Isoniazid Derivatives Research Articles

Isoniazid: the magic molecule

The resurgence of tuberculosis and emergence of multidrug resistant isolates has focused attention on the need for an improved understanding of molecular aspects of the disease, and for elucidation of the factors responsible for drug action and resistance. Isoniazid is the frontline drug employed in the treatment of tuberculosis. Recent research has probed the mechanism of action of isoniazid (INH), a key drug in the chemotherapy of tuberculosis and also the anti-mycobacterial potential of derivatives of isoniazid has been evaluated. We have made an attempt to compile an account of various derivatives of isoniazid reported for their diverse biological activities like anti-mycobacterial, -bacterial, -fungal and -viral activities.

Isonicotinic Acid Hydrazide Derivatives: Synthesis, Antimycobacterial, Antiviral, Antimicrobial Activity and QSAR Studies

A series of isonicotinic acid hydrazide derivatives (1-14) was synthesized and tested for their in vitro antimycobacterial activity against Mycobacterium tuberculosis and the compounds with bromo, N2-2,4-hexadienoyl, N2-lauryl and N2-octadecanoyl groups were found to be the most effective, especially isonicotinic acid-N'-octadecanoyl hydrazide (12) was more active than the standard drug isoniazid. The results of antiviral activity testing showed that none of the tested compounds were active at subtoxic concentrations. The synthesized compounds were also screened for their antimicrobial potential against S. aureus, B. subtilis, E. coli, C. albicans and A. niger and the results indicated that compounds 4, 11, 12 and 14 were found to be active with Benzoic acid N'-(4-hydroxy-3,5-dimethoxy-benzylidene)-N-(pyridine-4- carbonyl)-hydrazide (14) having highest antimicrobial potential. The QSAR studies indicated the importance of topological parameters 3χ and κ1 in governing the antimicrobial activity of synthesized derivatives. Keywords: Acylated isoniazid derivatives, Antimycobacterial, Antiviral, Antimicrobial, QSAR, Tuberculosis, Mycobacterium tuberculosis, ontubercular mycobacterial infections, human immunodeficiency virus (HIV), capreomycin, multi-antibiotic-resistant (MAR), mammalian proteins, Acquired immunodeficiency syndrome (AIDS), viral RNA, mRNA

Isoniazid metal complex reactivity and insights for a novel anti-tuberculosis drug design

For over a decade, tuberculosis (TB) has been the leading cause of death among infectious diseases. Since the 1950s, isoniazid has been used as a front-line drug in the treatment of TB; however, resistant TB strains have limited its use. The major route of isoniazid resistance relies on KatG enzyme disruption, which does not promote an electron transfer reaction. Here, we investigated the reactivity of isoniazid metal complexes as prototypes for novel self-activating metallodrugs against TB with the aim to overcome resistance. Reactivity studies were conducted with hydrogen peroxide, hexacyanoferrate(III), and aquopentacyanoferrate(III). The latter species showed a preference for the inner-sphere electron transfer reaction pathway. Additionally, electron transfer reaction performed with either free isoniazid or (isoniazid)pentacyanoferrate(II) complex resulted in similar oxidized isoniazid derivatives as observed when the KatG enzyme was used. However, upon metal coordination, a significant enhancement in the formation of isonicotinic acid was observed compared with that of isonicotinamide. These results suggest that the pathway of a carbonyl-centered radical might be favored upon coordination to the Fe(II) owing to the π-back-bonding effect promoted by this metal center; therefore, the isoniazid metal complex could serve as a potential metallodrug. Enzymatic inhibition assays conducted with InhA showed that the cyanoferrate moiety is not the major player involved in this inhibition but the presence of isoniazid is required in this process. Other isoniazid metal complexes, [Ru(CN)(5)(izd)](3-) and [Ru(NH(3))(5)(izd)](2+) (where izd is isoniazid), were also unable to inhibit InhA, supporting our proposed self-activating mechanism of action. We propose that isoniazid reactivity can be rationally modulated by metal coordination chemistry, leading to the development of novel anti-TB metallodrugs.

Novel 1,2,3-Triazole Derivatives for Use against Mycobacterium tuberculosis H37Rv (ATCC 27294) Strain

The purpose of this study was to prepare various 4-substituted N-phenyl-1,2,3-triazole derivatives using click chemistry. The derivatives were screened in vitro for antimicrobial activity against Mycobacterium tuberculosis strain H37Rv (ATCC 27294) using the Alamar Blue susceptibility test. The activity was expressed as the minimum inhibitory concentration (MIC) in μg/mL (μM). Derivatives of isoniazid (INH), (E)-N'-[(1-aryl)-1H-1,2,3-triazole-4-yl)methylene] isonicotinoyl hydrazides, exhibited significant activity with MIC values ranging from 2.5 to 0.62 μg/mL. In addition, they displayed low cytotoxicity against liver cells (hepatoma HepG2) and kidney cells (BGM), thereby providing a high therapeutic index. The results demonstrated the potential and importance of developing new INH derivatives to treat mycobacterial infections.

Synthesis, Characterization of (E)-N'-(substituted-benzylidene)isonicotinohydrazide Derivatives as Potent Antitubercular Agents

A series of 19 isonicotinic acid hydrazide derivatives has been synthesized and evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv using alamar blue susceptibility test. The synthesized compounds inhibit Mycobacterium tuberculosis H37Rv strain with minimum inhibitory concentration ranging from (0.00014-0.01174 mM). Among all synthesized compounds seven derivatives 2a, 2b, 2e, 2h, 2l, 2m and 2q were more potent than isoniazid and the compound 2q emerged as the most potent derivative, being more effective than isoniazid with an (MIC 0.00023 mM) in vitro. The results demonstrated the potential and importance of developing new isoniazid derivatives against Mycobacterium infections.

Isonicotinic acid hydrazide derivatives: synthesis, antimicrobial activity, and QSAR studies

A series of isonicotinic acid hydrazide derivatives (1–19) was synthesized and tested in vitro for antimycobacterial activity against Mycobacterium tuberculosis and antimicrobial activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Candida albicans, and Aspergillus niger and the results indicated that the compounds with OH, SCH3, and OCH3 groups were found to be active against the tested strains. None of the test compounds were active against a broad variety of RNA and DNA viruses at subtoxic concentrations, except 8, that showed some selective anti-reovirus-1 activity. The multi-target QSAR models were found to be effective in predicting the antimicrobial activity of the isoniazid derivatives and indicated the importance of nuclear repulsion energy (Nu.E) in explaining the antimicrobial activity of isoniazid derivatives. The developed QSAR models were validated using the external test set of synthesized derivatives.

Synthesis, characterization and antimicrobial evaluation of novel derivatives of isoniazid

In the present investigation, a series of new Mannich bases were prepared by the reaction of 2-ethoxybenzaldehyde with isoniazid to form acid hydrazone (3a). Further, C-Mannich bases of the above acid hydrazone were prepared by aminomethylation with formaldehyde and substituted secondary amines (3b–3k). The structures of newly synthesized compounds were evaluated by elemental analyses and spectral (IR, 1H NMR, 13C NMR) studies. All the synthesized compounds were evaluated for their antimicrobial activity. Amoxicillin was used as a standard drug for antibacterial activity while Nystatin was used as a standard drug for antifungal activity. Preliminary pharmacological evaluation revealed that the compound (3f, 3i, 3j, 3k) showed better performance against Bacillus subtilis,Staphylococcus aureus,Pseudomonas aeruginosa, Escherichia coli, Candida albicans and Candida gabrata. The result demonstrates the potential and importance of developing new mannich bases which would be effective against resistant bacterial and fungal strain.

ChemInform Abstract: Synthesis and Pharmacological Evaluation of Condensed Heterocyclic 6‐Substituted 1,2,4‐Triazolo‐[3,4‐b]‐1,3,4‐thiadiazole and 1,3,4‐Oxadiazole Derivatives of Isoniazid.

AbstractAll synthesized substances are evaluated for their anti‐inflammatory, analgesic, ulcerogenic, and lipid peroxidation activities.

(E)-N′-(2,3,4-Trihydroxybenzylidene)isonicotinohydrazide dihydrate

In the title isoniazid derivative, C13H11N3O4·2H2O, the Schiff base mol­ecule exists in an E configuration with respect to the acyclic C=N bond. An intra­molecular O—H⋯N hydrogen bond forms a six-membered ring, producing an S(6) ring motif. The essentially planar pyridine ring [maximum deviation = 0.0119 (8) Å] is inclined at a dihedral angle of 7.30 (4)° with respect to the benzene ring. In the crystal, inter­molecular O—H⋯N, O—H⋯O, N—H⋯O and C—H⋯O hydrogen bonds link the mol­ecules into two-dimensional arrays lying parallel to the (10) plane. These arrays are further inter­connected into a three-dimensional extended network via O—H⋯O and C—H⋯O hydrogen bonds. A weak inter­molecular π–π inter­action [centroid-to-centroid distance = 3.5627 (5) Å] is also observed.

Synthesis and pharmacological evaluation of condensed heterocyclic 6-substituted 1,2,4-triazolo-[3,4- b]-1,3,4-thiadiazole and 1,3,4-oxadiazole derivatives of isoniazid

The significance of this study was to prepare various isoniazid derivatives by introducing the isoniazid core into several molecules to explore the possibilities of some altered biological activities. Series of 6-substituted-1,2,4-triazolo-[3,4- b]-1,3,4-thiadiazole ( 3a– g) and 1,3,4-oxadiazole ( 4a– g and 5) derivatives of isoniazid were synthesized in satisfactory yield and pharmacologically evaluated for their anti-inflammatory, analgesic, ulcerogenic, and lipid peroxidation activities by known experimental models.

Investigation of adsorption of isoniazid derivatives at mild steel/hydrochloric acid interface: Electrochemical and weight loss methods

The corrosion inhibition properties of isoniazid derivatives, namely N-(morpholino methyl) isatin-3-isonicotinoyl hydrazone (MIIH), N-(piperazino methyl) isatin-3-isonicotinoyl hydrazone (PIIH), N-(2-Thio benzimidazolyl methyl) isatin-3-isonicotinoyl hydrazone (TBIH), N-(piperadino methyl) isatin-3-isonicotinoyl hydrazone (PIIIH) for mild steel corrosion in 1 M HCl medium were analysed by electrochemical impedance spectroscopy (EIS), potentiodynamic polarization and weight loss techniques. Electrochemical impedance data demonstrated that the addition of the isoniazid derivatives in the corrosive solution decreased the charge capacitance and simultaneously increased the function of the charge/discharge of the interface, facilitating the formation of an adsorbed layer over the steel surface. Adsorption of these inhibitors on the steel surface obeyed the Langmuir adsorption isotherm. Potentiodynamic polarization studies showed that all the tested inhibitors affected both the anodic and cathodic process, thus they can be classified as mixed type of inhibitor. The effect of chemical structure of the four tested inhibitors was discussed. It was found that the efficiency order followed by molecules tested was TBIH > PIIH > MIIH > PIIIH. Thus TBIH turned out to be the best inhibitor. This fact strongly suggests that, an efficient corrosion inhibitor molecule should be large one, planar, having unoccupied d-orbital and also containing an extensive number of π-electrons.

(E)-N′-(2,4,6-Trimethylbenzylidene)isonicotinohydrazide

The title isoniazid derivative, C16H17N3O, exists in an E configuration with respect to the Schiff base C=N bond. The pyridine ring is essentially planar [maximum deviation = 0.009 (3) Å]. The mean plane through the hydrazide unit forms dihedral angles of 38.38 (16) and 39.42 (16)°, respectively, with the pyridine and benzene rings. In the crystal structure, symmetry-related mol­ecules are linked via inter­molecular N—H⋯O hydrogen bonds into chains along [100]. The crystal structure is further stabilized by weak inter­molecular C—H⋯π inter­actions.

Elucidating drug-enzyme interactions and their structural basis for improving the affinity and potency of isoniazid and its derivatives based on computer modeling approaches.

The enoyl-ACP reductase enzyme (InhA) from M. tuberculosis is recognized as the primary target of isoniazid (INH), a first-line antibiotic for tuberculosis treatment. To identify the specific interactions of INH-NAD adduct and its derivative adducts in InhA binding pocket, molecular docking calculations and quantum chemical calculations were performed on a set of INH derivative adducts. Reliable binding modes of INH derivative adducts in the InhA pocket were established using the Autodock 3.05 program, which shows a good ability to reproduce the X-ray bound conformation with rmsd of less than 1.0 Å. The interaction energies of the INH-NAD adduct and its derivative adducts with individual amino acids in the InhA binding pocket were computed based on quantum chemical calculations at the MP2/6-31G (d) level. The molecular docking and quantum chemical calculation results reveal that hydrogen bond interactions are the main interactions for adduct binding. To clearly delineate the linear relationship between structure and activity of these adducts, CoMFA and CoMSIA models were set up based on molecular docking alignment. The resulting CoMFA and CoMSIA models are in conformity with the best statistical qualities, in which r2cv is 0.67 and 0.74, respectively. Structural requirements of isoniazid derivatives that can be incorporated into the isoniazid framework to improve the activity have been identified through CoMFA and CoMSIA steric and electrostatic contour maps. The integrated results from structure-based, ligand-based design approaches and quantum chemical calculations provide useful structural information facilitating the design of new and more potentially effective antitubercular agents as follow: the R substituents of isoniazid derivatives should contain a large plane and both sides of the plane should contain an electropositive group. Moreover, the steric and electrostatic fields of the 4-pyridyl ring are optimal for greater potency.

Molecular Modeling and Receptor‐Dependent (RD) 3D‐QSAR Approach to a Set of Antituberculosis Derivatives

AbstractIn this study, receptor‐dependent (RD) 3D‐QSAR models were built for a set of thirty‐seven isoniazid derivatives bound to the enoyl‐acp reductase from M. tuberculosis, called InhA (PDB entry code 1zid). Ligand‐receptor (L‐R) molecular dynamics (MD) simulations [500 000 steps; the step size was 0.001 ps (1 fs)] were carried out at 310 K (biological assay temperature). The hypothesized active conformations resulting from a previously reported receptor‐independent (IR) 4D‐QSAR analysis were used as the molecular geometries of each ligand in this structure‐based L‐R binding research. The dependent variable is the reported MIC values against M. tuberculosis var. bovis. The independent variables (descriptors) are energy terms of a modified first‐generation AMBER force field combined with a hydration shell aqueous solvation model. Genetic function approximation (GFA) formalism and partial least squares (PLS) regression were employed as the fitting functions to develop 3D‐QSAR models. The bound ligand solvation energy, the sum of electrostatic and hydrogen bonding energies of the unbound ligand, the bending energy of the unbound ligand, the electrostatic intermolecular L‐R energy, and the change in hydrogen bonding energy upon binding were found as important energy contributions to the binding process. The 3D‐QSAR model at 310 K has good internal and external predictability and may be regarded as representative of the binding process of ligands to InhA.

Three-Dimensional Quantitative Structure-Activity Relationships for a Large Series of Potent Antitubercular Agents

Abstract: Comparative molecular field analysis (CoMFA) studies were conducted on a series of 100 isoniazid derivatives as anti-tuberculosis agents using two receptor-independent structural data set alignment strategies: (1) rigid-body fit, and (2) pharmacophore-based. Significant cross-validated correlation coefficients were obtained (CoMFA(1), q2= 0,75 and CoMFA(2), q = 0.74), indicating the potential of the models for untested compounds. The models were then used to predict the inhibitory potency of 20 test set compounds that were not included in the training set, and the predicted values were in good agreement with the experimental results.

Monolayers of the lipid derivatives of isoniazid at the air/water interface and the formation of self-assembled nanostructures in water

Isoniazid (INH, isonicotinic acid hydrazide) is one of the most commonly used anti-tubercular drugs. However, resistance of Mycobacterium tuberculosis strains to anti-mycobacterial agents including INH is an increasing problem worldwide. Development of new anti-mycobacterial agents thus has attracted attention. Five lipid derivatives of INH were prepared in this study. They formed monolayers at the air/water interface, and some nanostructures with different morphologies were obtained through molecular self-assembly in water. The derivatives included one fatty acyl derivative containing a 12-C hydrocarbon-long chain ( 1), three fatty alcohol derivatives with a succinyl as spacer and an 8, 12 or 16-C hydrocarbon-long chain ( 2, 3 and 4), and one tetrahydro-2 H-1,3,5-thiadiazine-2-thione (THTT) derivative containing a 12-C hydrocarbon-long chain ( 5). The surface pressure–area isotherms depended on the volume and configuration of heads and the length of tails of derivatives. Compound 2 had a relatively large head and a short tail, easily standing uprightly at the interface. Under a certain surface pressure, the linear polar head groups of 3 could be partly squeezed out and insert into subphase because the length of heads were comparable to the one of tails. The very long tails of 4 always maintained above the interface and led to a high collapse pressure. Compound 5 possessed an extended and large head consisting of the THTT and INH groups so that the relatively short tails tilted at the interface and difficultly contact with each other. The THTT rings might be partly squeezed out and enter into air under a certain surface pressure. The self-assembly behaviours of derivatives in water depended on the molecular configuration and agreed with the corresponding monolayer behaviours. The flexible and medium-long tails ( 1 and 3) led to the derivatives to form nanoscale vesicles, though the short or very long tails did not ( 2 and 4). Interestingly, intermolecular hydrogen bonding could occur between the molecules of 5, and improve the derivative forming helical nanofibres other than vesicles. The molecular self-assembly of INH's lipid derivatives was explored in details in this study. The formation mechanisms of self-assembled nanostructures were analyzed. Various types of self-assembled nanostructures were obtained and the formation mechanisms were analyzed. The relationship between the self-assembly and the molecular configuration of amphiphilic derivatives was also revealed. The lipid derivatives of INH show promising anti- Mycobacterium action because the amphiphilic prodrugs allow for better penetration of the bacterial cells. The self-assembled nanostructures may likely be the potential self-assembled drug delivery systems for tuberculosis therapy.

Fragment-based and classical quantitative structure–activity relationships for a series of hydrazides as antituberculosis agents

Worldwide, tuberculosis (TB) is the leading cause of death among curable infectious diseases. Multidrug-resistant Mycobacterium tuberculosis is an emerging problem of great importance to public health, and there is an urgent need for new anti-TB drugs. In the present work, classical 2D quantitative structure-activity relationships (QSAR) and hologram QSAR (HQSAR) studies were performed on a training set of 91 isoniazid derivatives. Significant statistical models (classical QSAR, q (2) = 0.68 and r (2) = 0.72; HQSAR, q (2) = 0.63 and r (2) = 0.86) were obtained, indicating their consistency for untested compounds. The models were then used to evaluate an external test set containing 24 compounds which were not included in the training set, and the predicted values were in good agreement with the experimental results (HQSAR, r(2)(pred) = 0.87; classical QSAR, r(2)(pred) = 0.75).

Application of Quantitative Structure−Activity Relationships to the Modeling of Antitubercular Compounds. 1. The Hydrazide Family

A QSAR/QSPR methodology was used to analyze a set of 173 hydrazides, a great part of which are isoniazid (INH) derivatives. Nineteen molecular descriptors of various types (physicochemical, steric, geometrical, and electronic) have been systematically tested through a careful application of MLR. The analysis revealed that the biological activity of these compounds against M. tuberculosis does not depend on lipophilicity, as measured by log P. Properties that account for the biological response of isoniazid and related compounds, consistent with a mechanism involving the formation of radical species, were identified. The role of substituents in the stabilization of the intermediate species that gives rise to the active agent, the acyl radical, is discussed. It is postulated that the activation of INH derivatives' prodrugs (hydrazines and hydrazones) occurs near the surface of M. tuberculosis.

Evaluation of anti-tubercular activity of nicotinic and isoniazid analogues

Several nicotinic and isoniazid derivatives, most of them containing nitro groups were synthesized by our group, and evaluated for their in vitro antibacterial activity against Mycobacterium tuberculosis H37Rv using the Alamar Blue susceptibility test and the activity expressed as the minimum inhibitory concentration (MIC) in mg/mL. The compound 11d exhibited the best result (1.2 µg/mL) when compared with first line drugs such as isoniazid (INH) and rifampicin (RIP). Therefore this class of compounds could be a good starting point to develop new lead compounds in the treatment of multi-drug resistant tuberculosis.

The lipophilicity estimation of 5‐arylidene derivatives of (2‐thio)hydantoin with antimycobacterial activity

The lipophilicity of antituberculotic 5-arylidene derivatives of (thio)hydantoin, thioacetazone and isoniazid has been determined by reversed-phase thin-layer chromatography (RP-TLC). Mixtures of acetone and water (with acetone content 60-85%) were used as the mobile phase. The R(M) (relative lipophilicity) of each compound (except isoniazid) decreased linearly with the increasing concentration of acetone. The partition coefficients (log P) of the compounds were calculated by the use of eight computer programs (ClogP, KowWin, XlogP, AlogPs, CAChe, Pallas, Interactive analysis and Slipper) and compared with the experimental lipophilicity (R(M0)). According to the observations the best tools for in silico predicting log P of (2-thio)hydantoins are programs KowWin and AlogPs.