Preparation and antitubercular activities in vitro and in vivo of novel Schiff bases of isoniazid

Abstract

Structural modification of the frontline antitubercular isonicotinic acid hydrazide (INH) provides lipophilic adaptations (3-46) of the drug in which the hydrazine moiety of the parent compound has been chemically blocked from the deactivating process of N2-acetylation by N-arylaminoacetyl transferases. As a class, these compounds show high levels of activity against Mycobacterium tuberculosis in vitro and in tuberculosis-infected macrophages. They provide strong protection in tuberculosis-infected mice and have low toxicity. With some representatives of this class achieving early peak plasma concentrations approximately three orders of magnitude above minimum inhibitory concentration, they may serve as tools for improving our understanding of INH-based treatment modalities, particularly for those patients chronically underdosed in conventional INH therapy.

Design and Synthesis of New Bioactive 1,2,4-Triazoles, Potential Antitubercular and Antimicrobial Agents

“…The 1,2,4-triazole, as well found to exhibit antiasthmatic [14] , antiviral (ribavirin) [15] , antifungal (fluconazole) [16] , antimicrobial [17,18] , antibacterial [19][20][21] , insecticidal [22] , hypnotic [23] , cytotoxic [24] , antitubercular [25] and hypotensive [26,27] activities. This moiety was also found in potent agonist and antagonist receptor ligands [28,29] in HIV-1 protease inhibitors [30] and in thrombin inhibitors [31] .…”

Antitubercular Drugs Development: Recent Advances in Selected Therapeutic Targets and Rational Drug Design

“…Due to the substitution in 5-position on the oxadiazole ring, the compounds obtained showed high lipophilicity, hypothesizing that this lipophilicity could facilitate passage of these compounds through the M. tuberculosis bacterial membrane (Navarrete-Vazquez et al, 2007). Also, structural modification of the hydrazide moiety on INH (4, figure 1) provided lipophilic adaptations of the drug that blocked the N-acetylation process, obtained high levels of in vitro activity against M. tuberculosis and macrophages infected, as well as low toxicity (Hearn et al, 2009). Another strategy in drug design is the formation of molecules that mimic the natural substrate of an enzyme.…”

Chemotherapeutic Strategies and Targets Against Resistant TB

“…Several INH derived Schiff bases were investigated by Hearn et al (Hearn et al, 2009). These compounds showed high in vitro activity against Mtb and mycobacteria-infected macrophages.…”