Isoniazid Analogue Research Articles

Design, synthesis and antimycobacterial activity of benzoxazinone derivatives and open-ring analogues: Preliminary data and computational analysis.

This study examines in depth benzoxazine nucleus for antimycobacterial property. We synthesized some benzoxazin-2-one and benzoxazin-3-one derivatives, which were tested for activity against a panel of Mycobacterium tuberculosis (Mtb) strains, including H37Ra, H37Rv and some resistant strains. Several compounds displayed a high antimycobacterial activity and the three isoniazid analogue derivatives 8a-c exhibited a MIC range of 0.125-0.250 μg/mL (0.37-0.75 μM) against strain H37Ra, therefore lower than the isoniazid reference drug. Two benzoxazin-2-one derivatives, 1c and 5j, together with isoniazid-analogue compound 8a, also revealed low MIC values against resistant strains and proved highly selective for mycobacterial cells, compared to mammalian Vero cells. To predict whether molecule 8a is able to interact with the active site of InhA, we docked it into the crystal structure; indeed, during the molecular dynamic simulation the compound never left the protein pocket. The more active compounds were predicted for ADME properties and all proved to be potentially orally active in humans.

JVA, an isoniazid analogue, is a bioactive compound against a clinical isolate of the Mycobacterium avium complex

Bacteria belonging to Mycobacterium avium complex are organisms of low pathogenicity that infect immunosuppressed individuals. Infection is treated with an antimicrobial macrolide, Clarithromycin (CAM) or Azitromycin, associated with Ethambutol and Rifabutin during 12 months. Regimen long duration and side effects hinder patient's commitment to treatment favoring emergence of antibiotic resistance. In this present study, we evaluated the activity of JVA, an Isoniazid (INH) derivative, against M. avium 2447, a clinical isolate. We demonstrated that JVA reduces M. avium 2447 growth in macrophages, more efficiently than CAM and INH. In order to explore JVA mechanism of action, we investigated compound properties and performed pH-dependent stability studies. Our results suggest an enhanced ability of JVA to cross biological membranes. Furthermore, we suggest that in acidic conditions of macrophages' phagosomes, where mycobacteria replicate, JVA would be promptly hydrolyzed to INH, delivering the adduct INH-nicotinamide adenine dinucleotide and thus inhibiting M. avium 2447 growth.

A long-range tautomeric effect on a new Schiff isoniazid analogue, evidenced by NMR study and X-ray crystallography

Isoniazid analogues were cyclized through acid catalysis by closing a THF ring, as favoured by Baldwin's rules (5-exo-trig).

A Review on Effect of Antitubercular Activity on Structural Modification of Isoniazide

Tuberculosis remains the leading cause of mortality worldwide. The facts relating to a front-line antitubercular drug isoniazide and its analogues. The antitubercular pharmacophore moiety of isoniazide has been introduced in various compounds to improve their antitubercular activity against mycobacterium, as well as their multidrug resistant mycobacterium strains. Various compounds like Schiff bases, hydrazones, hydrazides and metal complexes of isoniazid have shown good antitubercular activity. A series of isoniazid analogues have been evaluated for their activity against Mycobacterium tuberculosis. Some compounds exhibited significant antitubercular activity when compared with first line drugs like isoniazid and rifampicin and could be a good starting spot to develop new compounds in the fight against multi-drug resistant tuberculosis.

Development of a Mycobacterium smegmatis transposon mutant array for characterising the mechanism of action of tuberculosis drugs: Findings with isoniazid and its structural analogues

The development of new drugs is required to control human tuberculosis (TB). This study examined whether drug hypersensitive mutants could be used to reveal novel aspects of the mechanism of action of a TB drug. A transposon mutant collection with an estimated 1.1-fold genome coverage (7680 mutants) was constructed in Mycobacterium smegmatis and screened in high-throughput against isoniazid. Hypersensitive transposants with mutations in genes known to influence the mode of action of isoniazid were isolated. To further investigate the role of one of these genes, nudC, the corresponding mutant was tested for sensitivity towards isoniazid structural analogues. Overexpression of nudC, as well as inhA which encodes a known target of isoniazid, increased M.smegmatis resistance to isoniazid, but failed to increase resistance to three of the analogues, NSC27607, NSC33759, and NSC40350. In contrast, overexpression of katG resulted in increased sensitivity to each of the isoniazid analogues tested including NSC27607, NSC33759, and NSC40350. This provides evidence that the latter isoniazid analogues are activated by KatG in a NudC-independent manner and that InhA may not be their primary target. In summary, characterisation of drug hypersensitive mutants detected genes involved in the mode of action of isoniazid. Furthermore, it identified isoniazid analogues which are resilient to both InhA- and NudC-dependent mechanisms of resistance.

Solubility of N-(4-Chlorophenyl)-2-(pyridin-4-ylcarbonyl)hydrazinecarbothioamide (Isoniazid Analogue) in Five Pure Solvents at (298.15 to 338.15) K

The aim of the present investigation was to measure and correlate the solubility of N-(4-chlorophenyl)-2-(pyridin-4-ylcarbonyl)hydrazinecarbothioamide [isoniazid (INH) analogue] in five different pure solvents, namely, ethanol, ethylene glycol (EG), propylene glycol (PG), polyethylene glycol-400 (PEG-400), and isopropyl alcohol (IPA) at (298.15 to 338.15) K using the shake flask method. The experimental solubilities of INH analogue were regressed with Apelblat equation with root-mean-square deviations in the range of (0.22 to 4.42) %. The correlation coefficients were observed in the range of 0.996 to 0.999, indicating good fitting of experimental data. The solubility of INH analogue was found to increase with an increase in temperature in each solvent investigated. The mole fraction solubility of INH analogue was found to be highest in PEG-400 (1.08 × 10–1 at 298.15 K) followed by EG (7.70 × 10–3 at 298.15 K), PG (7.38 × 10–3 at 298.15 K), IPA (1.13 × 10–3 at 298.15 K), and ethanol (6.47 × 10–4 at 298.15 K). Dissolution thermodynamic studies indicated nonspontaneous and endothermic dissolution of INH analogue in each solvent investigated. Based on these results, INH analogue has been considered as freely soluble in PEG-400, soluble in IPA, EG, and PG, and slightly soluble in ethanol. The solubility data of this study could be useful in crystallization/purification and formulation development of INH analogue.

Solubility of N-(4-chlorophenyl)-2-(pyridin-4-ylcarbonyl)hydrazinecarbothioamide in PEG 400 + water co-solvent mixtures at 298.15 K to 338.15 K

The solubility of N-(4-chlorophenyl)-2-(pyridin-4-ylcarbonyl) hydrazinecarbothioamide (isoniazid analogue) in mono-solvents (water and polyethylene glycol 400 (PEG 400)) and various PEG 400 + water co-solvent mixtures was measured from (298.15 to 338.15) K using the shake flask method. The experimental solubilities were correlated with Apelblat equation and log-linear model of Yalkowsky. The root mean square deviations were observed in the range of 0.007–0.052 for Apelblat equation. However, the mean absolute errors were observed in the range of (0.36–4.94)% for log-linear model of Yalkowsky. Experimental solubilities of isoniazid analogue were correlated well with Apelblat equation and Yalkowsky model. The solubility of isoniazid analogue was observed highest and lowest in pure PEG 400 (0.108 at 298.15 K) and pure water (5.17 × 10−7 at 298.15 K), respectively. Based on solubility results, isoniazid analogue has been considered as freely soluble in PEG 400 and practically insoluble in water. The solubility data of this study could be useful in formulation development of isoniazid analogue in pharmaceutical industries.

Solubility of N-(4-Chlorophenyl)-2-(pyridin-4-ylcarbonyl)hydrazinecarbothioamide (Isoniazid Analogue) in Transcutol + Water Cosolvent Mixtures at (298.15 to 338.15) K

The solubility of N-(4-chlorophenyl)-2-(pyridin-4-ylcarbonyl)hydrazinecarbothioamide (isoniazid analogue) in various diethylene glycol monoethyl ether (Transcutol) + water cosolvent mixtures was measured at (298.15 to 338.15) K using the shake flask method. In order to investigate the influence of temperature on solubility, the experimental solubilities of the isoniazid analogue were correlated with the Apelblat equation. To investigate the influence of cosolvent mixtures on solubility, the log–linear model of Yalkowsky was used. For the Apelblat equation, the root-mean-square deviations (RMSDs) were observed in the range of 0.004 to 0.033. For the Yalkowsky model, the RMSDs were observed in the range of 0.021 to 0.114. The correlation coefficients were observed in the range of 0.996 to 0.999. These results indicated the good fitting of experimental solubilities with the Apelblat equation and Yalkowsky model. The solubility of isoniazid analogue was found to be highest and lowest in pure Transcutol (4.23·...

Synthesis of highly potent novel anti-tubercular isoniazid analogues with preliminary pharmacokinetic evaluation

Thirty two novel isoniazid analogues were prepared by one-pot three component condensations of isoniazid (INH), 3-mercaptopropionic acid and various aryl/heteroaryl aldehydes. The synthesized compounds were evaluated for their anti-TB activity against Mycobacterium tuberculosis H37Rv (MTB) and cytotoxicity. Among the compounds, compound N-(2-(4-(benzyloxy) phenyl)-4-oxo-1,3-thiazinan-3-yl) isonicotinamide (17) inhibited MTB with MIC of 0.12μM and was three times more potent than INH. The main pharmacokinetic parameters after intravenous administration (10mg/kg body weight) in male Wistar rats viz. t½, Kel, mean plasma clearance and mean volume of distribution were found to be 1.14±0.20h, 0.62±0.10h−1, 22.48±0.16mL/kg/min and 1.99±0.49L, respectively. The systemic absorption was slow after oral administration (50mg/kg body weight). The peak plasma concentration was found to be 1.31±0.06μg/mL attained in 3h. The bioavailability was found to be 16.7%.

An Isoniazid Analogue Promotes Mycobacterium tuberculosis-Nanoparticle Interactions and Enhances Bacterial Killing by Macrophages

Nanoenabled drug delivery systems against tuberculosis (TB) are thought to control pathogen replication by targeting antibiotics to infected tissues and phagocytes. However, whether nanoparticle (NP)-based carriers directly interact with Mycobacterium tuberculosis and how such drug delivery systems induce intracellular bacterial killing by macrophages is not defined. In the present study, we demonstrated that a highly hydrophobic citral-derived isoniazid analogue, termed JVA, significantly increases nanoencapsulation and inhibits M. tuberculosis growth by enhancing intracellular drug bioavailability. Importantly, confocal and atomic force microscopy analyses revealed that JVA-NPs associate with both intracellular M. tuberculosis and cell-free bacteria, indicating that NPs directly interact with the bacterium. Taken together, these data reveal a nanotechnology-based strategy that promotes antibiotic targeting into replicating extra- and intracellular mycobacteria, which could actively enhance chemotherapy during active TB.

ChemInform Abstract: Microwave Assisted One‐Pot Synthesis of Highly Potent Novel Isoniazid Analogues.

AbstractThe isoniazid analogues (IV) are tested for their in vitro activity against Mycobacterium tuberculosis H37Rv and the multi‐drug resistant Mycobacterium tuberculosis.

Microwave assisted one-pot synthesis of highly potent novel isoniazid analogues

A series of novel isoniazid (INH) analogues were synthesized by microwave assisted one pot reaction of INH, various benzaldehydes and dimedone in water with catalytic amount of DBSA. The synthesized compounds were evaluated for their anti-TB activity against Mycobacterium tuberculosis H37Rv (MTB) and multi-drug resistant Mycobacterium tuberculosis (MDR-TB). Among the 29 compounds, compound N-[9-[2-(benzyloxy)phenyl]-3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-10(1H)-acridinyl]isonicotinamide (12) inhibited MTB with MIC of <0.17 μM and MDR-TB with MIC of 0.69 μM.

New Anti-Tuberculosis Drugs with Novel Mechanisms of Action

It is estimated that a third of the world's population is currently infected with tuberculosis, leading to 1.6 million deaths annually. The current drug regimen is 40 years old and takes 6-9 months to administer. In addition, the emergence of drug resistant strains and HIV co-infection mean that there is an urgent need for new anti-tuberculosis drugs. The twenty-first century has seen a revival in research and development activity in this area, with several new drug candidates entering clinical trials. This review considers new potential first-line anti-tuberculosis drug candidates, in particular those with novel mechanisms of action, as these are most likely to prove effective against resistant strains. A brief overview of current first-line and recent drugs (such as fluoroquinolones, rifampicin and isoniazid analogues) is initially presented. This is followed by a description of structure-activity relationships, in vitro and in vivo activity, pharmacokinetics, mechanism of action, combination regimens and clinical trials of the new drug candidates SQ109, PA-824, OPC-67683, TMC207 and others.

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.