad de Navarra , Department of Organic and Pharmaceutical Chemistry, Instituto de Salud Tropical, Pamplona 31008, Spain., Chegaev K; Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino , Turin 10124, Italy., Guglielmo S; Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino , Turin 10124, Italy., Lazzarato L; Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino , Turin 10124, Italy., Fruttero R; Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino , Turin 10124, Italy., Man Chin C; São Paulo State University (UNESP) , School of Pharmaceutical Sciences, Araraquara 14800903, Brazil., da Silva PB; São Paulo State University (UNESP) , School of Pharmaceutical Sciences, Araraquara 14800903, Brazil., Chorilli M; São Paulo State University (UNESP) , School of Pharmaceutical Sciences, Araraquara 14800903, Brazil., Solcia MC; São Paulo State University (UNESP) , School of Pharmaceutical Sciences, Araraquara 14800903, Brazil., Ribeiro CM; São Paulo State University (UNESP) , School of Pharmaceutical Sciences, Araraquara 14800903, Brazil., Silva CSP; São Paulo State University (UNESP) , School of Pharmaceutical Sciences, Araraquara 14800903, Brazil., Marino LB; São Paulo State University (UNESP) , School of Pharmaceutical Sciences, Araraquara 14800903, Brazil., Bosquesi PL; São Paulo State University (UNESP) , School of Pharmaceutical Sciences, Araraquara 14800903, Brazil., Hunt DM; Mycobacterial Metabolism and Antibiotic Research Laboratory, The Francis Crick Institute , 1 Midland Road, London NW1 1AT, United Kingdom., de Carvalho LPS; Mycobacterial Metabolism and Antibiotic Research Laboratory, The Francis Crick Institute , 1 Midland Road, London NW1 1AT, United Kingdom., de Souza Costa CA; São Paulo State University (UNESP) , School of Odontology, Araraquara 14801903, Brazil., Cho SH; Institute of Tuberculosis Research, University of Illinois at Chicago , Chicago, Illinois 60607, United States., Wang Y; Institute of Tuberculosis Research, University of Illinois at Chicago , Chicago, Illinois 60607, United States., Franzblau SG; Institute of Tuberculosis Research, University of Illinois at Chicago , Chicago, Illinois 60607, United States., Pavan FR; São Paulo State University (UNESP) , School of Pharmaceutical Sciences, Araraquara 14800903, Brazil., Dos Santos JL; São Paulo State University (UNESP) , Institute of Chemistry, Araraquara 14800060, Brazil.; São Paulo State University (UNESP) , School of Pharmaceutical Sciences, Araraquara 14800903, Brazil.
المصدر: Journal of medicinal chemistry [J Med Chem] 2017 Oct 26; Vol. 60 (20), pp. 8647-8660. Date of Electronic Publication: 2017 Oct 16.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE
أسماء مطبوعة: Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
مواضيع طبية MeSH: Antitubercular Agents/*chemistry , Antitubercular Agents/*pharmacology , Heterocyclic Compounds/*chemistry , Heterocyclic Compounds/*pharmacology, Animals ; Antitubercular Agents/chemical synthesis ; Antitubercular Agents/pharmacokinetics ; Biological Availability ; Caco-2 Cells ; Heterocyclic Compounds/chemical synthesis ; Heterocyclic Compounds/pharmacokinetics ; Humans ; Mice ; Mice, Inbred BALB C ; Microbial Sensitivity Tests ; Mycobacterium tuberculosis/drug effects ; Oxides/chemistry ; Spectrum Analysis/methods
مستخلص: Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is the infectious disease responsible for the highest number of deaths worldwide. Herein, 22 new N-oxide-containing compounds were synthesized followed by in vitro and in vivo evaluation of their antitubercular potential against Mtb. Compound 8 was found to be the most promising compound, with MIC 90 values of 1.10 and 6.62 μM against active and nonreplicating Mtb, respectively. Additionally, we carried out in vivo experiments to confirm the safety and efficacy of compound 8; the compound was found to be orally bioavailable and highly effective, leading to a reduction of Mtb to undetectable levels in a mouse model of infection. Microarray-based initial studies on the mechanism of action suggest that compound 8 blocks translation. Altogether, these results indicate that benzofuroxan derivative 8 is a promising lead compound for the development of a novel chemical class of antitubercular drugs.
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معلومات مُعتمدة: HHSN272201100009I United States AI NIAID NIH HHS; FC001060 United Kingdom CRUK_ Cancer Research UK; HHSN272201100009C United States AI NIAID NIH HHS; United Kingdom WT_ Wellcome Trust; FC001060 United Kingdom MRC_ Medical Research Council; FC001060 United Kingdom WT_ Wellcome Trust
المشرفين على المادة: 0 (Antitubercular Agents)
0 (Heterocyclic Compounds)
0 (Oxides)
تواريخ الأحداث: Date Created: 20171003 Date Completed: 20171121 Latest Revision: 20220129
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC5677254
DOI: 10.1021/acs.jmedchem.7b01332
PMID: 28968083
قاعدة البيانات: MEDLINE
الوصف
تدمد:1520-4804
DOI:10.1021/acs.jmedchem.7b01332