An inorganic complex that inhibits Mycobacterium tuberculosis enoyl reductase as a prototype of a new class of chemotherapeutic agents to treat tuberculosis

Abstract

Descrevemos a atividade inibitória do IQG607, pentaciano(isoniazida)ferrato(II), frente a cepas de Mycobacterium tuberculosis tanto resistentes quanto sensíveis à isoniazida, assim como a toxicidade oral e a adaptação da síntese química do IQG607 para reatores maiores. O IQG607 representa um potencial agente quimioterápico que inibe um alvo molecular definido.Here we describe the inhibitory activity of IQG607, pentacyano(isoniazid)ferrate(II), on isoniazid-sensitive and isoniazid-resistant strains of Mycobacterium tuberculosis, its oral toxicity, and efforts to adapt IQG607 synthesis to large chemical reactors. IQG607 represents a promising chemotherapeutic agent aiming at the inhibition of a validated and druggable molecular target. Keywords: Mycobacterium tuberculosis, enoyl reductase, toxicology, large-scale synthesis, metallodrug IntroductionTuberculosis (TB) remains the leading cause of mortality due to a bacterial pathogen, Mycobacterium tuberculosis. 1 In 2007, there were an estimated 9.27 million cases of TB, and 1.37 million (15%) were also HIV-positive patients, who are more likely to develop active TB. 2 Brazil ranks 14 th in terms of the total number of incident cases amongst the high-burden countries. 2 There were an estimated 0.5 million cases of multidrugresistant TB (MDR-TB), which is caused by strains resistant to, at least, isoniazid and rifampicin. 2 The emergence of extensively drug-resistant (XDR) TB cases, which are found in TB-infected patients whose isolates are MDR and also resistant to a fluoroquinolone and, at least, one second-line injectable agent, 2,3 its widespread distribution, 4 and unprecedented fatality rate, 5 raise the prospect of virtually incurable and deadly TB worldwide. The factors that most influence the emergence of drugresistant strains include inappropriate treatment regimens and patient noncompliance in completing the prescribed courses of therapy due to the lengthy standard "shortcourse" treatment (isoniazid, rifampicin, pyrazinamide, and ethambutol or streptomycin for two months, followed by a combination of isoniazid and rifampicin for additional four months) or when the side effects become unbearable. 6 Moreover, no sustainable control of TB epidemic can be reached in any country without properly addressing this global public health problem, including research as a key component. 7 M. tuberculosis has been considered the world's most successful pathogen, and this is largely due to the ability of the bacillum to persist in host tissues, where drugs that are rapidly bactericidal in vitro require prolonged administration to achieve comparable in vivo effects. 8 Hence, more effective and less toxic anti-tubercular agents are immediately needed to shorten the duration of current treatment, improve the treatment of drug-resistant TB, and to provide effective treatment of latent TB infection.The modern approach in the development of new chemical entities (NCEs) against TB is based on the use of defined molecular targets. This involves (i) the search and identification ...

Revisiting Activation of and Mechanism of Resistance to Compound IQG-607 in Mycobacterium tuberculosis

“…These findings challenge its planned usage against INH-resistant strains. Nonetheless, the compound has already been reported to be less toxic than INH in a preclinical study using mice (5,24). This is a remarkable feature, since INH was previously associated with hepatotoxicity in animal and humans due to its toxic metabolites, such as hydrazine (25).…”

Synthesis, Inhibition of Mycobacterium tuberculosis Enoyl-acyl Carrier Protein Reductase and Antimycobacterial Activity of Novel Pentacyanoferrate(II)-isonicotinoylhydrazones

“…Pentacyanoferrate(II)-isonicotinoylhydrazones 4a-e were prepared by a similar procedure used before for the 3-was synthesized from sodium nitroprusside dissolved in ammonium solution followed by NH 3 gas bubbling into the reaction mixture, in accordance with a previously described protocol. 26 The complexes 4a-e were obtained from the reaction between hydrazones 3a-e and aminpentacyanoferrate(II) in water, at room temperature for 10 h, with yields of 76-98% (Scheme 1). The E-stereochemistry of imine-double bond was assigned for both series of compounds based on the magnitude of the imine-proton chemical shifts.…”

Conformational changes in 2-trans-enoyl-ACP (CoA) reductase (InhA) from M. tuberculosis induced by an inorganic complex: a molecular dynamics simulation study

“…These compounds are not expected to be activated prior to interacting with its cellular target. Within this approach Basso, Moreira, Santos and collaborators [26][27][28][29] have proposed an INH analog, namely pentacyano (isoniazid)ferrate(II) that contains a cyanoferrate moiety, a metal center and the INH ligand [26]. This class of compounds constitutes a suitable model system for new perspectives of novel drug development for the treatment of MDR-TB [27].…”