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

Abstract

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.

Antibacterial Activity of Novel Sulfonylureas, Ureas and Thioureas of 15-Membered Azalides

“…All compounds demonstrated good in vitro, metabolic stability with t 1/2 greater than 120 min (t 1/2 = 103 min for compound 14d in human liver microsomes). As was observed with azithromycin, and in line with the in vitro data, these analogs had a low systemic clearance, moderate to high volume of distribution and a very long half-life, however, the oral bioavailability was low (12c, 12e) to moderate (Bukvić Krajačić et al, 2011b CL -blood clearance, Vd -apparent volume of distribution at the terminal phase based on drug concentration in blood, t 1/2 -half life, a -IV parameters determined in one rat Table 1. Pharmacokinetic parameters estimated in blood after intravenous (IV) and oral gavage (PO) administration to Sprague-Dawley rats (10 mg/kg IV and 30 mg/kg PO) (Bukvić Krajačić t al., 2011b).…”

“…In comparison to azithromycin, known for its extensive tissue distribution, (Schönfeld & Mutak, 2002) these derivatives had a tendency toward higher volumes of distribution, in line with their increased lipophilic character (approx. 2-3 log units higher than azithromycin, according to calculated logP values, data not shown) due to the presence of strong lipophilic aromatic phenyl and naphtyl rings in the 9a-N substituent (Bukvić Krajačić et al, 2011b). Overall, with increased in vitro activity and promising pharmacokinetic properties, this series of molecules represents a good starting platform for the design of novel antibacterial and antimalarial azalides.…”

“…In acidic conditions compounds exhibited azithromycin like stability (Bukvić Krajačić et al, 2009). In vitro cytotoxicity on Hep G2 and THP-1 cell lines measured for the selected set of compounds revealed that all compounds showed relatively low cytotoxicity in vitro (IC 50 s ≥ 4 μM) (Bukvić Krajačić et al, 2011b). These marked them as potent and selective compounds for further profiling (Steinmeyer, 2006).…”

“…, sulfonylcarbamoyl derivatives 3a-3f (Bukvić Krajačić et al, 2005) and azithromycinsulfonamide conjugates 10a-10d (Bukvić Krajačić et al, 2007). Also, these compounds exhibited a substantially improved in vitro antimalarial activity against P. falciparum (Bukvić Krajačić et al, 2011b;Hutinec et al, 2011). Several ureas bearing naphthyl supstituents (11f, 11g, 11h) were superior in vitro to the azithromycin against inducible resistant S. pyogenes (MIC 2 µg/ml).…”

“…These marked them as potent and selective compounds for further profiling (Steinmeyer, 2006). Metabolic stability of ureas and thioureas were screened in vitro using human and mouse liver microsomes and only a few were selected for in vivo rat pharmacokinetic studies in order to determine their pharmacokinetic profiles (Table 1) (Bukvić Krajačić et al, 2011b). All compounds demonstrated good in vitro, metabolic stability with t 1/2 greater than 120 min (t 1/2 = 103 min for compound 14d in human liver microsomes).…”