کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10584429 | 981334 | 2013 | 37 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Tetrazole-based deoxyamodiaquines: Synthesis, ADME/PK profiling and pharmacological evaluation as potential antimalarial agents
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کلمات کلیدی
AntiplasmodialMABAADMEMicroplate Alamar Blue AssayLoRaLC–MS - LC-MSTrimethylsilyl azide - تری متیل سیلیل آزیدAbsorption distribution metabolism excretion - جذب توزیع متابولیسم توزیعCytochrome P450 - سیتوکروم پی۴۵۰Liquid chromatography mass spectrometry - طیف سنجی جرمی کروماتوگرافی مایعPharmacokinetics - فارماکوکینتیکMulti-component reaction - واکنش چند جزءHigh pressure liquid chromatography - کروماتوگرافی مایع با فشار بالاHPLC - کروماتوگرافی مایعی کارا
موضوعات مرتبط
مهندسی و علوم پایه
شیمی
شیمی آلی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
A series of new deoxyamodiaquine-based compounds was synthesized via the modified TMSN3-Ugi multi-component reaction and evaluated in vitro for antiplasmodial activity. The most potent compounds, 6b, 6c and 6j, showed IC50 values in the range of 6-77Â nM against chloroquine-resistant K1- and W2-strains of Plasmodium falciparum. In vitro ADME characterization of frontrunner compounds 6b and 6c indicates that these two compounds are rapidly metabolized and have a high clearance rate in human and rat liver microsomes. This result correlated well with an in vivo pharmacokinetics study, which showed low bioavailability of 6c in rats. Tentative metabolite identification was determined by LC-MS and suggested metabolic lability of groups attached to the tertiary nitrogen. Preliminary studies on 6b and 6c suggested strong inhibitory activity against the major CYP450 enzymes. In silico docking studies were used to rationalize strong inhibition of CYP3A4 by 6c. Full characterization and biological evaluation of the metabolites is currently underway in our laboratories.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Bioorganic & Medicinal Chemistry - Volume 21, Issue 17, 1 September 2013, Pages 4904-4913
Journal: Bioorganic & Medicinal Chemistry - Volume 21, Issue 17, 1 September 2013, Pages 4904-4913
نویسندگان
Matshawandile Tukulula, Mathew Njoroge, Grace C. Mugumbate, Jiri Gut, Philip J. Rosenthal, Samuel Barteau, Judith Streckfuss, Olivier Heudi, Jacques Kameni-Tcheudji, Kelly Chibale,