title: An automated, polymer-assisted strategy for the preparation of urea and thiourea derivatives of 15-membered azalides as potential antimalarial chemotherapeutics.
abstract: A series of 15-membered azalide urea and thiourea derivatives has been synthesized and evaluated for their in vitro antimalarial activity against chloroquine-sensitive (D6), chloroquine/pyremethamine resistant (W2) and multidrug resistant (TM91C235) strains of Plasmodium falciparum. We have developed an effective automated synthetic strategy for the rapid synthesis of urea/thiourea libraries of a macrolide scaffold. Compounds have been synthesized using a solution phase strategy with overall yields of 50-80%. Most of the synthesized compounds had inhibitory effects. The top 10 compounds were 30-65 times more potent than azithromycin, an azalide with antimalarial activity, against all three strains.
authors.affiliation: GlaxoSmithKline Research Centre Zagreb Ltd, Zagreb, Croatia. antun.hutinec@glpg.com
authors.forename: Antun
authors.initials: A
authors.lastname: Hutinec
authors.forename: Renata
authors.initials: R
authors.lastname: Rupčić
authors.forename: Dinko
authors.initials: D
authors.lastname: Ziher
authors.forename: Kirsten S
authors.initials: KS
authors.lastname: Smith
authors.forename: Wilbur
authors.initials: W
authors.lastname: Milhous
authors.forename: William
authors.initials: W
authors.lastname: Ellis
authors.forename: Colin
authors.initials: C
authors.lastname: Ohrt
authors.forename: Zrinka Ivezić
authors.initials: ZI
authors.lastname: Schönfeld
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001331:Automation; D017963:Azithromycin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D020128:Inhibitory Concentration 50; D018942:Macrolides / Q000494:pharmacology; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014508:Urea / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000962:Antimalarials; D018942:Macrolides; D017963:Azithromycin; D014508:Urea; D013890:Thiourea