pH-Dependent Coordination of Metal–Lisinopril Complex Investigated by Attenuated Total Reflection/Fourier Transform Infrared Spectroscopy

Abstract

In order to simulate the in vivo binding behavior of angiotensin-converting enzyme (ACE) inhibitors to the zinc-containing active center of ACE, the in vitro interaction between lisinopril and zinc or nickel ions was investigated in aqueous solutions of different pH by using attenuated total reflection (ATR)/Fourier transform infrared (FT-IR) spectroscopy with second-derivative IR spectral analysis. The results indicated that the lisinopril dissociation process occurred in a stepwise fashion during increase in pH. The IR peaks at 1642 cm⁻¹ (carbonyl stretching of tertiary amide) and at 1582 cm⁻¹ (asymmetric COO⁻ stretching) for lisinopril in solution at pH 3.5 shifted to 1606 and 1586 cm⁻¹ after addition of Ni²⁺ ions, respectively, but there was no marked changes in IR spectra of lisinopril after addition of Zn²⁺ ions. When the Zn²⁺ ions were added to lisinopril solution at pH 5.0, the peak at 1642 cm⁻¹ also shifted to 1604 cm⁻¹ and the peak at 1582 cm⁻¹ shifted to 1586 cm⁻¹, similar to the changes at pH 3.5 after adding Ni²⁺ ions. However, the peaks at 1582 and 1642 cm⁻¹ both shifted to 1599 cm⁻¹ after addition of Ni²⁺ ions at pH 5.0 or at pH 7.3. The peak at 1576 cm⁻¹ also shifted to 1599 cm⁻¹ after addition of Zn²⁺ ions to lisinopril solution at pH 7.3. Different coordination sites or types (chelating, bridging or pseudo-unidentate complex) between lisinopril and Zn²⁺ or Ni²⁺ ions were proposed, based on the separation value between ν_as (COO⁻) and ν_s (COO⁻), and the shifting of carbonyl groups. Coordination of the secondary amine in lisinopril to metal ions was also evidenced.