Superfast Synthesis of Stabilized Silver Nanoparticles Using Aqueous Allium sativum (Garlic) Extract and Isoniazid Hydrazide Conjugates: Molecular Docking and In-Vitro Characterizations.

Green synthesis of silver nanoparticles (AgNPs) was synthesized from fresh garlic extract coupled with isoniazid hydrazide (INH), a commonly used antibiotic to treat tuberculosis. A molecular docking study conducted with the selected compounds compared with anthranilate phosphoribosyltransferase (trpD) from Mycobacterium tuberculosis. The aqueous extract of garlic was prepared and mixed with silver nitrate (AgNO3) solution for the superfast synthesis of stable AgNPs. INH was then conjugated with AgNPs at different ratios (v/v) to obtain stable INH-AgNPs conjugates (AgNCs). The resulting AgNCs characterized by FTIR spectra revealed the ultrafast formation of AgNPs (<5 s) and perfectly conjugated with INH. The shifting of λmax to longer wavelength, as found from UV spectral analysis, confirmed the formation of AgNCs, among which ideal formulations (F7, F10, and F13) have been pre-selected. The zeta particle size (PS) and the zeta potential (ZP) of AgNPs were found to be 145.3 ± 2.1 nm and -33.1 mV, respectively. These data were significantly different compared to that of AgNCs (160 ± 2.7 nm and -14.4 mV for F7; 208.9 ± 2.9 nm and -19.8 mV for F10; and 281.3 ± 3.6 nm and -19.5 mV for F13), most probably due to INH conjugation. The results of XRD, SEM and EDX confirmed the formation of AgNCs. From UV spectral analysis, EE of INH as 51.6 ± 5.21, 53.6 ± 6.88, and 70.01 ± 7.11 %, for F7, F10, and F13, respectively. The stability of the three formulations was confirmed in various physiological conditions. Drug was released in a sustainable fashion. Besides, from the preferred 23 compounds, five compounds namely Sativoside R2, Degalactotigonin, Proto-desgalactotigonin, Eruboside B and Sativoside R1 showed a better docking score than trpD, and therefore may help in promoting anti-tubercular activity.

Phenolic acid-tethered isoniazid for abrogation of drug-induced hepatotoxicity: design, synthesis, kinetics and pharmacological evaluation.

Morphological and metabolic aberrations in the liver caused by long-term use of anti-tubercular agent isoniazid (INH) have been an issue of great concern in tuberculosis treatment. To resolve this issue, a novel hepatoprotective prodrug strategy was developed by combining the antioxidant property of phenolic acids with INH moiety for probable synergistic effect. In this work, INH was conjugated with phenolic antioxidants using Schotten-Baumann reaction through biocleavable amide linkage. Synthesized prodrugs were characterized by spectral analysis and in vitro release studies were carried out using HPLC. They were found to be stable in acidic (pH 1.2), basic (pH 7.4) buffers, stomach homogenates of rat whereas hydrolyzed significantly (56.03-88.62%) in intestinal homogenates over a period of 6 h. Further their hepatoprotective potential was evaluated in male Wistar rats by performing liver function tests, oxidative stress markers, and histopathology studies. All the prodrugs were effective in abating oxidative stress and re-establishing normal hepatic physiology. Especially the effect of prodrugs of INH with gallic acid and syringic acid in restoring levels of enzymes superoxide dismutase and glutathione peroxidase and abrogating liver damage was noteworthy. The findings of this investigation demonstrated that reported prodrugs can add safety and efficacy to future clinical protocols of tuberculosis treatment.

Synthesis and mechanistic investigation of iron(II) complexes of isoniazid and derivatives as a redox-mediated activation strategy for anti-tuberculosis therapy.

The emergence of multidrug-resistant strains of Mycobacterium tuberculosis (MTB) represents a major threat to global health. Isoniazid (INH) is a prodrug used in the first-line treatment of tuberculosis. It undergoes oxidation by a catalase-peroxidase KatG, leading to generation of an isonicotinoyl radical that reacts with NAD(H) forming the INH-NADH adduct as the active metabolite. A redox-mediated activation of isoniazid using an iron metal complex was previously proposed as a strategy to overcome isoniazid resistance due to KatG mutations. Here, we have prepared a series of iron metal complexes with isoniazid and analogues, containing alkyl substituents at the hydrazide moiety, and also with pyrazinamide derivatives. These complexes were activated by H2O2 and studied by ESR and LC-MS. For the first time, the formation of the oxidized INH-NAD adduct from the pentacyano(isoniazid)ferrate(II) complex was detected by LC-MS, supporting a redox-mediated activation, for which a mechanistic proposition is reported. ESR data showed all alkylated hydrazides, in contrast to non-substituted hydrazides, only generated alkyl-based radicals. The structural modifications did not improve minimal inhibitory concentration (MIC) against MTB in comparison to isoniazid iron complex, providing support to isonicotinoyl radical formation as a requirement for activity. Nonetheless, the pyrazinoic acid hydrazide iron complex showed redox-mediated activation using H2O2 with generation of a pyrazinoyl radical intermediate and production of pyrazinoic acid, which is in fact the active metabolite of pyrazinamide prodrug. Thereby, this strategy can also unveil new opportunities for activation of this type of drug.

Nevirapine derivatives with broad-spectrum chemotherapeutic properties for the effective treatment of HIV/AIDS.

A series of nevirapine derivatives has been synthesized in an effort to enhance the spectrum of chemotherapeutic properties for the effective treatment of AIDS and AIDS-related opportunistic infections. The nevirapine derivative bearing isoniazid moiety (3a) was found to be the most potent compound with EC50 of<0.0636 microM, CC50 of>1000 microM and selectivity index of>15,723 which also exhibited 90% inhibition against Mycobacterium tuberculosis at 6.25 microg/ml. Compound 3c showed 100% inhibition against M. tuberculosis and also exhibited potent antibacterial activity against 24 pathogenic bacteria with MIC less than 1 microg/ml.

Development of novel aroylhydrazone ligands for iron chelation therapy: 2-pyridylcarboxaldehyde isonicotinoyl hydrazone analogs.

Previous studies have demonstrated that aroylhydrazone iron (Fe) chelators of the pyridoxal isonicotinoyl hydrazone (PIH) class have high Fe chelation efficacy both in vitro and in vivo. Depending on their design, these drugs may have potential as agents for the treatment of Fe overload disease or cancer. Considering the high potential of this class of ligands, we have synthesized seven novel aroylhydrazones in an attempt to identify Fe chelators more efficient than desferrioxamine (DFO) and more soluble than those of the PIH class. These compounds belong to a new series of tridentate chelators known as the 2-pyridylcarboxaldehyde isonicotinoyl hydrazones (PCIH). In this study we have examined the Fe chelation efficacy and antiproliferative activity of these chelators including their effects on the expression of genes (WAF1 and GADD45) known to be important in mediating cell cycle arrest at G1/S. From seven chelators synthesized, three ligands, namely 2-pyridylcarbox-aldehyde benzoyl hydrazone (PCBH), 2-pyridylcarboxaldehyde m-bromobenzoyl hydrazone (PCBBH), and 2-pyridylcarboxaldehyde 2-thiophenecarboxyl hydrazone (PCTH), showed greater Fe chelation activity than DFO and comparable or greater efficiency than PIH. These ligands were highly effective at both mobilizing 59Fe from cells and preventing 59Fe uptake from 59Fe-transferrin and caused a marked increase in the RNA-binding activity of the iron-regulatory proteins (IRP). Our studies have also demonstrated that compared with the cytotoxic Fe chelator, 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311), these ligands have far less effect on cellular growth and 3H-thymidine, 3H-leucine, or 3H-uridine incorporation. In addition, in contrast to 311, which markedly increased WAF1 and GADD45 mRNA expression, PCBH and PCTH did not have any effect, whereas PCBBH increased the expression of GADD45 mRNA. Collectively, these results demonstrate the potential of several of these ligands as agents for the management of Fe overload disease.

[Toxicology of a polymerized modification of isonicotinic acid hydrazide]. / Toksikologischeskaia kharakteristika polimernoi modifikatsii gidrazida izonikotinovoi kisloty.

The biologic side effects were studied of a polymer of isonicotinic acid hydrazide (PINH) synthesized on the basis of the copolymer vinylpyrrolidone and crotonaldehyde. The influence of dosage and conditions of administration as a functional and morphologic indicator in animals were also investigated. Threshold dosage and optimal conditions of administration in clinical practice are recommended.