TY - JOUR
T1 - Synthesis, structure-activity relationship, and antimalarial activity of ureas and thioureas of 15-membered azalides
AU - Bukvić Krajačić, Mirjana
AU - Perić, Mihaela
AU - Smith, Kirsten S.
AU - Ivezić Schönfeld, Zrinka
AU - Žiher, Dinko
AU - Fajdetić, Andrea
AU - Kujundžić, Nedjeljko
AU - Schönfeld, Wolfgang
AU - Landek, Goran
AU - Padovan, Jasna
AU - Jelić, Dubravko
AU - Ager, Arba
AU - Milhous, Wilbur K.
AU - Ellis, William
AU - Spaventi, Radan
AU - Ohrt, Colin
PY - 2011/5/26
Y1 - 2011/5/26
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79957754724&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79957754724&partnerID=8YFLogxK
U2 - 10.1021/jm2001585
DO - 10.1021/jm2001585
M3 - Article
C2 - 21476508
AN - SCOPUS:79957754724
VL - 54
SP - 3595
EP - 3605
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 10
ER -