title: Synthesis, structure-activity relationship, and antimalarial activity of ureas and thioureas of 15-membered azalides.
abstract: Azithromycin, a first member of the azalide family of macrolides, while having substantial antimalarial activity, failed as a single agent for malaria prophylaxis. In this paper we present the first analogue campaign to identify more potent compounds from this class. Ureas and thioureas of 15-membered azalides, N''-substituted 9a-(N'-carbamoyl-β-aminoethyl), 9a-(N'-thiocarbamoyl-β-aminoethyl), 9a-[N'-(β-cyanoethyl)-N'-(carbamoyl-β-aminoethyl)], 9a-[N'-(β-cyanoethyl)-N'-(thiocarbamoyl-β-aminoethyl)], 9a-{N'-[β-(ethoxycarbonyl)ethyl]-N'(carbamoyl-β-aminoethyl)}, and 9a-[N'-(β-amidoethyl)-N'-(carbamoyl-β-aminoethyl)] of 9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A, were synthesized and their biological properties evaluated. The results obtained indicate a substantial improvement of the in vitro activity against P. falciparum (up to 88 times over azithromycin), particularly for compounds containing both sugars on the macrocyclic ring and aromatic moiety on 9a-position. The improved in vitro activity was not confirmed in the mouse model, likely due to an increase in lipophilicity of these analogues leading to a higher volume of distribution. Overall, with increased in vitro activity, promising PK properties, and modest in vivo efficacy, this series of molecules represents a good starting platform for the design of novel antimalarial azalides.
authors.affiliation: GlaxoSmithKline Research Centre Zagreb Ltd., Prilaz Baruna Filipovića 29, 10000 Zagreb, Croatia.
authors.forename: Mirjana
authors.initials: M
authors.lastname: Bukvić Krajačić
authors.forename: Mihaela
authors.initials: M
authors.lastname: Perić
authors.forename: Kirsten S
authors.initials: KS
authors.lastname: Smith
authors.forename: Zrinka Ivezić
authors.initials: ZI
authors.lastname: Schönfeld
authors.forename: Dinko
authors.initials: D
authors.lastname: Žiher
authors.forename: Andrea
authors.initials: A
authors.lastname: Fajdetić
authors.forename: Nedjeljko
authors.initials: N
authors.lastname: Kujundžić
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schönfeld
authors.forename: Goran
authors.initials: G
authors.lastname: Landek
authors.forename: Jasna
authors.initials: J
authors.lastname: Padovan
authors.forename: Dubravko
authors.initials: D
authors.lastname: Jelić
authors.forename: Arba
authors.initials: A
authors.lastname: Ager
authors.forename: Wilbur K
authors.initials: WK
authors.lastname: Milhous
authors.forename: William
authors.initials: W
authors.lastname: Ellis
authors.forename: Radan
authors.initials: R
authors.lastname: Spaventi
authors.forename: Colin
authors.initials: C
authors.lastname: Ohrt
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry; D017963:Azithromycin / Q000031:analogs & derivatives; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D018942:Macrolides / Q000737:chemistry*; D051379:Mice; D008956:Models, Chemical; D010963:Plasmodium falciparum / Q000378:metabolism; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000737:chemistry*; D014508:Urea / Q000737:chemistry*
chemical_list: D000962:Antimalarials; D018942:Macrolides; D017963:Azithromycin; D014508:Urea; D013890:Thiourea