eprintid: 18816
rev_number: 16
userid: 1419
dir: disk0/00/01/88/16
datestamp: 2013-06-07 20:47:39
lastmod: 2019-02-02 15:56:58
status_changed: 2013-06-07 20:47:39
type: article
metadata_visibility: show
item_issues_count: 0
eprint_status: archive
creators_name: Milner, E
creators_name: McCalmont, W
creators_name: Bhonsle, J
creators_name: Caridha, D
creators_name: Cobar, J
creators_name: Gardner, S
creators_name: Gerena, L
creators_name: Goodine, D
creators_name: Lanteri, C
creators_name: Melendez, V
creators_name: Roncal, N
creators_name: Sousa, J
creators_name: Wipf, P
creators_name: Dow, GS
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creators_email: pwipf@pitt.edu
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creators_id: PWIPF
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title: Anti-malarial activity of a non-piperidine library of next-generation quinoline methanols
ispublished: pub
divisions: sch_as_chemistry
full_text_status: public
abstract: Background. The clinical utility for mefloquine has been eroded due to its association with adverse neurological effects. Better-tolerated alternatives are required. The objective of the present study was the identification of lead compounds that are as effective as mefloquine, but exhibit physiochemical properties likely to render them less susceptible to passage across the blood-brain barrier. Methods. A library of drug-like non-piperidine analogs of mefloquine was synthesized. These compounds are diverse in structure and physiochemical properties. They were screened in appropriate in vitro assays and evaluated in terms of their potential as lead compounds. The correlation of specific structural attributes and physiochemical properties with activity was assessed. Results. The most potent analogs were low molecular weight unconjugated secondary amines with no heteroatoms in their side-chains. However, these compounds were more metabolically labile and permeable than mefloquine. In terms of physiochemical properties, lower polar surface area, lower molecular weight, more freely rotatable bonds and fewer H-bond acceptors were associated with greater potency. There was no such relationship between activity and LogP, LogD or the number of hydrogen bond donors (HBDs). The addition of an H-bond donor to the side-chain yielded a series of active diamines, which were as metabolically stable as mefloquine but showed reduced permeability. Conclusions. A drug-like library of non-piperidine analogs of mefloquine was synthesized. From amongst this library an active lead series of less permeable, but metabolically stable, diamines was identified. © 2010 Milner et al; licensee BioMed Central Ltd.
date: 2010-03-16
date_type: published
publication: Malaria Journal
volume: 9
number: 1
refereed: TRUE
id_number: 10.1186/1475-2875-9-51
other_id: NLM PMC2833169
pmcid: PMC2833169
pmid: 20149249
mesh_headings: Antimalarials--pharmacokinetics
mesh_headings: Antimalarials--pharmacology
mesh_headings: Drug Discovery
mesh_headings: Hypoxanthine
mesh_headings: Mefloquine--pharmacology
mesh_headings: Mefloquine--toxicity
mesh_headings: Methanol--pharmacokinetics
mesh_headings: Methanol--pharmacology
mesh_headings: Permeability
mesh_headings: Plasmodium falciparum--drug effects
mesh_headings: Quinolines--pharmacokinetics
mesh_headings: Quinolines--pharmacology
chemical_names: Antimalarials
chemical_names: Quinolines
chemical_names: Mefloquine
chemical_names: Methanol
chemical_names: Hypoxanthine
chemical_names: quinoline
citation:   Milner, E and McCalmont, W and Bhonsle, J and Caridha, D and Cobar, J and Gardner, S and Gerena, L and Goodine, D and Lanteri, C and Melendez, V and Roncal, N and Sousa, J and Wipf, P and Dow, GS  (2010) Anti-malarial activity of a non-piperidine library of next-generation quinoline methanols.  Malaria Journal, 9 (1).       
document_url: http://d-scholarship-dev.library.pitt.edu/18816/1/licence.txt