| 1. |
- Akbaba, Yusuf, et al.
(författare)
-
Novel tetrahydronaphthalen-1-yl-phenethyl ureas : synthesis and dual antibacterial-anticancer activities
- 2024
-
Ingår i: Journal of enzyme inhibition and medicinal chemistry (Print). - : Informa UK Limited. - 1475-6366 .- 1475-6374. ; 39:1
-
Tidskriftsartikel (refereegranskat)abstract
- Cancer and antibiotic-resistant bacterial infections are significant global health challenges. The resistance developed in cancer treatments intensifies therapeutic difficulties. In addressing these challenges, this study synthesised a series of N,N '-dialkyl urea derivatives containing methoxy substituents on phenethylamines. Using isocyanate for the efficient synthesis yielded target products 14-18 in 73-76% returns. Subsequently, their antibacterial and anticancer potentials were assessed. Cytotoxicity tests on cancer cell lines, bacterial strains, and a healthy fibroblast line revealed promising outcomes. All derivatives demonstrated robust antibacterial activity, with MIC values ranging from 0.97 to 15.82 mu M. Notably, compounds 14 and 16 were particularly effective against the HeLa cell line, while compounds 14, 15, and 17 showed significant activity against the SH-SY5Y cell line. Importantly, these compounds had reduced toxicity to healthy fibroblast cells than to cancer cells, suggesting their potential as dual-functioning agents targeting both cancer and bacterial infections.
|
|
| 2. |
- Cruz-Lopez, Olga, et al.
(författare)
-
Design, synthesis, HER2 inhibition and anticancer evaluation of new substituted 1,5-dihydro-4,1-benzoxazepines
- 2021
-
Ingår i: Journal of enzyme inhibition and medicinal chemistry (Print). - : Taylor & Francis. - 1475-6366 .- 1475-6374. ; 36:1, s. 1553-1563
-
Tidskriftsartikel (refereegranskat)abstract
- A series of 11 new substituted 1,5-dihydro-4,1-benzoxazepine derivatives was synthesised to study the influence of the methyl group in the 1-(benzenesulphonyl) moiety, the replacement of the purine by the benzotriazole bioisosteric analogue, and the introduction of a bulky substituent at position 6 of the purine, on the biological effects. Their inhibition against isolated HER2 was studied and the structure-activity relationships have been confirmed by molecular modelling studies. The most potent compound against isolated HER2 is 9a with an IC50 of 7.31 mu M. We have investigated the effects of the target compounds on cell proliferation. The most active compound (7c) against all the tumour cell lines studied (IC50 0.42-0.86 mu M) does not produce any modification in the expression of pro-caspase 3, but increases the caspase 1 expression, and promotes pyroptosis.
|
|
| 3. |
- Deplano, Alessandro, et al.
(författare)
-
Benzylamides and piperazinoarylamides of ibuprofen as fatty acid amide hydrolase inhibitors
- 2019
-
Ingår i: Journal of enzyme inhibition and medicinal chemistry (Print). - : Taylor & Francis. - 1475-6366 .- 1475-6374. ; 34:1, s. 562-576
-
Tidskriftsartikel (refereegranskat)abstract
- Fatty Acid Amide Hydrolase (FAAH) is a serine hydrolase that plays a key role in controlling endogenous levels of endocannabinoids. FAAH inhibition is considered a powerful approach to enhance the endocannabinoid signalling, and therefore it has been largely studied as a potential target for the treatment of neurological disorders such as anxiety or depression, or of inflammatory processes. We present two novel series of amide derivatives of ibuprofen designed as analogues of our reference FAAH inhibitor Ibu-AM5 to further explore its structure-activity relationships. In the new amides, the 2-methylpyridine moiety of Ibu-AM5 was substituted by benzylamino and piperazinoaryl moieties. The obtained benzylamides and piperazinoarylamides showed FAAH inhibition ranging from the low to high micromolar potency. The binding of the new amides in the active site of FAAH, estimated using the induced fit protocol, indicated arylpiperazinoamides binding the ACB channel and the cytosolic port, and benzylamides binding the ACB channel.
|
|
| 4. |
- Deplano, Alessandro, et al.
(författare)
-
Design, synthesis and in vitro and in vivo biological evaluation of flurbiprofen amides as new fatty acid amide hydrolase/cyclooxygenase-2 dual inhibitory potential analgesic agents
- 2021
-
Ingår i: Journal of enzyme inhibition and medicinal chemistry (Print). - : Taylor & Francis. - 1475-6366 .- 1475-6374. ; 36:1, s. 940-953
-
Tidskriftsartikel (refereegranskat)abstract
- Compounds combining dual inhibitory action against FAAH and cyclooxygenase (COX) may be potentially useful analgesics. Here, we describe a novel flurbiprofen analogue, N-(3-bromopyridin-2-yl)-2-(2-fluoro-(1,1'-biphenyl)-4-yl)propanamide (Flu-AM4). The compound is a competitive, reversible inhibitor of FAAH with a Ki value of 13 nM and which inhibits COX activity in a substrate-selective manner. Molecular modelling suggested that Flu-AM4 optimally fits a hydrophobic pocket in the ACB region of FAAH, and binds to COX-2 similarly to flurbiprofen. In vivo studies indicated that at a dose of 10 mg/kg, Flu-AM4 was active in models of prolonged (formalin) and neuropathic (chronic constriction injury) pain and reduced the spinal expression of iNOS, COX-2, and NFκB in the neuropathic model. Thus, the present study identifies Flu-AM4 as a dual-action FAAH/substrate-selective COX inhibitor with anti-inflammatory and analgesic activity in animal pain models. These findings underscore the potential usefulness of such dual-action compounds.
|
|
| 5. |
- Deplano, Alessandro, et al.
(författare)
-
Exploring the fatty acid amide hydrolase and cyclooxygenase inhibitory properties of novel amide derivatives of ibuprofen
- 2020
-
Ingår i: Journal of enzyme inhibition and medicinal chemistry (Print). - : Taylor & Francis. - 1475-6366 .- 1475-6374. ; 35:1, s. 815-823
-
Tidskriftsartikel (refereegranskat)abstract
- Inhibition of fatty acid amide hydrolase (FAAH) reduces the gastrointestinal damage produced by non-steroidal anti-inflammatory agents such as sulindac and indomethacin in experimental animals, suggesting that a dual-action FAAH-cyclooxygenase (COX) inhibitor could have useful therapeutic properties. Here, we have investigated 12 novel amide analogues of ibuprofen as potential dual-action FAAH/COX inhibitors. N-(3-Bromopyridin-2-yl)−2-(4-isobutylphenyl)propanamide (Ibu-AM68) was found to inhibit the hydrolysis of [3H]anandamide by rat brain homogenates by a reversible, mixed-type mechanism of inhibition with a Ki value of 0.26 µM and an α value of 4.9. At a concentration of 10 µM, the compound did not inhibit the cyclooxygenation of arachidonic acid by either ovine COX-1 or human recombinant COX-2. However, this concentration of Ibu-AM68 greatly reduced the ability of the COX-2 to catalyse the cyclooxygenation of the endocannabinoid 2-arachidonoylglycerol. It is concluded that Ibu-AM68 is a dual-acting FAAH/substrate-selective COX inhibitor.
|
|
| 6. |
|
|
| 7. |
- Ehrenberg, Angelica, et al.
(författare)
-
Accounting for strain variations and resistance mutations in the characterization of hepatitis C NS3 protease inhibitors
- 2014
-
Ingår i: Journal of enzyme inhibition and medicinal chemistry (Print). - : Informa UK Limited. - 1475-6366 .- 1475-6374. ; 29:6, s. 868-876
-
Tidskriftsartikel (refereegranskat)abstract
- Context: Natural strain variation and rapid resistance development makes development of broad spectrum hepatitis C virus (HCV) drugs very challenging and evaluation of inhibitor selectivity and resistance must account for differences in the catalytic properties of enzyme variants.Objective: To understand how to study selectivity and relationships between efficacy and genotype or resistant mutants for NS3 protease inhibitors.Materials and methods: The catalytic properties of NS3 protease from genotypes 1a, 1b and 3a, and their sensitivities to four structurally and mechanistically different NS3 protease inhibitors have been analysed under different experimental conditions.Results: The optimisation of buffer conditions for each protease variant enabled the comparison of their catalytic properties and sensitivities to the inhibitors. All inhibitors were most effective against genotype 1a protease, with VX-950 having the broadest selectivity.Discussion and conclusion: A new strategy for evaluation of inhibitors relevant for the discovery of broad spectrum HCV drugs was established.
|
|
| 8. |
- Floris, Sonia, et al.
(författare)
-
Washingtonia filifera seed extracts inhibit the islet amyloid polypeptide fibrils formations and alpha-amylase and alpha-glucosidase activity
- 2021
-
Ingår i: Journal of enzyme inhibition and medicinal chemistry (Print). - : Taylor & Francis. - 1475-6366 .- 1475-6374. ; 36:1, s. 517-524
-
Tidskriftsartikel (refereegranskat)abstract
- Washingtonia filifera seeds have revealed to possess antioxidant properties, butyrylcholinesterase and xanthine oxidase inhibition activities. The literature has indicated a relationship between Alzheimer's disease (AD) and type-2 diabetes (T2D). Keeping this in mind, we have now evaluated the inhibitory properties of W. filifera seed extracts on alpha-amylase, alpha-glucosidase enzyme activity and the Islet Amyloid Polypeptide (IAPP) fibrils formation. Three extracts from seeds of W. filifera were evaluated for their enzyme inhibitory effect and IC50 values were calculated for all the extracts. The inhibition mode was investigated by Lineweaver-Burk plot analysis and the inhibition of IAPP aggregate formation was monitored. W. filifera methanol seed extract appears as the most potent inhibitor of alpha-amylase, alpha-glucosidase, and for the IAPP fibril formation. Current findings indicate new potential of this extract that could be used for the identification or development of novel potential agents for T2D and AD.
|
|
| 9. |
- Fowler, Christopher J., et al.
(författare)
-
Inhibitory properties of ibuprofen and its amide analogues towards the hydrolysis and cyclooxygenation of the endocannabinoid anandamide
- 2013
-
Ingår i: Journal of enzyme inhibition and medicinal chemistry (Print). - : Informa UK Limited. - 1475-6366 .- 1475-6374. ; 28:1, s. 172-182
-
Tidskriftsartikel (refereegranskat)abstract
- A dual-action cyclooxygenase (COX)-fatty acid amide hydrolase (FAAH) inhibitor may have therapeutic usefulness as an analgesic, but a key issue is finding the right balance of inhibitory effects. This can be done by the design of compounds exhibiting different FAAH/COX-inhibitory potencies. In the present study, eight ibuprofen analogues were investigated. Ibuprofen (1), 2-(4-Isobutylphenyl)-N-(2-(3-methylpyridin-2-ylamino)-2-oxoethyl)propanamide (9) and N-(3-methylpyridin-2-yl)-2-(4'-isobutylphenyl) propionamide (2) inhibited FAAH with IC50 values of 134, 3.6 and 0.52 mu M respectively. The corresponding values for COX-1 were similar to 29, similar to 50 and similar to 60 mu M, respectively. Using arachidonic acid as substrate, the compounds were weak inhibitors of COX-2. However, when anandamide was used as COX-2 substrate, potency increased, with approximate IC50 values of similar to 6, similar to 10 and similar to 19 mu M, respectively. Compound 2 was confirmed to be active in vivo in a murine model of visceral nociception, but the effects of the compound were not blocked by CB receptor antagonists.
|
|
| 10. |
- Makatini, Maya M., et al.
(författare)
-
Synthesis, 2D-NMR and molecular modelling studies of pentacycloundecane lactam-peptides and peptoids as potential HIV-1 wild type C-SA protease inhibitors
- 2013
-
Ingår i: Journal of enzyme inhibition and medicinal chemistry (Print). - : Informa UK Limited. - 1475-6366 .- 1475-6374. ; 28:1, s. 78-88
-
Tidskriftsartikel (refereegranskat)abstract
- In this study, eight non-natural peptides and peptoids incorporating the pentacycloundecane (PCU) lactam were designed and synthesized as potential inhibitors of the wild type C-SA HIV-protease. Five of these inhibitors gave IC50 values ranging from 0.5 up to 0.75 mu M against the resistance-prone wild type C-South African HIV-protease. NMR EASY-ROESY studies enabled us to describe the secondary structure of three of these compounds in solution. The 3D structures of the selected cage peptides were also modelled in solution using QM/MM/MD simulations. Satisfactory agreement between the NMR observations and the low energy calculated structures exists. Only one of these inhibitors (11 peptoid), which showed the best IC50 (0.5 mu M), exhibited a definable 3-D structure in solution. Autodock4 and AutodockVina were used to model the potential interaction between these inhibitors and the HIV-PR. It appears that the docking results are too crude to be correlated with the relative narrow range of experimental IC50 values (0.5-10 mu M). The PCU-peptides and peptoides were several orders less toxic (145 mu M for 11 and 102 mu M for 11 peptoid) to human MT-4 cells than lopinavir (0.025 mu M). This is the first example of a polycyclic cage framework to be employed as an HIV-PR transition state analogue inhibitor and can potentially be utilized for other diseases related proteases.
|
|
