New isoniazid derivatives with improved pharmaco-toxicological profile: Obtaining, characterization and biological evaluation

New Isoniazid Derivatives for Antimicrobial Spectrum Extension and Hepatotoxicity Reduction of Parent Compound: In Vitro and in Vivo Assays

“…Regarding the antimicrobial action, chemical modifications made to the functional amino group of isoniazid, changed the biological profile of the obtained HIN derivatives. The obtained results show, for isoniazid and its derivatives an extended antimicrobial spectrum, unlimited for the M. tuberculosis strains (as shown in previous papers[5,6]), including Gram positive and fungal species. Isoniazid and its synthesized derivatives exhibited no action against the Gram negative bacteria tested.…”

“…On the other hand, improving the pharmacotoxicological profile of isoniazid by introducing chemical modifications into its main structure in order to increase the biological response to Mycobacterium tuberculosis, to reduce liver toxicity or to avoid the resistance phenomena, continues to be an increasingly intriguing scientific challenge [4,8]. In addition, the present work is outlined as a continuation of previous research [5], where the new derivatives obtained by synthesis (HIN-a, HIN-b and HIN-c) (Figure 1) demonstrated remarkable antimicrobial activity against M. tuberculosis strains and significantly reduced toxicity.…”

“…The animals were divided into 6 groups (7 animals per group) -groups 1 to 4 received suspensions of HIN and its derivatives (HIN-a, HIN-b and HIN-c); group 5 received the vehicle sodium carboxy-methylcellulose (1% CMC-Na solution) and group 6 has been preserved as an untreated control. On the basis of the results obtained in the acute toxicity test [5], the evaluation of biochemical parameters was monitored after administering the new compounds at doses of 1/10 from LD50, by oral gavage. Thus, the substances were dispersed in 1% CMC-Na solution and administered in a single dose, for 30 days.…”

Chitosan Microparticles Loaded with New Non-Cytotoxic Isoniazid Derivatives for the Treatment of Tuberculosis: In Vitro and In Vivo Studies

“…In one of our previous research works [1], isoniazid was subjected to a structural modulation process that aimed to synthesize new isonicotinoyl hydrazones, which proved to have an improved pharmacotoxicological profile. As part of an ongoing research process, the present paper focused on the effects of the encapsulation of isoniazid derivatives in polymer matrices (chitosan microparticles).…”

Biological Profiling Enables Rapid Mechanistic Classification of Phenotypic Screening Hits and Identification of KatG Activation-Dependent Pyridine Carboxamide Prodrugs With Activity Against Mycobacterium tuberculosis

“…It would likewise be useful to assess whether the compounds differ from INH in terms of activity in models of slow-or non-replicating persistence induced by low oxygen, mild hypoxia (Cho et al, 2015;Zheng et al, 2017), carbon starvation (Grant et al, 2013), or a combination of multiple stresses (Deb et al, 2009;Gold et al, 2015). Extensive effort has been made to improve the antitubercular potency while lowering the cytotoxicity of INH, albeit with limited success (Martins et al, 2014;Oliveira et al, 2017;Dragostin et al, 2019). Consistent with this, the pyridine carboxamides investigated here are significantly less potent against Mtb and have lower SI values than INH (SI>2941 based on Vero cell line toxicity) (Phillips et al, 2012).…”