Synthesis, structure-activity relationship, and antimalarial activity of ureas and thioureas of 15-membered azalides.

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-beta-aminoethyl), 9a-(N'-thiocarbamoyl-beta-aminoethyl), 9a-[N'-(beta-cyanoethyl)-N'-(carbarrioyl-beta-aminoethyl)], [N'-(beta-cyanoethyl)-N'-(thiocarbamoyl-beta-aminoethyl)], 9a-{N'-[beta-(ethoxycarbonyl)ethyl]-N'-(carbamoyl-beta-aminoethyl)}, and 9a-[N'-(beta-amidoethyl)-N'-(carbamoyl-beta-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 sugar; 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.