A Cobalt Schiff-Base Complex as a Putative Therapeutic for Azide Poisoning

Abstract

There is presently no antidote available to treat azide poisoning. Here, the Schiff-base compound Co(II)-2, 12-dimethyl-3,7,11,17-tetraazabicyclo-[11.3.1]heptadeca-1(17)2,11,13,15-pentaenyl dibromide (Co(II)N 4 [11.3.1]) is investigated to determine if it has the capability to antagonize azide toxicity through a decorporation mechanism. The stopped-flow kinetics of azide binding to Co(II)N 4 [11.3.1] in the absence of oxygen exhibited three experimentally observable phases: I (fast); II (intermediate); and III (slow). The intermediate phase II accounted for ∼70% of the overall absorbance changes, representing the major process observed, with second-order rate constants of 29 (±4) M −1 s −1 at 25 °C and 70 (±10) M −1 s −1 at 37 °C. The data demonstrated pH independence of the reaction around neutrality, suggesting the unprotonated azide anion to be the attacking species. The binding of azide to Co(II)N 4 [11.3.1] appears to have a complicated mechanism leading to less than ideal antidotal capability; nonetheless, this cobalt complex does protect against azide intoxication. Administration of Co(II)N 4 [11.3.1] at 5 min post sodium azide injection (ip) to mice resulted in a substantial decrease of righting-recovery times, 12 (±4) min, compared to controls, 40 (±8) min. In addition, only two out of seven mice "knocked down" when the antidote was administered compared to the controls given toxicant only (100% knockdown).

A Comparison of Potential Azide Antidotes in a Mouse Model

“…The righting-recovery behavior of mice has recently been employed to assess the ability of potential antidotes to ameliorate sublethal doses of toxicants (especially cyanide). − In the present study, Swiss-Webster mice (8 weeks old) were injected (ip) with sodium azide ( t = 0) then, after “knockdown” (loss of consciousness), placed on their backs, and the time until they “righted” themselves onto four feet was recorded. Previously, when a dose of 26 mg/kg sodium azide was administered (ip) to adults (16+ weeks), the mice knocked down ∼6–8 min later and then righted themselves 30 to 40 min after the toxicant dose . In the present study, when sodium azide, 27 mg (415 μmol)/kg, was administered (ip) to juveniles (7–8 weeks), roughly half of the mice did not knockdown, and the recovery times were less reproducible (Figure B) than those observed previously with the older mice.…”

“…Recently, Praekunatham et al . examined the binding of azide to CoN 4 [11.3.1] and could find evidence for only a single azide anion binding to the Co­(II) form of the compound; subsequent oxidation to Co­(III) resulted in the one azide anion remaining bound to the complex.…”

Recent Progress in Metal‐Incorporated Acyclic Schiff‐Base Derivatives: Biological Aspects

“…Co III Schiff‐base complexes 51 and 52 synthesized from Schiff‐base ligands L32 and L33 (Figure 23) by Arunachalam and co‐workers, showed remarkable anti‐angiogenic potential in chicken chorioallantoic membrane (CAM) assay [61] . Pearce, Peterson and co‐workers synthesized the Co II complex, Co II N 4 [11.3.1] 106 (Figure 45) which was found to have potential to protect against azide intoxication [125] . Jurisson‘s group studied Schiff‐base metal complexes as potential candidates for therapeutic nuclear medicine [126] .…”

“…The incorporation of metal ions into the Schiff-base ligands may render remarkable structural changes which, as a consequence, may affect the biological properties of the Schiff-base derivatives. In determining antibacterial behaviour of the metal complexes whereas chelation plays a significant role, several other important factors such as geometry of complexes, bond length between metal and the ligand, structural specificity, dipole moment, coordinating sites redox potential of metal ion, high toxicity of the metal complexes [125] and Cu II complexes, 107-110. [127] at cell surface, solubility, steric, pharmacokinetic, concentration and hydrophobicity, can also influence substantially.…”

“…[61] Pearce, Peterson and co-workers synthesized the Co II complex, Co II N 4 [11.3.1] 106 (Figure 45) which was found to have potential to protect against azide intoxication. [125] Jurisson's group studied Schiff-base metal complexes as potential candidates for therapeutic nuclear medicine. [126] Khan's group reported that Cu complexes 69-71 (Figure 29a) showed significant binding affinities with human serum albumin (HSA).…”