54-85-3 Usage
Uses
Used in Pharmaceutical Industry:
Isoniazid is used as an antimicrobial agent for the prevention of tuberculosis infection or used concurrently with another agent for the treatment of tuberculosis infection. It is commonly used with rifampin, pyrazinamide, or both of these agents. Isoniazid is the only Food and Drug Administration approved drug to treat latent tuberculosis in order to prevent it from becoming active.
Used in Tuberculosis Treatment:
Isoniazid is used as an antibiotic for the treatment of Mycobacterium tuberculosis, inhibiting mycolic acid biosynthesis. It is effective against both intracellular and extracellular organisms and is used for the treatment of all forms of tuberculosis in which organisms are susceptible.
Used in Drug Metabolism:
Isoniazid selectively induces the expression of cytochrome P450 2E1 (CYP2E1) and reversibly inhibits the activities of CYP2C19 and CYP3A4. It also mechanistically inactivates CYP1A2, CYP2A6, CYP2C19, and CYP3A4 at clinically relevant concentrations, playing a role in drug metabolism and interactions.
Originator
Nyrazid,Squibb,US,1952
Indications
Isoniazid (isonicotinic acid hydrazide, or INH) is the
most active drug for the treatment of tuberculosis
caused by susceptible strains. It is a synthetic agent with
a structural similarity to that of pyridoxine.
Manufacturing Process
4 parts of 4-cyanopyridine in 12 parts of water were reacted with 4 parts of
hydrazine hydrate in the presence of 0.08 part of sodium hydroxide at 100°C
under reflux for 7 hours. The product, after filtration and evaporation to
dryness, was crystallized from ethanol. The yield of isonicotinyl hydrazide
amounted to 3.27 parts which is 62% of the theoretical.
Therapeutic Function
Antitubercular
Biological Functions
Its action is bactericidal against replicating organisms, but it appears to be only bacteriostatic at best against semidormant and dormant populations. After treatment with INH, M . tuberculosis loses its acid fastness, which may be interpreted as indicating that the drug interferes with cell wall development.
Synthesis Reference(s)
The Journal of Organic Chemistry, 20, p. 412, 1955 DOI: 10.1021/jo01122a002
Antimicrobial activity
Susceptibility to isoniazid is virtually restricted to the M. tuberculosis
complex (MIC 0.01–0.2 mg/L). It is highly bactericidal
against actively replicating M. tuberculosis. Other mycobacteria
are resistant, except for some strains of M. xenopi (MIC 0.2 mg/L)
and a few strains of M. kansasii (MIC 1 mg/L).
Acquired resistance
Mutations in the katG gene, the inhA gene or its promoter
region, and in the intergenic region of the oxyR–ahpC locus
confer resistance to isoniazid. The relative
proportions of such mutations vary geographically and
are related to the distribution of the various lineages or superfamilies
of M. tuberculosis.
Isoniazid resistance is the commonest form of drug resistance
worldwide and the great majority of strains resistant to
another agent are also resistant to isoniazid.
Air & Water Reactions
Sensitive to air and light. Absorbs insignificant amounts of moisture at 77°F at relative humidities up to approximately 90%. Water soluble. Dust can be explosive when suspended in air at specific concentrations.
Reactivity Profile
Isoniazid is incompatible with chloral, aldehydes, iodine, hypochlorites and ferric salts. Isoniazid is also incompatible with oxidizers. Isoniazid may react with sugars and ketones. Isoniazid can react as a weak acid or a weak base. Isoniazid can be decomposed by oxidative and reductive reactions.
Fire Hazard
Isoniazid is combustible.
Pharmaceutical Applications
One of a number of nicotinamide analogs found to have antituberculosis
activity, following the observation that nicotinamide
inhibited the replication of M. tuberculosis. It is soluble
in water. The dry powder is stable if protected from light. It is
a prodrug requiring oxidative activation by KatG, a mycobacterial
catalase–peroxidase enzyme.
Biochem/physiol Actions
Antibiotic for treatment of Mycobacterium tuberculosis, inhibits mycolic acid biosynthesis. Metabolized by hepatic N-acetyltransferase (NAT) and cytochrome P450 2E1 (CYP2E1) to form hepatotoxins. Selectively induces expression of CYP2E1. Reversibly inhibits CYP2C19 and CYP3A4 activities, and mechanistically inactivates CYP1A2, CYP2A6, CYP2C19 and CYP3A4 at clinically relevant concentrations.
Mechanism of action
Isoniazid is active against susceptible bacteria only when
they are undergoing cell division. Susceptible bacteria
may continue to undergo one or two divisions before
multiplication is arrested. Isoniazid can inhibit the synthesis
of mycolic acids, which are essential components of
mycobacterial cell walls.The mycobacterial enzyme catalase–
peroxidase KatG activates the administered isoniazid
to its biologically active form.The target sites for the
activated isoniazid action are acyl carrier protein AcpM
and Kas A, a β-ketoaceyl carrier protein synthetase that
blocks mycolic acid synthesis. Isoniazid exerts its lethal
effects at the target sites by forming covalent complexes.
Pharmacology
Isoniazid is water soluble and is well absorbed when
administered either orally or parenterally. Oral absorption
is decreased by concurrent administration of
aluminum-containing antacids.
Isoniazid does not bind to serum proteins; it diffuses
readily into all body fluids and cells, including the
caseous tuberculous lesions. The drug is detectable in
significant quantities in pleural and ascitic fluids, as well
as in saliva and skin. The concentrations in the central
nervous system (CNS) and cerebrospinal fluid are generally
about 20% of plasma levels but may reach close
to 100% in the presence of meningeal inflammation.
Isoniazid is acetylated to acetyl isoniazid by N-acetyltransferase,
an enzyme in liver, bowel, and kidney.
Individuals who are genetically rapid acetylators will have
a higher ratio of acetyl isoniazid to isoniazid than will slow
acetylators. Rapid acetylators were once thought to be
more prone to hepatotoxicity, but this is not proved. The
slow or rapid acetylation of isoniazid is rarely important
clinically, although slow inactivators tend to develop peripheral
neuropathy more readily. Metabolites of isoniazid
and small amounts of unaltered drug are excreted in
the urine within 24 hours of administration.
Pharmacokinetics
Oral absorption: >95%
Cmax 300 mg oral: 3–5 mg/L after 1–2 h
Plasma half-life: 0.5–1.5 h (rapid acetylators):
2–4 h (slow acetylators)
Volume of distribution: 0.6–0.8 L/kg
Plasma protein binding: Very low
Absorption and distribution
Isoniazid is almost completely absorbed from the gut and is well distributed. Absorption is impaired by aluminum hydroxide. Therapeutic concentrations are achieved in sputum and CSF. It crosses the placenta and is found in breast milk.
Metabolism
Isoniazid is extensively metabolized to a variety of pharmacologically inactive derivatives, predominantly by acetylation. As a result of genetic polymorphism, patients are divisible into rapid and slow acetylators. About 50% of Caucasians and Blacks, but 80–90% of Chinese and Japanese, are rapid acetylators. Acetylation status does not affect the efficacy of daily administered therapy. The rate of acetylation is reduced in chronic renal failure.
Excretion
Nearly all the dose is excreted in the urine within 24 h, as unchanged drug and metabolic products.
Clinical Use
Isonicotinic acid hydrazide, isonicotinyl hydrazide, or INH(Nydrazid) occurs as a nearly colorless crystalline solid thatis very soluble in water. It is prepared by reacting the methylester of isonicotinic acid with hydrazine.Isoniazid is a remarkably effective agent and continuesto be one of the primary drugs (along with rifampin, pyrazinamide,and ethambutol) for the treatment of tuberculosis.It is not, however, uniformly effective against all formsof the disease. The frequent emergence of strains of the tuberclebacillus resistant to isoniazid during therapy wasseen as the major shortcoming of the drug. This problemhas been largely, but not entirely, overcome with the use ofcombinations.The activity of isoniazid is manifested on the growing tuberclebacilli and not on resting forms. Its action, which isconsidered bactericidal, is to cause the bacilli to lose lipidcontent by a mechanism that has not been fully elucidated.The most generally accepted theory suggests that the principaleffect of isoniazid is to inhibit the synthesis of mycolicacids, high–molecular-weight, branched β-hydroxyfatty acids that constitute important components of the cellwalls of mycobacteria.
Clinical Use
Isoniazid is among the safest and most active mycobactericidal
agents. It is considered the primary drug for
use in all therapeutic and prophylactic regimens for susceptible
tuberculosis infections. It is also included in the
first-line drug combinations for use in all types of tuberculous
infections. Isoniazid is preferred as a single
agent in the treatment of latent tuberculosis infections
in high-risk persons having a positive tuberculin skin reaction
with no radiological or other clinical evidence of
tuberculosis. Mycobacterium kansasii is usually susceptible
to isoniazid, and it is included in the standard multidrug
treatment regimen.
Clinical Use
Tuberculosis (intensive and continuation phases)
Prevention of primary tuberculosis in close contacts and reactivation
disease in infected but healthy persons (monotherapy)
Side effects
The incidence and severity of adverse reactions to isoniazid
are related to dosage and duration of therapy.
Isoniazid-induced hepatitis and peripheral neuropathy
are two major untoward effects.
Side effects
Toxic effects are unusual on recommended doses and are
more frequent in slow acetylators. Many side effects are neurological,
including restlessness, insomnia, muscle twitching
and difficulty in starting micturition. More serious but less
common neurological side effects include peripheral neuropathy,
optic neuritis, encephalopathy and a range of psychiatric
disorders, including anxiety, depression and paranoia.
Neurotoxicity is usually preventable by giving pyridoxine
(vitamin B6) 10 mg per day. Pyridoxine should be given
to patients with liver disease, pregnant women, alcoholics,
renal dialysis patients, HIV-positive patients, the malnourished
and the elderly. Encephalopathy, which has been reported in
patients on renal dialysis, may not be prevented by, or respond
to, pyridoxine, but usually resolves on withdrawal of isoniazid.
Isoniazid-related hepatitis occurs in about 1% of patients
receiving standard short-course chemotherapy. The incidence
is unaffected by acetylator status. It is more common in those
aged over 35 years and preventive isoniazid monotherapy
should be used with care in older people.
Less common side effects include arthralgia, a ‘flu’-like
syndrome, hypersensitivity reactions with fever, rashes and,
rarely, eosinophilia, sideroblastic anemia, pellagra (which
responds to treatment with nicotinic acid) and hemolysis in
patients with glucose-6-phosphate dehydrogenase deficiency.
It exacerbates acute porphyria and induces antinuclear antibodies,
but overt systemic lupus erythematosus is rare.
Synthesis
Isoniazid, isonicotinic acid hydrazide (34.1.1), is synthesized by reacting ethyl
ester of isonicotinic acid with hydrazine.
Veterinary Drugs and Treatments
Isoniazid (INH) is sometimes used for chemoprophylaxis in small
animals in households having a human with tuberculosis. It potentially
can be used in combination with other antimycobacterial
drugs to treat infections of M. bovis or M. tuberculosis in dogs or
cats. But because of the public health risks, particularly in the face of
increased populations of immunocompromised people, treatment
of mycobacterial (M. bovis, M. tuberculosis) infections in domestic
or captive animals is controversial. In addition, INH has a narrow
therapeutic index and toxicity is a concern (see Adverse Effects).
In humans, isoniazid (INH) is routinely used alone to treat latent
tuberculosis infections (positive tuberculin skin test) and in
combination with other antimycobacterial agents to treat active
disease.
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: increased risk of hepatotoxicity with
rifampicin.
Antiepileptics: metabolism of carbamazepine,
ethosuximide and phenytoin inhibited (enhanced
effect); also with carbamazepine, isoniazid
hepatotoxicity possibly increased.
Environmental Fate
Isoniazid is a colorless, odorless, white crystalline powder that
is slowly oxidized by exposure to air. It undergoes degradation
upon prolonged exposure to light. Isoniazid has a solubility of
1 g per 8 ml water, 1 g per 50 ml ethanol, and it is slightly
soluble in chloroform and very slightly soluble in ether. A 10%
solution of isoniazid has a pH of 6.0–8.0.
Metabolism
Isoniazid is extensively metabolized to inactive metabolites. The major metabolite is N-acetylisoniazid. The enzyme responsible for acetylation, cytosolic N-acetyltransferase, is produced under genetic control in an inherited autosomal fashion. Individuals who possess high concentrations of the enzyme are referred to as rapid acetylators, whereas those with low concentrations are slow acetylators. This may result in a need to adjust the dosage for fast acetylators. The N-acetyltransferase is located primarily in the liver and small intestine. Other metabolites include isonicotinic acid, which is found in the urine as a glycine conjugate, and hydrazine. Isonicotinic acid also may result from hydrolysis of acetylisoniazid, but in this case, the second product of hydrolysis is acetylhydrazine. Acetylhydrazine is acetylated by N-acetyltransferase to the inactive diacetyl product. This reaction occurs more rapidly in rapid acetylators. The formation of acetylhydrazine is significant in that this compound has been associated with the hepatotoxicity, which may occur during INH therapy.
Purification Methods
Crystallise isoniazide from 95% EtOH and dry it in a vacuum. [Beilstein 22 III/IV 545, 22/2 V 219.]
Toxicity evaluation
Isoniazid causes toxicity by altering the metabolism of pyridoxine
and creating a functional deficiency. Pyridoxine is
needed for transamination, transketolization, decarboxylation,
and biotransformation reactions. This occurs through three processes: (1) isoniazid metabolites form complexes with pyridoxine
increasing its urinary excretion with increasing doses; (2)
isoniazid metabolites disrupt the conversion of pyridoxine to its
active form, pyridoxine-50-phosphokinase; and (3) metabolites
directly inactivate pyridoxal-50-phosphate.
Isoniazid-induced seizures are thought to be caused by the
depletion of gamma-aminobutyric acid (GABA). GABA is the
primary inhibitory neurotransmitter in the central nervous
system that requires the cofactor pyridoxal-50-phosphate for its
synthesis from glutamate. Prolonged seizures commonly result
in plasma lactic acid accumulation that can lead to an anion
gap metabolic acidosis. Isoniazid may worsen the severity of
acidosis by inhibiting the production of nicotinamideadensosine
dinucleotide (NAD), a cofactor necessary for the
conversion of lactate to pyruvate. Long-term exposure to
isoniazid therapy commonly causes peripheral neuropathy due
to pyridoxine deficiency, and may induce pellagra, a niacin
deficiency disorder. Niacin requires the cofactor pyridoxal-50-
phosphate for its production from tryptophan.
The exact mechanism of isoniazid-induced hepatotoxicity is
unknown. However, it is thought to involve an idiopathic
autoimmune mechanism or result from direct hepatic injury
from isoniazid or its metabolites. The metabolite thought to be
responsible is acetyl hydrazine, produced from isoniazid
hydrolysis via cytochrome P450 (CYP)2E1. Persons with the
CYP2E1c1/c1 genotype may be more susceptible to hepatotoxicity.
The role acetylator status plays in hepatotoxicity
continues to be debated, but it is currently thought that slow
acetylators are at greater risk. Other risk factors include
increasing age, chronic isoniazid overdose, comorbid conditions
such as malnutrition, pregnancy, diabetes, HIV, renal
dysfunction, hepatic dysfunction, alcoholism, and concomitant
use of enzyme inducing drugs.
Other enzymes inhibited by isoniazid include the cytochrome
P450 mixed function oxidases, monoamine oxidase,
glutamate decarboxylase, and histaminase. The consequences
of these extensive enzymatic disturbances are mood elevation,
decreased central nervous system GABA levels, depressed catecholamine
synthesis, defects in glucose and fatty acid oxidation,
and impaired metabolism of other drugs. Important drug
interactions include those with carbamazepine, phenytoin,
rifampin, theophylline, valproate, and warfarin. Isoniazid is
also a weak monoamine oxidase inhibitor, and serotonin
syndrome and tyramine reactions to foods causing flushing,
tachycardia, and hypertension are reported.
Isoniazid does cross the placenta and enters the fetal
compartment; however, it has been determined to not be
a human teratogen in studies. In acute toxicity, fetal deformities
have been reported.
Precautions
High isoniazid plasma levels inhibit phenytoin metabolismand potentiate phenytoin toxicity when the twodrugs are coadministered. The serum concentrations ofphenytoin should be monitored, and the dose should beadjusted if necessary.
Check Digit Verification of cas no
The CAS Registry Mumber 54-85-3 includes 5 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 2 digits, 5 and 4 respectively; the second part has 2 digits, 8 and 5 respectively.
Calculate Digit Verification of CAS Registry Number 54-85:
(4*5)+(3*4)+(2*8)+(1*5)=53
53 % 10 = 3
So 54-85-3 is a valid CAS Registry Number.
InChI:InChI=1/C6H7N3O2/c7-9-11-6(10)5-1-3-8-4-2-5/h1-4,9H,7H2
54-85-3Relevant articles and documents
Solvent free biocatalytic synthesis of isoniazid from isonicotinamide using whole cell of Bacillus smithii strain IITR6b2
Agarwal, Shilpi,Gupta, Meenu,Choudhury, Bijan
, p. 67 - 73 (2013)
A biocatalytic route for the synthesis of isoniazid, an important first-line antitubercular drug, in aqueous system is presented. The reported bioprocess is a greener method, does not involve any hazardous reagent and takes place under mild reaction conditions. Whole cell amidase of Bacillus smithii strain IITR6b2 having acyltransferase activity was utilized for its ability to transfer acyl group of isonicotinamide to hydrazine-2HCl in aqueous medium. B. smithii strain IITR6b2 possessed 3 folds higher acyltransferase activity as compared to amide hydrolase activity and this ratio was further improved to 4.5 by optimizing concentration of co-substrate hydrazine-2HCl. Various key parameters were optimized and under the optimum reaction conditions of pH (7, phosphate buffer 100 mM), temperature (30 C), substrate/co-substrate concentration (100/1000 mM) and resting cells concentration (2.0 mg dcw/ml), 90.4% conversion of isonicotinamide to isoniazid was achieved in 60 min. Under these conditions, a fed batch process for production of isoniazid was developed and resulted in the accumulation of 439 mM of isoniazid with 87.8% molar conversion yield and productivity of 6.0 g/h/g dcw. These results demonstrated that enzymatic synthesis of isoniazid using whole cells of B. smithii strain IITR6b2 might present an efficient alternative route to the chemical synthesis procedures without the involvement of organic solvent.
Development of potent nanosized isatin-isonicotinohydrazide hybrid for management of Mycobacterium tuberculosis
Abdel-Aziz, Marwa M.,Abdelshafi, Nahla A.,Al-Rashood, Sara T.,Al-Zahraa Sayed, Fatma,Eissa, Noura G.,El Hassab, Mahmoud A.,Eldehna, Wagdy M.,Elkaeed, Eslam B.,Elsabahy, Mahmoud,Elsayed, Zainab M.,Fares, Mohamed
, (2021/12/20)
Inspired by the antitubercular activity of isoniazid (INH) and 5-bromoisatin, isatin–INH hybrid (WF-208) has been synthesized as a potent agent against multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of M. tuberculosis. In silico molecular docking studies indicated that DprE1, a critical enzyme in the synthesis of M. tuberculosis cell wall, is a potential enzymatic target for WF-208. The synthesized WF-208 was incorporated into a nanoparticulate system to enhance stability of the compound and to sustain its antimicrobial effect. Nanosized spherical niosomes (hydrodynamic diameter of ca. 500–600 nm) could accommodate WF-208 at a high encapsulation efficiency of 74.2%, and could impart superior stability to the compound in simulated gastric conditions. Interestingly, WF-208 had minimal inhibitory concentrations (MICs) of 7.8 and 31.3 μg/mL against MDR and XDR M. tuberculosis, respectively, whereas INH failed to demonstrate bacterial growth inhibition at the range of the tested concentrations. WF-208-loaded niosomes exhibited a 4-fold increase in the anti-mycobacterial activity as compared to the free compound (MIC of 1.9 vs. 7.8 μg/mL) against H37Rv M. tuberculosis, after three weeks of incubation with WF-208-loaded niosomes. Incorporation of the compound into nanosized vesicles allowed for a further increase in stability, potency and sustainability of the anti-mycobacterial activity, thus, providing a promising strategy for management of tuberculosis.
Design, docking, synthesis, and characterization of novel N'(2-phenoxyacetyl) nicotinohydrazide and N'(2-phenoxyacetyl)isonicotinohydrazide derivatives as anti-inflammatory and analgesic agents
Al-Ostoot, Fares Hezam,Khanum, Shaukath Ara,M, Pallavi H,Vivek, Hamse Kameshwar
, (2021/09/14)
Inflammation is the complex biological response of vascular tissues, which is partly determined by prostaglandins (PLA2). The cyclooxygenase (COX) enzyme exists in two isoforms: COX-1 and COX-2 and by the action of this, the PGs are produced. Besides, nonsteroidal anti-inflammatory drugs (NSAIDs) are therapeutic agents useful in the treatment of inflammation. Encouraged by this, the new derivatives of N'(2-phenoxyacetyl)nicotinohydrazide 9(a-e) and N'(2-phenoxyacetyl)isonicotinohydrazide 10(a-e) were designed, synthesized, characterized, and identified as remarkable anti-inflammatory and analgesic agents. These compounds were prepared in a series of steps starting with different phenol derivatives. Among the series, compound (10e) showed the highest IC50 value for COX-1 inhibition, whereas compounds (9e) and (10e) exhibited the highest COX-2SI. Further, molecular Docking Studies have been performed for the potent compound to check the three-dimensional geometrical view of the ligand binding to the targeted enzymes.
Development of Novel (+)-Nootkatone Thioethers Containing 1,3,4-Oxadiazole/Thiadiazole Moieties as Insecticide Candidates against Three Species of Insect Pests
Cheng, Wanqing,Fan, Jiangping,Guo, Yong,Han, Meiyue,Ma, Nannan,Yan, Xiaoting,Yang, Ruige
, p. 15544 - 15553 (2022/01/03)
To improve the insecticidal activity of (+)-nootkatone, a series of 42 (+)-nootkatone thioethers containing 1,3,4-oxadiazole/thiadiazole moieties were prepared to evaluate their insecticidal activities against Mythimna separata Walker, Myzus persicae Sulzer, and Plutella xylostella Linnaeus. Insecticidal evaluation revealed that most of the title derivatives exhibited more potent insecticidal activities than the precursor (+)-nootkatone after the introduction of 1,3,4-oxadiazole/thiadiazole on (+)-nootkatone. Among all of the (+)-nootkatone derivatives, compound 8c (1 mg/mL) exhibited the best growth inhibitory (GI) activity against M. separata with a final corrected mortality rate (CMR) of 71.4%, which was 1.54- and 1.43-fold that of (+)-nootkatone and toosendanin, respectively; 8c also displayed the most potent aphicidal activity against M. persicae with an LD50 value of 0.030 μg/larvae, which was closer to that of the commercial insecticidal etoxazole (0.026 μg/larvae); and 8s showed the best larvicidal activity against P. xylostella with an LC50 value of 0.27 mg/mL, which was 3.37-fold that of toosendanin and slightly higher than that of etoxazole (0.28 mg/mL). Furthermore, the control efficacy of 8s against P. xylostella in the pot experiments under greenhouse conditions was better than that of etoxazole. Structure-activity relationships (SARs) revealed that in most cases, the introduction of 1,3,4-oxadiazole/thiadiazole containing halophenyl groups at the C-13 position of (+)-nootkatone could obtain more active derivatives against M. separata, M. persicae, and P. xylostella than those containing other groups. In addition, toxicity assays indicated that these (+)-nootkatone derivatives had good selectivity to insects over nontarget organisms (normal mammalian NRK-52E cells and C. idella and N. denticulata fries) with relatively low toxicity. Therefore, the above results indicate that these (+)-nootkatone derivatives could be further explored as new lead compounds for the development of potential eco-friendly pesticides.
Design, synthesis, antibacterial evaluation, and computational studies of hybrid oxothiazolidin–1,2,4-triazole scaffolds
Pathak, Prateek,Novak, Jurica,Shukla, Parjanya K.,Grishina, Maria,Potemkin, Vladimir,Verma, Amita
, (2021/03/08)
Bacterial infections are a serious threat to human health due to the development of resistance against the presently used antibiotics. The problem of growing and widespread antibiotic resistance is only getting worse with the shortage of new classes of antibiotics, creating a substantial unmet medical need in the treatment of serious bacterial infections. Therefore, in the present work, we report 18 novel hybrid thiazolidine–1,2,4-triazole derivatives as DNA gyrase inhibitors. The derivatives were synthesized by multistep organic synthesis and characterized by spectroscopic methods (1H and 13C nuclear magnetic resonance and mass spectroscopy). The derivatives were tested for DNA gyrase inhibition, and the result emphasized that the synthesized derivatives have a tendency to inhibit the function of DNA gyrase. Furthermore, the compounds were also tested for antibacterial activity against three Gram-positive (Bacillus subtilis [NCIM 2063], Bacillus cereus [NCIM 2156], Staphylococcus aureus [NCIM 2079]) and two Gram-negative (Escherichia coli [NCIM 2065], Proteus vulgaris [NCIM 2027]) bacteria. The derivatives showed a significant-to-moderate antibacterial activity with noticeable antibiofilm efficacy. Quantitative structure–activity relationship (QSAR), ADME (absorption, distribution, metabolism, elimination) calculation, molecular docking, radial distribution function, and 2D fingerprinting were also performed to elucidate fundamental structural fragments essential for their bioactivity. These studies suggest that the derivatives 10b and 10n have lead antibacterial properties with significant DNA gyrase inhibitory efficacy, and they can serve as a starting scaffold for the further development of new broad-spectrum antibacterial agents.
Design, synthesis, in vitro and in vivo evaluation against MRSA and molecular docking studies of novel pleuromutilin derivatives bearing 1, 3, 4-oxadiazole linker
Liu, Jie,Zhang, Guang-Yu,Zhang, Zhe,Li, Bo,Chai, Fei,Wang, Qi,Zhou, Zi-Dan,Xu, Ling-Ling,Wang, Shou-Kai,Jin, Zhen,Tang, You-Zhi
, (2021/05/17)
A class of pleuromutilin derivatives containing 1, 3, 4-oxadiazole were designed and synthesized as potential antibacterial agents against Methicillin-resistant staphylococcus aureus (MRSA). The ultrasound-assisted reaction was proposed as a green chemistry method to synthesize 1, 3, 4-oxadiazole derivatives (intermediates 85–110). Among these pleuromutilin derivatives, compound 133 was found to be the strongest antibacterial derivative against MRSA (MIC = 0.125 μg/mL). Furthermore, the result of the time-kill curves displayed that compound 133 could inhibit the growth of MRSA in vitro quickly (- 4.36 log10 CFU/mL reduction). Then, compound 133 (- 1.82 log10 CFU/mL) displayed superior in vivo antibacterial efficacy than tiamulin (- 0.82 log10 CFU/mL) in reducing MRSA load in mice thigh model. Besides, compound 133 exhibited low cytotoxicity to RAW 264.7 cells. Molecular docking studies revealed that compound 133 was successfully localized in the binding pocket of 50S ribosomal subunit (ΔGb = -10.50 kcal/mol). The results indicated that these pleuromutilin derivatives containing 1, 3, 4-oxadiazole might be further developed into novel antibiotics against MRSA.
N-acylhydrazones confer inhibitory efficacy against New Delhi metallo-β-lactamase-1
Gao, Han,Li, Jia-Qi,Kang, Peng-Wei,Chigan, Jia-Zhu,Wang, Huan,Liu, Lu,Xu, Yin-Sui,Zhai, Le,Yang, Ke-Wu
, (2021/07/07)
The expression of β-lactamases, especially metallo-β-lactamases (MβLs) in bacteria is one of the main causes of drug resistance. In this work, an effective N-acylhydrazone scaffold as MβL inhibitor was constructed and characterized. The biological activity assays indicated that the synthesized N-acylhydrazones 1–11 preferentially inhibited MβL NDM-1, and 1 was found to be the most effective inhibitor with an IC50 of 1.2 μM. Analysis of IC50 data revealed a structure–activity relationship, which is that the pyridine and hydroxylbenzene substituents at 2-position improved inhibition of the compounds on NDM-1. ITC and enzyme kinetics assays suggested that it reversibly and competitively inhibited NDM-1 (Ki = 0.29 ± 0.05 μM). The synthesized N-acylhydrazones showed synergistic antibacterial activities with meropenem, reduced 4–16-fold MIC of meropenem on NDM-1- producing E. coli BL21 (DE3), while 1 restored 4-fold activity of meropenem on K. pneumonia expressing NDM-1 (NDM-K. pneumoniae). The mice experiments suggested that 1 combined meropenem to fight against NDM-K. pneumoniae infection in the spleen and liver. Cytotoxicity assays showed that 1 and 2 have low cytotoxicity. This study offered a new framework for the development of NDM-1 inhibitors.
A CONTINUOUS FLOW SYNTHESIS METHOD FOR THE MANUFACTURE OF ISONIAZID
-
Page/Page column 19, (2021/04/17)
A multistep continuous flow synthesis method for the manufacture of isonicotinyl-hydrazide (Isoniazid) comprising reacting 4-cyano pyridine with NaOH at a specified molar ratio and temperature range to produce the intermediate isonicotinamide, which intermediate is reacted with hydrazine hydrate, without isolation thereof, at a specified molar ratio and temperature range to produce isonicotinyl-hydrazide (Isoniazid) in a yield greater than about 90%.
Discovery, synthesis and in combo studies of Schiff’s bases as promising dipeptidyl peptidase-IV inhibitors
Abu Khalaf, Reema,Al-Essa, Luay,Al-Shalabi, Eveen,Awad, Maha,Mefleh, Sara,Sabbah, Dima,Shabeeb, Ihsan
, (2021/09/25)
Abstract: Diabetes mellitus is a main global health apprehension. Macrovascular illnesses, neuropathy, retinopathy, and nephropathy are considered some of its severe hitches. Gliptins are a group of hypoglycemic agents that inhibit dipeptidyl peptidase-IV (DPP-IV) enzyme and support blood glucose-lowering effect of incretins. In the current research, synthesis, characterization, docking, and biological evaluation of fourteen Schiff’s bases 5a–f and 9a–h were carried out. Compound 9f revealed the best in vitro anti-DPP-IV activity of 35.7% inhibition at a concentration of 100?μM. Compounds 9c and 9f with the highest in vitro DPP-IV inhibition were subjected to the in vivo glucose-lowering test using vildagliptin as a positive inhibitor. Vildagliptin, 9c, and 9f showed significant reduction in the blood glucose levels of the treated mice after 30?min of glucose administration. Moreover, induced fit docking showed that these derivatives accommodated the enzyme binding site with comparable docking scores. Schiff’s bases can serve as promising lead for the development of new DPP-IV inhibitors. Graphical Abstract: [Figure not available: see fulltext.].
Synthesis, in silico, in vitro and in vivo evaluations of isatin aroylhydrazones as highly potent anticonvulsant agents
Emami, Saeed,Valipour, Mehdi,Kazemi Komishani, Fatemeh,Sadati-Ashrafi, Fatemehsadat,Rasoulian, Maria,Ghasemian, Majid,Tajbakhsh, Mahmood,Honarchian Masihi, Patrick,Shakiba, Aidin,Irannejad, Hamid,Ahangar, Nematollah
, (2021/05/10)
In this study, a series of new isatin aroylhydrazones (5a-e and 6a-e) was synthesized and evaluated for their anticonvulsant activities. The (Z)-configuration of compounds was confirmed by 1H NMR. In vivo studies using maximal electroshock (MES) and pentylenetetrazole (PTZ) models of epilepsy in mice revealed that while most of compounds had no effect on chemically-induced seizures at the higher dose of 100 mg/kg but showed significant protection against electrically-induced seizures at the lower dose of 5 mg/kg. Certainly, N-methyl analogs 6a and 6e were found to be the most effective compounds, displaying 100% protection at the dose of 5 mg/kg. Protein binding and lipophilicity (logP) of the selected compounds (6a and 6e) were also determined experimentally. In silico evaluations of title compounds showed acceptable ADME parameters, and drug-likeness properties. Distance mapping and docking of the selected compounds with different targets proposed the possible action of them on VGSCs and GABAA receptors. The cytotoxicity evaluation of 6a and 6e against SH-SY5Y and Hep-G2 cell lines indicated safety profile of compounds on the neuronal and hepatic cells.
