Ibuprofen Conjugates Research Articles

Prednisone and ibuprofen conjugate Janus dendrimers and their anticancer activity

Drug release from hyperbranched Janus dendrimer-drug conjugates and their subsequent activity are influenced by the different drugs in each dendron and the linker. To understand these effects, we synthetized new Janus-type dendrimers of first and second generation. One dendron with 2,2-Bis(hydroxymethyl)propionic acid functionalized with ibuprofen and the second dendron was obtained with 3-aminopropanol-amidoamine and prednisone. The dendrimers were obtained by copper(I)-catalyzed Click azide-alkyne cycloaddition for the formation of a triazole as a dendrimeric nucleus of Janus dendrimer conjugates are reported.The influence of ibuprofen, prednisone, and spacer on cancer activity of Janus dendrimers conjugates is reported. The IC50 values of the anticancer activity on cancer cell lines the Janus dendrimer of second generation was higher in comparison to the first generation dendrimer. Similarly, the anticancer activity was higher compared to the dendron conjugates. Also, no cytotoxic effects of dendrons and dendrimers on non-cancerous kidney COS-7 cell line was observed. The interesting anticancer activity of the prepared prednisone-ibuprofen Janus dendrimer conjugates suggest that the dendrimers could be of potential use as new anticancer drug.

Novel ibuprofen prodrug: A possible promising agent for the management of complications of Alzheimer’s disease

BackgroundAlzheimer’s disease (AD) is a severe, varied, and complex brain condition that gradually impairs memory and cognitive function. Epidemiological studies have shown that patients who have a history of long-term NSAID use have a decreased risk of developing AD. The objective of this study is to conduct the structural analysis of a novel ibuprofen prodrug and test its anti-Alzheimer’s properties. MethodsComputational and docking studies were conducted using AMBER 18 package. The in-vivo studies were performed using aluminum chloride-induced experimental AD in rats. Adult Wistar rats of either sex were used and treated with aluminum chloride (32.5 mg/kg, p.o) and ibuprofen prodrug (50 mg/kg, p.o) daily for 30 days. The hole-board test and elevated plus maze were conducted on 10th, 20th and 30th day. Further, on 31st day, animals were euthanized and the brain tissue was used for histopathology. The results obtained were subjected to statistical analysis by one-way ANOVA and Dunnet’s test, p < 0.05 was considered to indicate the significance. ResultsThe structural configuration of the novel compound indicated the presence of several structures such as aliphatic, aromatic, and asymmetry in the compound. The geometrical analysis indicated that the ibuprofen conjugate has dreiding energy of 51.22 kcal/mol with a van der waals radius of 62.56 A. The Huckel analysis confirmed the presence of aromatic rings in the compound. The molecular docking studies suggested affinity towards beta-secretase and acetylcholinesterase, besides indicating that the compound has ideal characteristics for the oral route (Log P = 2.33), cellular absorption (TPSA = 95.50), and oral bioavailability (number of rotatable bonds = 10). The toxicity profile indicated devoid of major systemic toxicity with mild possibility of cytotoxicity. The in-vivo analysis showed that the Ibu-prodrug significantly (P < 0.001) reversed the changes induced by aluminum chloride and restored histomorphological features in brain tissue. ConclusionThe findings suggested that the ibuprofen conjugate might possess the potential to manage the complications of AD. The action appears to be mediated through inhibition of beta-secretase and acetylcholinesterase activities. More studies might aid in identifying a specific therapeutic intervention that is still lacking in the treatment of AD.

Conjugates of ibuprofen inhibit CHIKV infection and inflammation.

Chikungunya virus infection has become a global health concern because of its high rates of morbidity and mortality in patients with preexisting conditions. Inflammation and arthritis are the major symptoms of CHIKV that persist even after clearance of CHIKV. To develop an antiviral that can reduce infection and manage inflammation independent of the CHIKV infection, ibuprofen (IBU) conjugates with sulfonamide and thiosemicarbazide were synthesized. The conjugates, IBU-SULFA, IBU-ISS and IBU-IBT significantly inhibited CHIKV infection in vitro with a selectivity index (CC50/IC50) of > 11.9, > 25.1 and > 21, respectively. The reduction in infection was attributed to the interference of the conjugates in the early stages of CHIKV life cycle. With no acute oral toxicity, these compounds significantly reduced inflammation and arthritis in rats. Unlike IBU, the conjugates were not ulcerogenic. In conclusion, the conjugation imparted anti-CHIKV properties while retaining the anti-inflammatory properties of IBU. These findings can encourage further validation and research to develop an antiviral for CHIKV to manage both infection and arthritis.

New NSAID Conjugates as Potent and Selective COX-2 Inhibitors: Synthesis, Molecular Modeling and Biological Investigation.

New sets of ibuprofen and indomethacin conjugates comprising triazolyl heterocycle were synthesized via click chemistry, adopting an optimized protocol through the molecular hybridization approach affording the targeted agents in good yields. The new non-steroidal anti-inflammatory drug (NSAID) conjugates were designed and synthesized and could be considered as potential drug candidates for the treatment of pain and inflammation. The anti-inflammatory properties were investigated for all the synthesized conjugates. Among 14 synthesized conjugates, four (5a, 5b, 5d, and 5e) were found to have significant anti-inflammatory properties potency 117.6%, 116.5%, 93.8%, and 109.1% in comparison to reference drugs ibuprofen (97.2%) and indomethacin (100%) in the rat paw edema carrageenan test without any ulcerogenic liability. The suppression effect of cytokines IL-6, TNF-α, and iNOS in addition to NO in the LPS-induced RAW264.7 cells supports the promising anti-inflammatory properties observed in the ibuprofen conjugates. In addition, several conjugates showed promising peripheral and central analgesic activity. The selectivity index (SI) of compound 5a (23.096) indicates the significant efficacy and selectivity for COX-2 over COX-1. Molecular modeling (docking and QSAR) studies described the observed biological properties.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and nucleotide analog GS-441524 conjugates with potent in vivo efficacy against coronaviruses

Coronaviruses (CoVs) infect a broad range of hosts, including humans and various animals, with a tendency to cross the species barrier, causing severe harm to human society and fostering the need for effective anti-coronaviral drugs. GS-441524 is a broad-spectrum antiviral nucleoside with potent anti-CoVs activities. However, its application is limited by poor oral bioavailability. Herein, we designed and synthesized several conjugates via covalently binding NSAIDs to 5′-OH of GS-441524 through ester bonds. The ibuprofen conjugate, ATV041, exhibited potent in vitro anti-coronaviral efficacy against four zoonotic coronaviruses in the alpha- and beta-genera. Oral-dosed ATV041 resulted in favorable bioavailability and rapid tissue distribution of GS-441524 and ibuprofen. In MHV-A59 infected mice, ATV041 dose-dependently decreased viral RNA replication and significantly reduced the proinflammatory cytokines in the liver and the lung at 3 dpi. As a result, the MHV-A59-induced lung and liver inflammatory injury was significantly alleviated. Taken together, this work provides a novel drug conjugate strategy to improve oral PK and offers a potent anti-coronaviral lead compound for further studies.

From Combinations to Single-Molecule Polypharmacology-Cromolyn-Ibuprofen Conjugates for Alzheimer's Disease.

Despite Alzheimer’s disease (AD) incidence being projected to increase worldwide, the drugs currently on the market can only mitigate symptoms. Considering the failures of the classical paradigm “one target-one drug-one disease” in delivering effective medications for AD, polypharmacology appears to be a most viable therapeutic strategy. Polypharmacology can involve combinations of multiple drugs and/or single chemical entities modulating multiple targets. Taking inspiration from an ongoing clinical trial, this work aims to convert a promising cromolyn–ibuprofen drug combination into single-molecule “codrugs.” Such codrugs should be able to similarly modulate neuroinflammatory and amyloid pathways, while showing peculiar pros and cons. By exploiting a linking strategy, we designed and synthesized a small set of cromolyn–ibuprofen conjugates (4–6). Preliminary plasma stability and neurotoxicity assays allowed us to select diamide 5 and ethanolamide 6 as promising compounds for further studies. We investigated their immunomodulatory profile in immortalized microglia cells, in vitro anti-aggregating activity towards Aβ42-amyloid self-aggregation, and their cellular neuroprotective effect against Aβ42-induced neurotoxicity. The fact that 6 effectively reduced Aβ-induced neuronal death, prompted its investigation into an in vivo model. Notably, 6 was demonstrated to significantly increase the longevity of Aβ42-expressing Drosophila and to improve fly locomotor performance.

Improvement of the Anticancer Activity of Chlorambucil and Ibuprofen via Calix[4]arene Conjugates

One of the possible ways of improving the activity and selectivity profile of anticancer agents is to design drug carrier systems employing nanomolecules. Calix[4]arene derivatives and chlorambucil and ibuprofen are important compounds that exhibit interesting anticancer properties. The objective of this article is the synthesis of new calix[4]arene-derivative conjugates of chlorambucil or ibuprofen with potential anticancer activity. Cytotoxicity assays were determined using the protein-binding dye sulforhodamine B (SRB) in microculture to measure cell growth as described [19, 20]. Conjugates of chlorambucil and resorcinarene-dendrimers were prepared in 2% DMSO and added into the culture medium immediately before use. Control cells were treated with 2% DMSO. Thus, calix[4]arene-derivative conjugates of chlorambucil or ibuprofen showed good stability of the chemical link between drug and spacer. Evaluation of the cytotoxicity of the calix[4]arene chlorambucil or ibuprofen conjugates employing a sulforhodamine B (SRB) assay in K-562 (human chronic myelogenous leukemia cells) and U-251 (human glioblastoma cells) demonstrated that the conjugate was more potent as an antiproliferative agent than free chlorambucil and ibuprofen. The conjugates did not show any activity against the COS-7 African green monkey kidney fibroblast cell line. In the paper, we report the synthesis and spectroscopic analyses of new calix[4]arene derivative conjugates of chlorambucil or ibuprofen. Cytotoxicity assays revealed that at 10 μM, the conjugates were very active against K-562 (human chronic myelogenous leukemia cells) and U- 251 (human glioblastoma cells) cancer cells' proliferation. In order to explain the molecular mechanisms involved in the anticancer activity of calix[4]arene chlorambucil or ibuprofen conjugates, our research will be continued.

Synthesis and biological evaluation of closo-dodecaborate ibuprofen conjugate (DIC) as a new boron agent for neutron capture therapy

A closo-dodecaborate ibuprofen conjugate (DIC) 1 was synthesized via amide bond formation between ibuprofen activated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) and 4-aminoethoxyethoxy-closo-dodecaborate 3 which was synthesized via the ring opening reaction of 1,4-dioxane-closo-dodecaborate complex 2 with ammonia in aqueous solution. DIC showed no significant binding affinity to HSA site 2, which is known as an ibuprofen binding site. DIC accumulated in HeLa cells in a time-dependent manner, and the boron concentration reached 0.68 μg/106 cells 6 h after administration.

Synthesis, Characterization, and Nanomedical Applications of Conjugates between Resorcinarene-Dendrimers and Ibuprofen.

Ibuprofen has been reported to possess anticancer activity. In the present work, four ibuprofen conjugates of resorcinarene-Polyamidoamine PAMAM-dendrimers were synthesized with eight or 16 ibuprofen moieties. The ibuprofen was released from the dendrimers in a dependent manner. The drug-conjugated nanoresorcinarene-dendrimers showed higher cellular uptake than free ibuprofen. In vitro cytotoxicity studies were performed with free ibuprofen and with the synthesized conjugates in U251, PC-3, K-562, HCT-15, MCF-7, SKLU-1, and MDA U251 (human glioblastoma), PC-3 (human prostatic adenocarcinoma), K-562 (human chronic myelogenous leukemia cells), HCT-15 (human colorectal adenocarcinoma), MCF-7 (human mammary adenocarcinoma), SKLU-1 (human lung adenocarcinoma), and MDA-MB-231 (human mammary adenocarcinoma) cancer cell lines by different cytotoxicity assays. Ibuprofen conjugates of the first and second generations showed significant cytotoxic effects towards the human glioblastoma (U251) and human mammary adenocarcinoma (MCF-7, MDA) cell lines. Moreover, the ibuprofen conjugates improved cytotoxicity compared to free ibuprofen. Increased therapeutic efficacy was observed with specific ibuprofen conjugates of the second generation using low doses.

Synthesis of Ibuprofen Conjugated Molecular Transporter Capable of Enhanced Brain Penetration

Based on the strong evidences between inflammation and neurodegeneration, nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, are considered as effective agents to reduce the risk of Alzheimer’s and Parkinson’s disease. However, the clinical use of NSAIDs in these diseases is limited by low brain distribution. In this study, we had synthesized ibuprofen conjugate which has good brain penetration.S-(+)-Ibuprofen was covalently attached to a molecular transporter having FITC and eight terminal guanidine groups. This conjugate showed good cellular uptake property in live cells. It was also injected into a mouse and the distribution of the compound was examined in each organ. The conjugate was well delivered to mouse brain indicating the conjugate is able to cross the blood-brain barrier. Our novel synthetic ibuprofen conjugate will hopefully deliver other NSAIDs into brain and is therefore applicable to the neurodegenerative diseases treatment or prevention.

Design, characterization and pharmaceutical/pharmacological applications of ibuprofen conjugates based on hydroxyethylcellulose

We synthesized polymeric prodrugs of ibuprofen (IBU) based on hydroxyethylcellulose (HEC) which offered extended release and enhanced bioavailability of IBU as well as significant immunomodulatory potential in cytokine release assay.

Synthesis of New Acetaminophen Analogs and Their Ibuprofen Conjugates as Novel Analgesic Drugs

In this research, new analogs of acetaminophen (paracetamol, I) with dimethyl and ethyl substitutions on phenyl moiety and sulfonamide modified by inserting alkylpiperazine derivatives were synthesized (II – V). Then, their conjugated compounds with ibuprofen were also synthesized (VI – IX) and the analgesic and anti-inflammatory activities of new drugs (II – IX) were evaluated in formalin tests on rats. Results indicated that the best analgesic activity was observed for compounds II and VI in diminishing chronic and VI – IX in acute thermal pain tests; in addition, compound VIII showed the best activity in diminishing inflammation. It was concluded that chemical structural binding of the potent synthesized drugs (II – V) with ibuprofen produced new superior antinociceptive and anti-inflammatory drugs (VI – IX) which could alleviate both pain and inflammation.

Synthesis and Pharmacological Evaluation of New Chemical Entities Based on Paracetamol and Their Ibuprofen Conjugates as Novel and Superior Analgesic and Anti-Inflammatory Candidates

p-Aminophenol had been evaluated in the past as an analgesic–antipyretic drug, but its N-acetylated derivative acetaminophen (paracetamol) was found to be the most suitable therapeutically. Acetaminophen is still one of the most popular drugs, which is frequently used for the relief of acute and chronic pain. In this study, new analogs of paracetamol with dimethyl and ethyl substitutions in the phenyl moiety and sulfonamide, which was modified by inserting morpholine, were synthesized (compounds 4 and 5). Then, their conjugated compounds with ibuprofen (6) were synthesized (8 and 9) and the analgesic and anti-inflammatory activities of these new drugs (4, 5, 8, 9) were evaluated in formalin-induced edema test (as a model of acute and chronic chemical pain and also paw edema inflammation) on rats. The results were compared to paracetamol, ibuprofen (as standards), and control (saline) groups. Results showed that the new synthesized derivatives exhibit higher analgesic and anti-inflammatory effects compared to acetaminophen alone for compounds 4, 5, 8 and 9 or ibuprofen for compounds 4, 8 and 9. Moreover, it was concluded that chemical-structural binding of the potent synthesized drugs (4 and 5) with ibuprofen (6) produced new superior anti-nociceptive and anti-inflammatory drugs (8 and 9).

Synthesis, Evaluation of Analgesic and Gastric Ulcerogenic Activities and the Metabolites in Rat Plasma of Hydantoin Ibuprofen Conjugates

Synthesis, Evaluation of Analgesic and Gastric Ulcerogenic Activities and the Metabolites in Rat Plasma of Hydantoin Ibuprofen Conjugates

Synthesis and evaluation of mutual prodrugs of ibuprofen with menthol, thymol and eugenol

The present works deals with simple and efficient method of improving therapeutic efficacy of racemic ibuprofen by retarding gastrointestinal side effects through masking of carboxylic group chemically. This is achieved by synthesis and evaluation of ester derivatives of ibuprofen as mutual prodrugs with naturally occurring phenolic and alcoholic compounds. Promoieties like menthol; thymol and eugenol were selected with the aim of getting synergistic effect as these are natural analgesic having traditional medicinal values. Prodrugs are found to be highly lipophilic as compared to parent drug. All the prodrugs are found to be highly stable at acidic pH while undergoes hydrolysis at neutral and alkaline pH as indicated by their t1/2 values. Synthesized prodrugs derivatives show increased anti-inflammatory activity that might be attributed to synergistic effect as ibuprofen conjugates to natural analgesics. Ulcer index shows much reduction in gastric ulceration compared to ibuprofen concluding the successful masking of acidic group.

In Vivo Assessment of Parenteral Formulations of Oligo(3-Hydroxybutyric Acid) Conjugates with the Model Compound Ibuprofen

Polymer-drug conjugates have gained significant attention as pro-drugs releasing an active substance as a result of enzymatic hydrolysis in physiological environment. In this study, a conjugate of 3-hydroxybutyric acid oligomers with a carboxylic acid group-bearing model drug (ibuprofen) was evaluated in vivo as a potential pro-drug for parenteral administration. Two different formulations, an oily solution and an o/w emulsion were prepared and administered intramuscularly (IM) to rabbits in a dose corresponding to 40 mg of ibuprofen/kilogramme. The concentration of ibuprofen in blood plasma was analysed by HPLC, following solid–phase extraction and using indometacin as internal standard (detection limit, 0.05 μg/ml). No significant differences in the pharmacokinetic parameters (C max, T max, AUC) were observed between the two tested formulations of the 3-hydroxybutyric acid conjugate. In comparison to the non-conjugated drug in oily solution, the relative bioavailability of ibuprofen conjugates from oily solution, and o/w emulsion was reduced to 17% and 10%, respectively. The 3-hydroxybutyric acid formulations released the active substance over a significantly extended period of time with ibuprofen still being detectable 24 h post-injection, whereas the free compound was almost completely eliminated as early as 6 h after administration. The conjugates remained in a muscle tissue for a prolonged time and can hence be considered as sustained release systems for carboxylic acid derivatives.

Synthesis, Chemical Hydrolysis and Bioavailability Evaluation of Poly(HEMA)-Ibuprofen Conjugate as Macromolecular Prodrug.

Ibuprofen (IBU) suffers from the general side effects of NSAIDs owing to local and systemic action. The study aimed to retard the adverse effects of gastrointestinal origin. A macromolecular prodrug of IBU was synthesized by coupling the drug to 2-hydroxypropyl methacrylate (HEMA) to get a monomeric drug conjugate which was then polymerized to get polymeric prodrug. Purified synthesized prodrug was characterized by m.p, TLC, UV, FTIR, NMR and MS. The prodrug was evaluated for its in-vitro drug release behavior in buffers of pH 1.2 and 7.4 mimicking the upper and lower GIT respectively. The results showed that the drug release from the polymeric backbone takes place in a sustained manner over a period of 12 h and the amount of drug released was comparatively higher at pH 7.4 indicating that the drug release should takes place predominantly at the alkaline environment of the lower GIT rather than at the acidic environment of the upper GIT. The in-vivo release studies in rabbits after oral administration of IBU conjugate revealed sustained release characteristics within the prodrug treated animals. This study suggested that after oral administration, the drug –polymer conjugate can release IBU for prolonged periods and predominantly in the lower GIT in a site specific manner, thus reducing the direct contact of the drug to the gastric mucosa and hence the GIT complications.

Drug release characteristics of PAMAM dendrimer–drug conjugates with different linkers

Drug release from polymer–drug conjugates plays a crucial role on the efficacy. This is especially true for dendrimers where there is a steric crowding at the surface. The drug release characteristics of G4-polyamidoamine (PAMAM) dendrimer–ibuprofen conjugates with ester, amide, and peptide linkers were investigated, in addition to a linear PEG–ibuprofen conjugate to understand the effect of architecture and linker on drug release. Ibuprofen was directly conjugated to NH 2-terminated dendrimer by an amide bond and OH-terminated dendrimer by an ester bond. A tetra-peptide-linked dendrimer conjugate and a linear mPEG–ibuprofen conjugate were also studied for comparison to direct linked dendrimer conjugates. Amide-linked conjugates were relatively stable against hydrolysis, whereas the ester-linked conjugates showed pH-dependent release and the extent of release varied with pH from 3% (pH 5) to 38% (pH 8.5) for the 10-day period studied. Direct amide- and ester-linked conjugates did not release ibuprofen enzymatically in cathepsin B buffer and diluted human plasma. In contrast, mPEG conjugate released 65% of its payload within 12 h in diluted plasma by esterase activity, and the peptide-linked dendrimer conjugate released 40% of its payload within 48 h by cathepsin B activity. It is demonstrated that the steric crowding at the surface of PAMAM dendrimer–drug conjugates, along with linking chemistry govern the drug release mechanisms as well as kinetics. Understanding these structural and steric effects on their drug release characteristics is crucial for the design of dendrimer conjugates with high efficacy.

The in vitro transport of model thiodipeptide prodrugs designed to target the intestinal oligopeptide transporter, PepT1

A thiodipeptide carrier system is shown to be effective at enabling a range of covalently bound molecules, including benzyl, benzoyl and ibuprofen conjugates, to be transported via the intestinal peptide transporter PepT1, demonstrating its potential as a rational drug delivery target.

Synthesis, pharmacological activity and hydrolytic behavior of ethylenediamine and benzathine conjugates of ibuprofen

For reducing the gastrointestinal toxicity associated with ibuprofen, its carboxylic group was masked by synthesizing its amide conjugates with ethylenediamine and benzathine ( 4a, 4b, respectively) by carbodiimide assisted coupling method. In vitro hydrolysis of conjugates showed that they were stable in HCl buffer (pH 1.2) indicating that the prodrugs did not break in stomach and there was no release of ibuprofen at gastric pH, whereas in phosphate buffer (pH 7.4) they undergo significant hydrolysis and thus release ibuprofen in adequate amounts following first order kinetics. The ibuprofen conjugates 4a, 4b were retaining anti-inflammatory activity intact and exhibited better analgesic activity along with much reduced ulcerogenicity. These findings suggested that both the conjugates are better in action as compared to parent drug and are advantageous in having less gastrointestinal side effects. Compound 4b however showed better analgesic activity and longer action ( t 1/2) than 4a, and hence it could be considered as a better candidate for prodrug among the two.