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.
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