Recent events involving nerve agents of the A-Series, a once elusive class of chemical warfare agents, have provoked a great concern in the international community. In this paper, continuing our research efforts in Medicinal Chemistry at the Brazilian Institute of Chemical, Biological, Radiological and Nuclear Defense (IDQBRN) (an OPCW-designated Laboratory for environmental samples), we explore ANMP, an A-230 surrogate, in the search for new treatment options for intoxications caused by these chemicals. Five isatin-pyridine oxime hybrids were evaluated as acetylcholinesterase (AChE) reactivators using a modified Ellman's assay. Our results indicate that monocationic hybrids with five methylene units, as well as its oxa-analog, are promising compounds for the design of new AChE reactivators.
- Keywords
- Acetylcholinesterase, Antidotes, Chemical Weapons Convention, Isatin hybrids, Nerve agents,
- MeSH
- Acetylcholinesterase metabolism MeSH
- Chemical Warfare Agents * toxicity chemistry MeSH
- Cholinesterase Inhibitors * toxicity chemistry MeSH
- Isatin * chemistry pharmacology analogs & derivatives MeSH
- Oximes * chemistry pharmacology MeSH
- Computer Simulation MeSH
- Pyridines * chemistry pharmacology MeSH
- Cholinesterase Reactivators * pharmacology chemistry MeSH
- Structure-Activity Relationship MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Acetylcholinesterase MeSH
- Chemical Warfare Agents * MeSH
- Cholinesterase Inhibitors * MeSH
- Isatin * MeSH
- Oximes * MeSH
- Pyridines * MeSH
- Cholinesterase Reactivators * MeSH
Tuberculosis (TB) is a global issue that poses a significant economic burden as a result of the ongoing emergence of drug-resistant strains. The urgent requirement for the development of novel antitubercular drugs can be addressed by targeting specific enzymes. One such enzyme, Mycobacterium tuberculosis (MTB) enoyl-acyl carrier protein (enoyl-ACP) reductase (InhA), plays a crucial role in the survival of the MTB bacterium. In this research study, a series of hybrid compounds combining quinolone and isatin were synthesized and assessed for their effectiveness against MTB, as well as their ability to inhibit the activity of the InhA enzyme in this bacterium. Among the compounds tested, 7a and 5g exhibited the most potent inhibitory activity against MTB, with minimum inhibitory concentration (MIC) values of 55 and 62.5 µg/mL, respectively. These compounds were further evaluated for their inhibitory effects on InhA and demonstrated significant activity compared to the reference drug Isoniazid (INH), with IC50 values of 0.35 ± 0.01 and 1.56 ± 0.06 µM, respectively. Molecular docking studies investigated the interactions between compounds 7a and 5g and the target enzyme, revealing hydrophobic contacts with important amino acid residues in the active site. To further confirm the stability of the complexes formed by 5g and 7a with the target enzyme, molecular dynamic simulations were employed, which demonstrated that both compounds 7a and 5g undergo minor structural changes and remain nearly stable throughout the simulated process, as assessed through RMSD, RMSF, and Rg values.
- Keywords
- Biological activities, InhA inhibitors, Molecular docking, Molecular dynamics Simulation, Mycobacterium tuberculosis,
- MeSH
- Antitubercular Agents pharmacology chemistry MeSH
- Bacterial Proteins metabolism MeSH
- Quinolines * pharmacology MeSH
- Isatin * pharmacology MeSH
- Humans MeSH
- Microbial Sensitivity Tests MeSH
- Mycobacterium tuberculosis * MeSH
- Oxidoreductases metabolism MeSH
- Acyl Carrier Protein pharmacology MeSH
- Molecular Docking Simulation MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Antitubercular Agents MeSH
- Bacterial Proteins MeSH
- Quinolines * MeSH
- Isatin * MeSH
- Oxidoreductases MeSH
- Acyl Carrier Protein MeSH
Organophosphorus poisoning caused by some pesticides and nerve agents is a life-threating condition that must be swiftly addressed to avoid casualties. Despite the availability of medical countermeasures, the clinically available compounds lack a broad spectrum, are not effective towards all organophosphorus toxins, and have poor pharmacokinetics properties to allow them crossing the blood-brain barrier, hampering cholinesterase reactivation at the central nervous system. In this work, we designed and synthesised novel isatin derivatives, linked to a pyridinium 4-oxime moiety by an alkyl chain with improved calculated properties, and tested their reactivation potency against paraoxon- and NEMP-inhibited acetylcholinesterase in comparison to the standard antidote pralidoxime. Our results showed that these compounds displayed comparable in vitro reactivation also pointed by the in silico studies, suggesting that they are promising compounds to tackle organophosphorus poisoning.
- Keywords
- Isatin, antidotes, cholinesterase reactivators, nerve agents, organophosphorus poisoning, pyridine oximes,
- MeSH
- Acetylcholinesterase drug effects MeSH
- Isatin pharmacology MeSH
- Computer Simulation MeSH
- Pyridines pharmacology MeSH
- Cholinesterase Reactivators pharmacology MeSH
- In Vitro Techniques MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Acetylcholinesterase MeSH
- Isatin MeSH
- pyridine MeSH Browser
- Pyridines MeSH
- Cholinesterase Reactivators MeSH
Herein we describe the design and synthesis of two series of sulfonamides featuring N-unsubstituted (4a-c) or N-substituted (7a-o) isatin moieties (as tails) connected to benzenesulfonamide moiety via a hydrazine linker. All the prepared sulfonamides (4a-c and 7a-o) showed potent inhibitory activities toward transmembrane tumor-associated human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, IX and XII with KI range (8.3-65.4 nM) and (11.9-72.9 nM), respectively. Furthermore, six sulfonamides (7e, 7i, 7j, 7m, 7n and 7o) were assessed for their anti-proliferative activity, according to US-NCI protocol, toward a panel of sixty cancer cell lines. Compounds 7j and 7n were the most promising counterparts in this assay displaying broad spectrum anti-proliferative activity toward diverse cell lines. Also, sulfonamide 7n significantly inhibited clonogenicity of HCT-116 cells in a concentration dependent manner in the colony forming assay. Moreover, molecular modeling studies were performed to gain insights for the plausible binding interactions and affinities for the target isatin-based sulfonamides (4a-c and 7a-o) within hCA isoforms II and IX active sites.
- Keywords
- Anticancer, Benzenesulfonamides, Carbonic anhydrase inhibitors, Colony forming assay, Molecular dynamics,
- MeSH
- Benzenesulfonamides MeSH
- Hydrazines chemistry pharmacology MeSH
- Carbonic Anhydrase Inhibitors chemical synthesis chemistry pharmacology MeSH
- Isatin chemistry pharmacology MeSH
- Carbonic Anhydrases metabolism MeSH
- Humans MeSH
- Molecular Structure MeSH
- Tumor Cells, Cultured MeSH
- Cell Proliferation drug effects MeSH
- Antineoplastic Agents chemical synthesis chemistry pharmacology MeSH
- Drug Screening Assays, Antitumor MeSH
- Molecular Docking Simulation MeSH
- Sulfonamides chemical synthesis chemistry pharmacology MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- hydrazine MeSH Browser
- Hydrazines MeSH
- Carbonic Anhydrase Inhibitors MeSH
- Isatin MeSH
- Carbonic Anhydrases MeSH
- Antineoplastic Agents MeSH
- Sulfonamides MeSH
An asymmetric organocatalytic addition of fluorinated phenylsulfonylnitromethane to isatin-derived ketimines was developed. The reaction was efficiently catalyzed by a chiral tertiary amine, cinchonine. This methodology provides a new type of optically active compound with two adjacent quaternary carbon stereocenters in good yield (up to 96%), with moderate diastereoselectivity (up to 5.7 : 1 dr) and excellent enantioselectivity (up to 98/96% ee).
- MeSH
- Benzenesulfonates chemistry MeSH
- Imines chemistry MeSH
- Isatin chemistry MeSH
- Methane chemistry MeSH
- Nitriles chemistry MeSH
- Stereoisomerism MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- 1-fluoro-1-nitro(phenylsulfonyl)methane MeSH Browser
- Benzenesulfonates MeSH
- Imines MeSH
- Isatin MeSH
- ketimine MeSH Browser
- Methane MeSH
- Nitriles MeSH
The effect of various doses (40--160 mg/kg) of isatin (2,3-dioxoindoline) on electroencephalographic manifestations of vigilance, groups of rhythmic discharges (episodes) and the incidence of epileptiform pathological activities was studied in repeated chronic experiments on rats with implanted cortical and subcortical electrodes. After all the given doses of isatin the proportion of slow-wave sleep diminished and its onset was delayed (especially REM sleep) and the amount of quiet wakefulness increased. There were more spontaneous rhythmic episodes and their rhythm slowed down. In some cases large doses of isatin produced short groups of discharges without any motor signs; sometimes the episodes changed to epileptic activity composed of spike-wave complexes (2--3 Hz), accompanied by clonic jerks.
- MeSH
- Wakefulness drug effects physiology MeSH
- Electroencephalography * MeSH
- Indoles pharmacology MeSH
- Isatin pharmacology MeSH
- Rats MeSH
- Sleep drug effects MeSH
- Seizures chemically induced physiopathology MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Indoles MeSH
- Isatin MeSH
In doses of 160 and 80 mg/kg, isatin (2,3-dioxoindoline) significantly reduced the total incidence of audiogenic epileptic seizures in rats highly sensitive to an acoustic epileptogenic stimulus. The number of severest forms of seizure (running, clonic convulsions) was higher than in the control tests, however. The acoustic epileptogenic stimuls was applied one hour after the i.p. injection of isatin. At that time some postural reflexes were still inhibited after 160 mg isatin/kg, while after smaller doses they were already normal again. One hour after administering isatin there were marked changes in the electroencephalogram, the chief ones being an increase in rhythmic episodic activity against a desynchronization background and a decrease in slow wave sleep activity.
- MeSH
- Acoustic Stimulation MeSH
- Behavior, Animal drug effects MeSH
- Electroencephalography * MeSH
- Indoles pharmacology MeSH
- Isatin pharmacology MeSH
- Rats MeSH
- Reflex drug effects MeSH
- Seizures etiology physiopathology MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Indoles MeSH
- Isatin MeSH
- MeSH
- Arousal drug effects physiology MeSH
- Azoles administration & dosage MeSH
- Barbiturates administration & dosage MeSH
- Benzodiazepines administration & dosage MeSH
- Electroencephalography MeSH
- Isatin administration & dosage MeSH
- Rats MeSH
- Tubocurarine administration & dosage MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Azoles MeSH
- Barbiturates MeSH
- Benzodiazepines MeSH
- Isatin MeSH
- Tubocurarine MeSH
