Pentacyanoferrate(II) complex of pyridine-4- and pyrazine-2-hydroxamic acid as source of HNO: investigation of anti-tube
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ORIGINAL PAPER
Pentacyanoferrate(II) complex of pyridine‑4‑ and pyrazine‑2‑hydroxamic acid as source of HNO: investigation of anti‑tubercular and vasodilation activities Edinilton Muniz Carvalho1,2,3 · Tercio de Freitas Paulo1,2,3 · Alix Sournia Saquet1 · Bruno Lopes Abbadi4,5 · Fernanda Souza Macchi4,5 · Cristiano Valim Bizarro4,5 · Rafael de Morais Campos6 · Talles Luann Abrantes Ferreira6 · Nilberto Robson Falcão do Nascimento6 · Luiz Gonzaga França Lopes3,5 · Remi Chauvin1,2 · Eduardo Henrique Silva Sousa3,5 · Vania Bernardes‑Génisson1,2 Received: 4 May 2020 / Accepted: 5 July 2020 © Society for Biological Inorganic Chemistry (SBIC) 2020
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 N a3[FeII(CN)5] moiII − ety. The corresponding pentacyanoferrate(II) complex N a4[Fe (CN)5(PyzCONHO )] was synthesized and characterized by several spectroscopic techniques, cyclic voltammetry, and DFT calculations. Chemical oxidation of this complex with H2O2 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 H2O2- and N-coordinated pyrazine FeII 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. Keywords Blood vessel vasodilation · Hybrid pro-drug activation · Metallodrug · Pyrazinamide · Sodium nitroprusside derivative · Tuberculosis
Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00775-020-01805-z) contains supplementary material, which is available to authorized users. * Eduardo Henrique Silva Sousa [email protected] * Vania Bernardes‑Génisson vania.bernardes‑genisson@lcc‑toulouse.fr Extended author information available on the last page of the a
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