Synthesis and pharmacological evaluation of choroquine derivatives bearing long aminated side chains as antivirus and anti-inflammatory agents.
Ontology highlight
ABSTRACT:
SUBMITTER: Song Z
PROVIDER: S-EPMC8434889 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Triterpene acids are a class of pentacyclic natural carboxylic compounds endowed with a variety of biological activities including antitumor, antimicrobial, and hepatoprotective effects. In this work, several oleanolic acid derivatives were synthesized by structurally modifying them on the C-3 position. All synthesized derivatives were evaluated for possible antibacterial and antiviral activity, and among all the epimers, 6 and 7 demonstrated the best biological activities. Zone-of-inhibition analyses were conducted against two strains, E. coli as a Gram-negative and S. aureus as a Gram-positive model. Subsequently, experiments were performed using the microdilution method to determine the minimum inhibitory concentration (MIC). The results showed that only the derivative with reduced hydrogen bonding ability on ring A possesses remarkable activity toward E. coli. The conversion from acid to methyl ester implies a loss of activity, probably due to a reduced affinity with the bacterial membrane. Before the antiviral activity, the cytotoxicity of triterpenes was evaluated through a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Samples 6 and 7 showed less than 50% cytotoxicity at 0.625 and 1 mg/mL, respectively. The antiviral activity against SARS-CoV-2 and PV-1 did not indicate that triterpene acids had any inhibitory capacity in the sub-toxic concentration range.
| S-EPMC11312724 | biostudies-literature
Project description:p38α mitogen activated protein kinase (MAPK) inhibitors provide a novel approach for the treatment of inflammatory disorders. A series of fifteen pyrazolyl urea derivatives (3a-o) were synthesized and evaluated for their p38α MAPK inhibition and antioxidant potential. Compounds 3a-e, 3g and 3h showed low micromolar range potency (IC50 values ranging from 0.037 ± 1.56 to 0.069 ± 0.07 µmol/L) compared to the standard inhibitor SB 203580 (IC50 = 0.043 ± 3.62 µmol/L) when evaluated for p38α MAPK inhibition by an immunosorbent-based assay. Antioxidant activity was measured by a 2,2'-diphenyl-1-picryl hydrazyl radical (DPPH) free radical scavenging method and one of the compounds, 3c, showed better percentage antioxidant activity (75.06%) compared to butylated hydroxy anisole (71.53%) at 1 mmol/L concentration. Compounds 3a-e, 3g and 3h showed promising in vivo anti-inflammatory activity (ranging from 62.25% to 80.93%) in comparison to diclofenac sodium (81.62%). The ulcerogenic liability and lipid peroxidation activity of these compounds were observed to be less in comparison to diclofenac sodium. These compounds also potently inhibited the lipopolysaccharide (LPS)-induced TNF-α release in mice (ID50 of 3a-c = 19.98, 11.32 and 9.67 mg/kg, respectively). Among the screened compounds, derivative 3c was found to be the most potent and its binding mode within the p38α MAPK is also reported.
| S-EPMC5343109 | biostudies-literature
Project description:We report here on the covalent conversion of the anti-inflammatory agent ketoprofen into self-assembling prodrugs that enable the effective purification of ketoprofen enantiomers, the improved selectivity and potency of ketoprofen, as well as the formation of one-component drug-bearing supramolecular hydrogels. We found that the ketoprofen hydrogelator could exhibit much-enhanced selectivity for cyclooxygenase 2 (COX-2) over COX-1, reduce the concentration of inflammatory cytokines (IL-1 and TNFα), and induce apoptosis in fibroblast-like synoviocytes while maintaining biocompatibility with healthy chondrocytes. In addition, these anti-inflammatory agent-containing hydrogels demonstrated the ability to retain the therapeutic within a joint cavity after intra-articular injection, exhibiting a slow, steady release into the plasma. We believe that upon further optimization these drug-based injectable supramolecular hydrogels could provide the basis for a local treatment strategy for rheumatoid arthritis and similar conditions.
| S-EPMC5485419 | biostudies-literature
Project description:A series of N-(2-(4-chlorobenzyl)benzo[d]oxazol-5-yl)-3-substituted-propanamide (3a-3n) were synthesized and evaluated for their acute and chronic anti-inflammatory potential. The structure of the compounds was elucidated by elemental and spectral (IR, 1H NMR and MS) analysis. The synthesized compounds (at a dose of 20 mg/kg b.wt. p.o.) have shown their ability to provide 45.1-81.7% protection against carrageenan-induced paw edema, in comparison with diclofenac sodium (69.5%) and ibuprofen (64.7%). The most active compounds 3a, 3l and 3n were screened for chronic anti-inflammatory activity (cotton-pellet-induced granuloma) and to study their ulcerogenic activity. Compounds 3a, 3l and 3n showed 48.4%, 39.3% and 44.0% protection against cotton pellets-induced granuloma compared to diclofenac sodium (60.2%). The tested compounds were less ulcerogenic than the ibuprofen. Molecular modeling studies suggest that these compounds have strong interaction with the COX-2 enzyme, which is responsible for the activity.
| S-EPMC5094471 | biostudies-literature
Project description:Background and aim: Naproxen is a member of the Nonsteroidal anti-inflammatory drugs (NSAIDs). This work aimed to synthesize a safe NSAID agent based on a peptide derivative. Methods: The structure of compounds 5-20 was established on the basis of spectral data. Frontier molecular orbitals and chemical reactivity were discussed to clarify inter- and intramolecular interactions among tested compounds. We applied competitive molecular docking using polynomial logarithms to identify the most accurate algorithm for pharmacological activity prediction for the tested compounds. The docking protocol with the lowest RMSD was selected for analyzing binding affinity. Results: Docking results illustrated that the binding interaction increased after introduction of an acidic fragment to the parent compound. These compounds were selected for additional study against adsorption, distribution, metabolism, excretion, and toxicity (ADMET) in silico. The compounds tested had good oral bioavailability without any carcinogenesis effect; no marked health effects were observed via rodent toxicity. Compounds passed through docking and ADMET profiles for them (5-16) were examined as anti-inflammatory and analgesic agents. Compounds 8 and 16 showed higher anti-inflammatory potency than the reference drug and tested compounds. Compounds 8, 10, and 14 exhibited the highest analgesic potency compared to the other tested compounds. Conclusion: The tested compounds have shown negligible ulcerogenic effects, and may be considered safer drugs than naproxen for treating inflammatory conditions.
| S-EPMC6540076 | biostudies-literature
Project description:The outer surfaces of Gram-negative bacteria are composed of lipopolysaccharide (LPS) molecules exposing oligo- and polysaccharides to the aqueous environment. This unique, structurally complex biological interface is of great scientific interest as it mediates the interaction of bacteria with antimicrobial agents as well as with neighboring bacteria in colonies and biofilms. Structural studies on LPS surfaces, however, have so far dealt almost exclusively with rough mutant LPS of reduced molecular complexity and limited biological relevance. Here, by using neutron reflectometry, we structurally characterize planar monolayers of wild-type LPS from Escherichia coli O55:B5 featuring strain-specific O-side chains in the presence and absence of divalent cations and under controlled interaction conditions. The model used for the reflectivity analysis is self-consistent and based on the volume fraction profiles of all chemical components. The saccharide profiles are found to be bimodal, with dense inner oligosaccharides and more dilute, extended O-side chains. For interacting LPS monolayers, we establish the pressure-distance curve and determine the distance-dependent saccharide conformation.
| S-EPMC5954297 | biostudies-literature
Project description:A series of diclofenac N-derivatives (2, 4, 6, 8c, 9c, 10a-c) were synthesized in order to test their anti-cancer and anti-inflammatory effects. The anticarcinogen activity has been assayed against three cancer cell lines: HT29, human colon cancer cells; Hep-G2, human hepatic cells; and B16-F10, murine melanoma cells. First, we determined the cytotoxicity of the different compounds, finding that the most effective compound was compound 8c against all cell lines and both compounds 4 and 6 in human Hep-G2 and HT29 cell lines. Compounds 4 and 8c were selected for the percentage of apoptosis determination, cell cycle distribution, and mitochondrial membrane potential measure because these products presented the lowest IC50 values in two of the three cancer cell lines assayed (B16-F10 and HepG2), and were two of the three products with lowest IC50 in HT29 cell line. Moreover, the percentages of apoptosis induction were determined for compounds 4 and 8c, showing that the highest values were between 30 to 60%. Next, the effects of these two compounds were observed on the cellular cycle, resulting in an increase in the cell population in G2/M cell cycle phase after treatment with product 8c, whereas compound 4 increased the cells in phase G0/G1, by possible differentiation process induction. Finally, to determine the possible apoptosis mechanism triggered by these compounds, mitochondrial potential was evaluated, indicating the possible activation of extrinsic apoptotic mechanism. On the other hand, we studied the anti-inflammatory effects of these diclofenac (DCF) derivatives on lipopolysaccharide (LPS) activated RAW 264.7 macrophages-monocytes murine cells by inhibition of nitric oxide (NO) production. As a first step, we determined the cytotoxicity of the synthesized compounds, as well as DCF, against these cells. Then, sub-cytotoxic concentrations were used to determine NO release at different incubation times. The greatest anti-inflammatory effect was observed for products 2, 4, 8c, 10a, 10b, and 9c at 20 µg·mL-1 concentration after 48 h of treatment, with inhibition of produced NO between 60 to 75%, and a concentration that reduces to the 50% the production of NO (IC50 NO) between 2.5 to 25 times lower than that of DCF. In this work, we synthesized and determined for the first time the anti-cancer and anti-inflammatory potential of eight diclofenac N-derivatives. In agreement with the recent evidences suggesting that inflammation may contribute to all states of tumorigenesis, the development of these new derivatives capable of inducing apoptosis and anti-inflammatory effects at very low concentrations represent new effective therapeutic strategies against these diseases.
| S-EPMC8151993 | biostudies-literature
Project description:BackgroundPrevention and treatment of chronic inflammatory diseases require effective and low-toxic medicines. Molecular hybridization is an effective strategy to enhance the biological activity of new compounds. Triterpenoid scaffolds are in the focus of attention owing to their anti-inflammatory, antiviral, antiproliferative, and immunomodulatory activities. Heteroprostanoids have different pleiotropic effects in acute and chronic inflammatory processes.ObjectiveThe study aimed to develop structurally new and low toxic anti-inflammatory agents via hybridization of betulinic acid with azaprostanoic acids.MethodsA series of betulinic acid-azaprostanoid hybrids was synthesized. The synthetic pathway included the transformation of betulin via Jones' oxidation into betulonic acid, reductive amination of the latter and coupling obtained by 3β-amino-3-deoxybetulinic acid with the 7- or 13-azaprostanoic acids and their homo analogues. The hybrids 1-9 were investigated in vivo on histamine-, formalin- and concanavalin A-induced mouse paw edema models and two models of pain - the acetic acid-induced abdominal writhing and the hotplate test. The hybrids were in vitro evaluated for cytotoxic activity on cancer (MCF7, U- 87 MG) and non-cancer humane cell lines.ResultsIn the immunogenic inflammation model, the substances showed a pronounced anti-inflammatory effect, which was comparable to that of indomethacin. In the models of the exudative inflammation, none of the compounds displayed a statistically significant effect. The hybrids produced weak or moderate analgesic effects. All the agents revealed low cytotoxicity on human immortalized fibroblasts and cancer cell lines compared with 3β- amino-3-deoxybetulinic acid and doxorubicin.ConclusionThe results indicate that the principal anti-inflammatory effect of hybrids is substantially provided with the triterpenoid scaffold and in some cases with the azaprostanoid scaffold, but the latter makes a significant contribution to reducing the toxicity of hybrids. Hybrid 1 is of interest as a potent low toxic agent against immune-mediated inflammation.
| S-EPMC7499346 | biostudies-literature
Project description:(Z)-α-Santalol, which has a unique woody odor, is a main constituent of sandalwood essential oil. We investigated the structure-odor relationship of (Z)-α-santalol and its derivatives, focusing on the relationship between the structure of the side chain and the odor of the compounds. Various α-santalol derivatives (aldehydes, formates, and acetates) were synthesized from (Z)- and (E)-α-santalol, which were prepared from (+)-3-bromocamphor through modifications of a reported synthetic route. The Z- and E-isomers of α-santalols have different double-bond configurations in the side chain. Analogues with saturated side chains were also prepared from the corresponding α-santalols, and the odors of the all the prepared compounds were evaluated. We found that the odors of the Z-isomers (woody) were similar to those of the corresponding saturated compounds, but clearly different from the odors of the corresponding E-isomers (odorless, fresh, or fatty). These results indicate that the relative configuration of the side chain with respect to the santalane frame plays an important role in the odor of α-santalol. E-configuration in the side chain eliminates the woody odor character of α-santalol and its examined derivatives, whereas the Z-configuration or saturation of the carbon side chain does not.
| S-EPMC6268821 | biostudies-literature
Project description:G-quadruplexes (G4s), which are structures formed in guanine-rich regions of DNA, are involved in a variety of significant biological functions, and therefore "sequence-dependent" selective G4-stabilizing agents are required as tools to investigate and modulate these functions. Here, we describe the synthesis of a new series of macrocyclic hexaoxazole-type G4 ligand (6OTD) bearing three side chains. One of these ligands, 5b, stabilizes telomeric G4 preferentially over the G4-forming DNA sequences of c-kit and K-ras, due to the interaction of its piperazinylalkyl side chain with the groove of telomeric G4.
| S-EPMC6358838 | biostudies-literature