Pentacyanoferrate(II) complex of pyridine-4- and pyrazine-2-hydroxamic acid as source of HNO: investigation of anti-tubercular and vasodilation activities

Abstract

A pharmacophore design approach, based on the coordination chemistry of an intimate molecular hybrid of active metabolites of pro-drugs, known to release active species upon enzymatic oxidative activation, is devised. This is exemplified by combining two anti-mycobacterial drugs: pyrazinamide (first line) and delamanid (third line) whose active metabolites are pyrazinoic acid (PyzCOOH) and likely nitroxyl (HNO (or NO . )), respectively. Aiming to generate those active species, a hybrid compound was envisaged by coordination of pyrazine-2-hydroxamic acid (PyzCONHOH) with a Na 3 [Fe II (CN) 5 ] moiety. The corresponding pentacyanoferrate(II) complex Na 4 [Fe II (CN) 5 (PyzCONHO − )] was synthesized and characterized by several spectroscopic techniques, cyclic voltammetry, and DFT calculations. Chemical oxidation of this complex with H 2 O 2 was shown to induce the release of the metabolite PyzCOOH, without the need of the Mycobacterium tuberculosis (Mtb) pyrazinamidase enzyme (PncA). Control experiments show that both H 2 O 2 -and N-coordinated pyrazine Fe II species are required, ruling out a direct hydrolysis of the hydroxamic acid or an alternative oxidative route through chelation of a metal center by a hydroxamic group. The release of HNO was observed using EPR spectroscopy in the presence of a spin trapping agent. The devised iron metal complex of pyrazine-2-hydroxamic acid was found inactive against an actively growing/non-resistant Mtb strain; however, it showed a strong dose-dependent and reversible vasodilatory activity with mostly lesser toxic effects than the reference drug sodium nitroprussiate, unveiling thus a potential indication for acute or chronic cardiovascular pathology. This is a priori a further indirect evidence of HNO release from this metal complex, standing as a possible pharmacophore model for an alternative vasodilator drug.

Antimycobacterial Activities of Hydroxamic Acids and Their Iron(II/III), Nickel(II), Copper(II) and Zinc(II) Complexes

“…Para-nitrobenzohydroxamic acid demonstrated a minimum inhibitory concentration (MIC) of 0.71 µM in a glycerol-alanine salt medium or an MIC of 7.79 µM in a 7H12 medium on M. tuberculosis [17]. The pentacyanoferrate moiety in Fe(II) coordination hydroxamic complexes benefited the release of HNO from HA, improving pyrazinamide and dela-manid efficiency against M. tuberculosis [18]. Suberoylanilide hydroxamic acid (SAHA) also had adjunctive potential to enhance the effects of first-line anti-TB drugs (isoniazid and rifampicin) against intracellular M. tuberculosis [19].…”

Nitroprusside─Expanding the Potential Use of an Old Drug Using Nanoparticles

“…This issue motivated many innovative ways to deliver NO in a controlled manner, mostly by using NO releasing compounds also known as NO donors, which includes the clinically approved sodium nitroprusside (SNP). These organic and inorganic molecules are stable species that can release NO either spontaneously or upon a stimulus (e.g., pH, light, oxidative or reductive action) − enabling the safer and easier use of NO.…”