Barteau, Samuel, Heudi, Olivier, Kameni Tcheudji, Jacques, Streckfuss, Judith, Tukulula, Matshawandile, Njoroge, Mathew, Mugumbate, Grace, Little, Susan, Grut, Jiri, Rosenthal, Philip J, Wan, Baojie, Franzblau, Scott G and Chibale, Kelly (2013) Tetrazole-based deoxyamodiaquines: synthesis, ADME/PK profiling and pharmacological evaluation as potential antimalarial and antituberculosis agents. Journal of medicinal chemistry, 21 (17). pp. 4904-4913. ISSN 09680896

Abstract

A series of new deoxyamodiaquine-based compounds was synthesized via the modified TMSN3-Ugi multi-component reaction and evaluated in vitro for antiplasmodial and antimycobacterial activity. The most potent compounds, 6b, 6c and 6j, showed IC50 values in the range of 6 to 77 nM against chloroquine-resistant K1- and W2-strain P. falciparum and MABA MIC90 values in the range of 7.6 to 59.3 µM against M. tuberculosis H37Rv. In vitro ADME characterization of 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.

Item Type:	Article
Date Deposited:	09 May 2016 23:45
Last Modified:	09 May 2016 23:45
URI:	https://oak.novartis.com/id/eprint/9593