Synthesis, pH-dependent, and plasma stability of meropenem prodrugs for potential use against drug-resistant tuberculosis

Abstract

Meropenem, a broad-spectrum parenteral β-lactam antibiotic, in combination with clavulanate has recently shown efficacy in patients with extensively drug-resistant tuberculosis. As a result of meropenem's short half-life and lack of oral bioavailability, the development of an oral therapy is warranted for TB treatment in underserved countries where chronic parenteral therapy is impractical. To improve the oral absorption of meropenem, several alkyloxycarbonyloxyalkyl ester prodrugs with increased lipophilicity were synthesized and their stability in physiological aqueous solutions and guinea pig as well as human plasma was evaluated. The stability of prodrugs in aqueous solution at pH 6.0 and 7.4 was significantly dependent on the ester promoiety with the major degradation product identified as the parent compound meropenem. However, in simulated gastrointestinal fluid (pH 1.2) the major degradation product identified was ring-opened meropenem with the promoiety still intact, suggesting the gastrointestinal environment may reduce the absorption of meropenem prodrugs in vivo unless administered as an enteric-coated formulation. Additionally, the stability of the most aqueous stable prodrugs in guinea pig or human plasma was short, implying a rapid release of parent meropenem.

Keywords: Aqueous stability; Meropenem; XDR-TB; β-Lactam prodrugs.

Figure 1

A. Ester prodrugs strategies for β-lactams and mechanism of release. Carboxyesterase catalyzes cleavage at the remote carbonyl (highlighted in yellow), which results in formation of an acyl hemiacetal intermediate that spontaneously breaks down to release the parent drug. B. Representative acyloxyalkyl and alkyloxycarbonyloxyalkyl (AOCO) promoieties found in clinically approved β-lactams.

Figure 2

Aqueous stability of prodrug 19 at pH 7.4. The concentration of (●) prodrug 19, the released meropenem (▲), and 1-benzosuberol (■) are shown. The concentration for each species is plotted as a function of incubation time. All measurements were performed in triplicate and error bars represent the standard deviation.

Scheme 1^a

^aReaction conditions: (a) 1-iodoethyl isopropyl carbonate, Cs₂CO₃, DMF, 0 °C, 30 min, 64%.

Scheme 2^a

^aReaction conditions: (a) (+) or (-)-CBS, BH₃⋅SMe₃, THF, 0 °C–rt, quant. yield; (b) for 12a: ClCO₂CH(CH₃)Cl, pyridine, CH₂Cl₂, rt, 30 min, 85%; for 9a,b–11a,b: ClCO₂CH₂Cl, pyridine, CH₂Cl₂, rt, 30 min, 76–98%; (c) NaI, acetone, 40 °C, 5 h, 25% for 16a, 70–95% for 13a,b-15a,b; (d) for 17–22 and 23a: 1, Cs₂CO₃, DMF, 0 °C, 30 min, 57–84%; for 24a: i) Ac₂O, 1, DMF, 0 °C, 15 min; ii) then add 16a, 30 min, 0 °C, 62%

Scheme 3^a

^aReaction Conditions: (a) Ref. , ; (b) for 28: NaBH_4, MeOH, rt, 97%; for 29–30: CBS, BH₃·SMe₃, THF, 0 °C–rt, 68–89%; (c) ClCO₂CH₂Cl, pyridine, CH₂Cl₂, rt, 30 min, 70–94%; (d) NaI, acetone, 40 °C, 5 h, 62–70%; (e) 1, Cs₂CO₃, DMF, 0 °C, 30 min, 68–84%.

Scheme 4

Scheme 5