Characterisation of artemisinin-chloroquinoline hybrids for potential metabolic liabilities.

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Roslyn S ThelingwaniCollen M Masimirembwa

Abstract

1. Chemotherapy remains the effective way of controlling malaria infections. Many of the treatments have been rendered ineffective as a result of drug resistance by plasmodia species as well as toxicity. Molecular hybridisation is one of the techniques used in the synthesis of new-generation antimalarial techniques. In this paper, we explore some potential metabolic challenges associated with this technique. 2. In vitro metabolic clearance and metabolite identification were performed in cryopreserved hepatocytes. Reaction phenotyping and inhibition studies were conducted in human liver microsomes and recombinant cytochrome P450s (CYPs) 3. Metabolism in hepatocytes was not extensive with less than 25% of the hybrids being metabolised by contributing CYP enzymes. The hybrids were, however, potent inhibitors of CYPs 2C9 2C19 and 3A4. 4. Our data indicated that artemisinin-chloroquinoline hybrid both gained and lost favourable properties from the individual pharmacophoric units from which they were built. This highlights the challenges associated with the molecular hybridisation technique and a need to optimise the chemistry in an effort to maintain good properties while addressing new liabilities that arise.

References

Apr 1, 1996·Clinical Pharmacokinetics·S Krishna, N J White
May 15, 1997·Analytical Biochemistry·C L CrespiB W Penman
Jan 9, 1998·Drug Metabolism Reviews·J B Houston, D J Carlile
Dec 3, 1999·British Journal of Clinical Pharmacology·U S Svensson, M Ashton
Apr 5, 2000·Nature·S PagolaS K Madsen
May 21, 2003·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Denis ProjeanJulie Ducharme
Jun 10, 2003·Clinical Pharmacokinetics·Collen M MasimirembwaTommy B Andersson
Sep 12, 2003·Archives of Pharmacal Research·Kyoung-Ah KimSabina Lim
Sep 13, 2003·British Journal of Clinical Pharmacology·Z E WilsonG T Tucker
Jan 15, 2004·Drug Safety : an International Journal of Medical Toxicology and Drug Experience·W Robert J Taylor, Nicholas J White
Jul 20, 2004·Clinical Microbiology Reviews·Peter WinstanleyAlasdair Breckenridge
Nov 2, 2005·European Journal of Clinical Pharmacology·Tashinga E BapiroCollen M Masimirembwa
Mar 21, 2009·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Roslyn S ThelingwaniCollen M Masimirembwa
Jul 31, 2009·The New England Journal of Medicine·Arjen M DondorpNicholas J White
Sep 17, 2009·Current Pharmaceutical Design·J J Walsh, A Bell
Jul 29, 2010·The Journal of Infectious Diseases·Miriam K LauferChristopher V Plowe
Aug 3, 2011·Antimicrobial Agents and Chemotherapy·Rita CapelaMiguel Prudêncio
Feb 25, 2014·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Juan P JoubertDavid D N'Da
Mar 8, 2014·European Journal of Medicinal Chemistry·Theunis T CloeteDavid D N'Da

❮ Previous
Next ❯

Citations

Mar 16, 2017·Antimicrobial Agents and Chemotherapy·Drishti AgarwalSatish K Awasthi

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antimalarial Agents (ASM)

Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.

Antimalarial Agents

Antimalarial agents, also known as antimalarials, are designed to prevent or cure malaria. Discover the latest research on antimalarial agents here.