title: Antimalarial activity of 9a-N substituted 15-membered azalides with improved in vitro and in vivo activity over azithromycin.
abstract: Novel classes of antimalarial drugs are needed due to emerging drug resistance. Azithromycin, the first macrolide investigated for malaria treatment and prophylaxis, failed as a single agent and thus novel analogues were envisaged as the next generation with improved activity. We synthesized 42 new 9a-N substituted 15-membered azalides with amide and amine functionalities via simple and inexpensive chemical procedures using easily available building blocks. These compounds exhibited marked advances over azithromycin in vitro in terms of potency against Plasmodium falciparum (over 100-fold) and high selectivity for the parasite and were characterized by moderate oral bioavailability in vivo. Two amines and one amide derivative showed improved in vivo potency in comparison to azithromycin when tested in a mouse efficacy model. Results obtained for compound 6u, including improved in vitro potency, good pharmacokinetic parameters, and in vivo efficacy higher than azithromycin and comparable to chloroquine, warrant its further development for malaria treatment and prophylaxis.
authors.affiliation: GlaxoSmithKline Research Centre Zagreb Ltd., Prilaz baruna Filipovića 29, 10000 Zagreb, Croatia. mihaela.peric@mef.hr
authors.forename: Mihaela
authors.initials: M
authors.lastname: Perić
authors.forename: Andrea
authors.initials: A
authors.lastname: Fajdetić
authors.forename: Renata
authors.initials: R
authors.lastname: Rupčić
authors.forename: Sulejman
authors.initials: S
authors.lastname: Alihodžić
authors.forename: Dinko
authors.initials: D
authors.lastname: Ziher
authors.forename: Mirjana
authors.initials: M
authors.lastname: Bukvić Krajačić
authors.forename: Kirsten S
authors.initials: KS
authors.lastname: Smith
authors.forename: Zrinka
authors.initials: Z
authors.lastname: Ivezić-Schönfeld
authors.forename: Jasna
authors.initials: J
authors.lastname: Padovan
authors.forename: Goran
authors.initials: G
authors.lastname: Landek
authors.forename: Dubravko
authors.initials: D
authors.lastname: Jelić
authors.forename: Antun
authors.initials: A
authors.lastname: Hutinec
authors.forename: Milan
authors.initials: M
authors.lastname: Mesić
authors.forename: Arba
authors.initials: A
authors.lastname: Ager
authors.forename: William Y
authors.initials: WY
authors.lastname: Ellis
authors.forename: Wilbur K
authors.initials: WK
authors.lastname: Milhous
authors.forename: Colin
authors.initials: C
authors.lastname: Ohrt
authors.forename: Radan
authors.initials: R
authors.lastname: Spaventi
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000588:Amines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D017963:Azithromycin / Q000494:pharmacology; D045744:Cell Line, Tumor; D004351:Drug Resistance; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D018942:Macrolides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008288:Malaria / Q000188:drug therapy; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei; D010963:Plasmodium falciparum / Q000187:drug effects; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: C571534:9a-(3-(7-chloroquinolin-4-ylamino)propyl)-9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A; D000577:Amides; D000588:Amines; D000634:Aminoquinolines; D000962:Antimalarials; D018942:Macrolides; D004917:Erythromycin; D017963:Azithromycin