thiosemicarbazide and Inflammation

Neuroinflammation and cholinergic deficit are key detrimental processes involved in Alzheimer's disease. Hence, in the search for novel and effective treatment strategies, the multi-target-directed ligand paradigm was applied to the rational design of two series of new hybrids endowed with anti-inflammatory and anticholinesterase activity via triple targeting properties, namely able to simultaneously hit cholinesterases, cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX) enzymes. Among the synthesized compounds, triazoles 5b and 5d, and thiosemicarbazide hybrid 6e emerged as promising new hits, being able to effectively inhibit human butyrylcholinesterase (hBChE), COX-2 and 15-LOX enzymes with a higher inhibitory potency than the reference inhibitors tacrine (for hBChE inhibition), celecoxib (for COX-2 inhibition) and both NDGA and Zileuton (for 15-LOX inhibition). In addition, compound 6e proved to be a submicromolar mixed-type inhibitor of human acetylcholinesterase (hAChE). The anti-neuroinflammatory activity of the three most promising hybrids was confirmed in a cell-based assay using PC12 neuron cells, showing decreased expression levels of inflammatory cytokines IL-1β and TNF-α. Importantly, despite the structural resemblance to tacrine, they showed ideal safety profiles on hepatic and murine brain cell lines and were safe up to 100 μM when assayed in PC12 cells. All three hybrids were also predicted to have superior BBB permeability than tacrine in the PAMPA assay, and good physicochemical properties, drug-likeness and ligand efficiency indices. Finally, molecular docking studies highlighted key structural elements impacting selectivity and activity toward the selected target enzymes. To the best of our knowledge, compounds 5b, 5d and 6e are the first balanced, safe and multi-target compounds hitting the disease at the three mentioned hubs.

Topics: Acetylcholine; Alzheimer Disease; Animals; Cell Line; Cholinesterase Inhibitors; Cyclooxygenase 2 Inhibitors; Drug Design; Humans; Inflammation; Lipoxygenase Inhibitors; Mice; Molecular Docking Simulation; Neurons; PC12 Cells; Rats; Semicarbazides; Triazoles

Studying of synthesis and anti-inflammatory activity of a number of new derivatives of N-acylsubstituted of thiosemicarbazide and product of their heterocyclization (thiadiazole). In work the following reagents are used: hydrazide of N-morfolinilacetic acids, allil-, benzoil-, 4-brom-benzoil isothiocyanates. IR spectrums of compounds are removed on a spectrometer from Fourier converter by "AVATAR-320" in tablets with KBr, 1H NMR spectra were recorded on Bruker DRX500 spectrometer with a frequency of 500 MHz in DMSO-d6 solution relative to internal tetramethylsilane standard. X-ray diffraction analysis was carried out on four circuitous automatic diffractometer "Xcalibur". Mass spectra were recorded on a device FINNIGAN MAT.INCOS 50 direct input material with an ionization energy of 70 eV. Thin-layer chromatographic (TLC) analysis was performed on plates «Sorbfil» system benzene-isopropanol-ammonia 10:5:2, display iodine vapor. Melting point defined on the device «Boetius». Anti-inflammatory activity of compounds is studied on white not purebred rats. Statistical processing of results was carried out with use of the software package of "Statistica 6,0". The experimental results showed that, among the received new hydrazide derivatives of N-morpholinilacetyc acids are compounds (II-IV and VI), which have anti-inflammatory activity. It is possible that novel anti-inflammatory properties associated with their antibacterial properties due to the presence in their chemical structure and thiosemicarbazides 1,3,4-thiadiazol-2 (3H)-thione fragments. The obtained results allow us to recommend the test compounds for advanced pre-clinical trials to study their properties. Based on N-hydrazide morpholinil acetic acid, a number of new N-acyl-substituted derivatives of thiosemicarbazide is synthesized and described, composition and structure of which is proved by IR, 1H NMR spectroscopy and X-ray analysis. In an experimentation rats is founded anti-inflammatory activity of N-acyl-substituted thiosemicarbazide.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Humans; Inflammation; Rats; Semicarbazides; X-Ray Diffraction

The objective of this study was to investigate the anti-inflammatory and antioxidant activity of new thiazolyl-carbonyl-thiosemicarbazides and thiazolyl-azole derivatives as potential iNOS inhibitors. The in vivo anti-inflammatory effects of the new thiazole compounds were studied in a turpentine oil induced inflammation model. Their anti-inflammatory activity was assessed by evaluating the acute phase bone marrow response, phagocytes' activity, NO synthesis and antioxidant capacity. The new thiazole compounds have anti-inflammatory effects by lowering bone marrow acute phase response and oxidative stress. The best anti-inflammatory and antioxidant effect was found for thiazolyl-carbonyl-thiosemicarbazides Th-1-8, thiazolyl-1,3,4-oxadiazole Th-20 and thiazolyl-1,3,4-thiadiazole Th-21. Virtual screening of thiazole derivatives against the oxygenase domain of chain A from 2Y37 revealed that all twenty-two compounds bind the active site of inducible nitric oxide synthase (iNOS). Based on the virtual screening and on the results obtained above, the activity may be due to their capacity to reduce the NO synthesis by blocking the bind of L-Arg in the active site of iNOS, the compounds binding the synthase by hydrogen bonds between the NH (2 and/or 4) of thiosemicarbazide fragment (Th-2-8) or N2/N3 from azole cycles and by the thiol function (Th-9-22).

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Azoles; Disease Models, Animal; Enzyme Inhibitors; Hydrogen Bonding; Inflammation; Male; Nitric Oxide; Nitric Oxide Synthase Type II; Oxidative Stress; Rats; Rats, Wistar; Semicarbazides

A series of substituted azole derivatives (3a-e, 4a-e and 5a-e) were synthesised by the cyclisation of N(1)(diphenylethanoyl)-N(4)-substituted phenyl thiosemicarbazides under various reaction conditions. These compounds were tested in vivo for their anti-inflammatory activity. The compounds which showed activity comparable to the standard drug ibuprofen, were screened for their analgesic, ulcerogenic and lipid peroxidation activities. The compounds 5-(diphenylmethyl)-N-(4-fluorophenyl)-1,3,4-oxadiazol-2-amine (3b) and 5-(diphenylmethyl)-N-(3-chloro-4-fluorophenyl)-1,3,4-oxadiazol-2-amine (3c) emerged as the most active compounds of the series, and were moderately more potent than the standard drug, ibuprofen. (This abstract was published in Inflammation Research, Supplement 2, Volume 56, page A101, 2008.).

Topics: Acetates; Analgesics; Animals; Anti-Inflammatory Agents; Drug Design; Gastric Mucosa; Ibuprofen; Inflammation; Lipid Peroxidation; Mice; Models, Animal; Oxadiazoles; Pyrazoles; Rats; Rats, Wistar; Semicarbazides; Severity of Illness Index; Stomach Ulcer