Synthesis, Structure–Activity Relationship, and Antimalarial Activity of Ureas and Thioureas of 15-Membered Azalides

Bukvić Krajačić, Mirjana: Perić, Mihaela; Smith, Kirsten S.; Ivezić Schonfeld, Zrinka; Žiher, Dinko; Fajdetić, Andreja; Kujundžić, Nedjeljko; Schonfeld, Wolfgang; Landek, Goran; Padovan, Jasna; Jelić, Dubravko; Ager, ArbaMilhous, Wilbur K.; Ellis, William; Spaventi, Radan; Ohrt, Colin

doi:10.1021/jm2001585

Pregled bibliografske jedinice broj: 552624

Synthesis, Structure–Activity Relationship, and Antimalarial Activity of Ureas and Thioureas of 15-Membered Azalides

Bukvić Krajačić, Mirjana: Perić, Mihaela; Smith, Kirsten S.; Ivezić Schonfeld, Zrinka; Žiher, Dinko; Fajdetić, Andreja; Kujundžić, Nedjeljko; Schonfeld, Wolfgang; Landek, Goran; Padovan, Jasna; Jelić, Dubravko et al.

Synthesis, Structure–Activity Relationship, and Antimalarial Activity of Ureas and Thioureas of 15-Membered Azalides // Journal of medicinal chemistry, 54 (2011), 10; 3595-3605 doi:10.1021/jm2001585 (međunarodna recenzija, članak, znanstveni)

CROSBI ID: 552624 Za ispravke kontaktirajte CROSBI podršku putem web obrasca

Naslov
Synthesis, Structure–Activity Relationship, and Antimalarial Activity of Ureas and Thioureas of 15-Membered Azalides

Autori
Bukvić Krajačić, Mirjana: Perić, Mihaela ; Smith, Kirsten S. ; Ivezić Schonfeld, Zrinka ; Žiher, Dinko ; Fajdetić, Andreja ; Kujundžić, Nedjeljko ; Schonfeld, Wolfgang ; Landek, Goran ; Padovan, Jasna ; Jelić, Dubravko ; Ager, ArbaMilhous, Wilbur K. ; Ellis, William ; Spaventi, Radan ; Ohrt, Colin

Izvornik
Journal of medicinal chemistry (0022-2623) 54 (2011), 10; 3595-3605

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
SAR; antimalarial acivity; urea; thiourea; azalides

Sažetak
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.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Farmacija

POVEZANOST RADA

Projekti:
006-0000000-3216 - Sinteza, karakterizacija i djelovanje potencijalnih i poznatih ljekovitih tvari (Zorc, Branka, MZOS ) ( CroRIS)

Ustanove:
Farmaceutsko-biokemijski fakultet, Zagreb

Profili:

Goran Landek (autor)