Early treatment with fluvoxamine, bromhexine, cyproheptadine, and niclosamide to prevent clinical deterioration in patients with symptomatic COVID-19: a randomized clinical trial.

Background: Repurposed drugs with host-directed antiviral and immunomodulatory properties have shown promise in the treatment of COVID-19, but few trials have studied combinations of these agents. The aim of this trial was to assess the effectiveness of affordable, widely available, repurposed drugs used in combination for treatment of COVID-19, which may be particularly relevant to low-resource countries. Methods: We conducted an open-label, randomized, outpatient, controlled trial in Thailand from October 1, 2021, to June 21, 2022, to assess whether early treatment within 48-h of symptoms onset with combinations of fluvoxamine, bromhexine, cyproheptadine, and niclosamide, given to adults with confirmed mild SARS-CoV-2 infection, can prevent 28-day clinical deterioration compared to standard care. Participants were randomly assigned to receive treatment with fluvoxamine alone, fluvoxamine + bromhexine, fluvoxamine + cyproheptadine, niclosamide + bromhexine, or standard care. The primary outcome measured was clinical deterioration within 9, 14, or 28 days using a 6-point ordinal scale. This trial is registered with ClinicalTrials.gov (NCT05087381). Findings: Among 1900 recruited, a total of 995 participants completed the trial. No participants had clinical deterioration by day 9, 14, or 28 days among those treated with fluvoxamine plus bromhexine (0%), fluvoxamine plus cyproheptadine (0%), or niclosamide plus bromhexine (0%). Nine participants (5.6%) in the fluvoxamine arm had clinical deterioration by day 28, requiring low-flow oxygen. In contrast, most standard care arm participants had clinical deterioration by 9, 14, and 28 days. By day 9, 32.7% (110) of patients in the standard care arm had been hospitalized without requiring supplemental oxygen but needing ongoing medical care. By day 28, this percentage increased to 37.5% (21). Additionally, 20.8% (70) of patients in the standard care arm required low-flow oxygen by day 9, and 12.5% (16) needed non-invasive or mechanical ventilation by day 28. All treated groups significantly differed from the standard care group by days 9, 14, and 28 (p < 0.0001). Also, by day 28, the three 2-drug treatments were significantly better than the fluvoxamine arm (p < 0.0001). No deaths occurred in any study group. Compared to standard care, participants treated with the combination agents had significantly decreased viral loads as early as day 3 of treatment (p < 0.0001), decreased levels of serum cytokines interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1ß) as early as day 5 of treatment, and interleukin-8 (IL-8) by day 7 of treatment (p < 0.0001) and lower incidence of post-acute sequelae of COVID-19 (PASC) symptoms (p < 0.0001). 23 serious adverse events occurred in the standard care arm, while only 1 serious adverse event was reported in the fluvoxamine arm, and zero serious adverse events occurred in the other arms. Interpretation: Early treatment with these combinations among outpatients diagnosed with COVID-19 was associated with lower likelihood of clinical deterioration, and with significant and rapid reduction in the viral load and serum cytokines, and with lower burden of PASC symptoms. When started very soon after symptom onset, these repurposed drugs have high potential to prevent clinical deterioration and death in vaccinated and unvaccinated COVID-19 patients. Funding: Ped Thai Su Phai (Thai Ducks Fighting Danger) social giver group.

Exploring indoor and outdoor dust as a potential tool for detection and monitoring of COVID-19 transmission.

This study investigated the potential of using SARS-CoV-2 viral concentrations in dust as an additional surveillance tool for early detection and monitoring of COVID-19 transmission. Dust samples were collected from 8 public locations in 16 districts of Bangkok, Thailand, from June to August 2021. SARS-CoV-2 RNA concentrations in dust were quantified, and their correlation with community case incidence was assessed. Our findings revealed a positive correlation between viral concentrations detected in dust and the relative risk of COVID-19. The highest risk was observed with no delay (0-day lag), and this risk gradually decreased as the lag time increased. We observed an overall decline in viral concentrations in public places during lockdown, closely associated with reduced human mobility. The effective reproduction number for COVID-19 transmission remained above one throughout the study period, suggesting that transmission may persist in locations beyond public areas even after the lockdown measures were in place.

Ca-EDTA restores the activity of ceftazidime-avibactam or aztreonam against carbapenemase-producing Klebsiellapneumoniae infections.

Developing an effective therapy to overcome carbapenemase-positive Klebsiella pneumoniae (CPKp) is an important therapeutic challenge that must be addressed urgently. Here, we explored a Ca-EDTA combination with aztreonam or ceftazidime-avibactam in vitro and in vivo against diverse CPKp clinical isolates. The synergy testing of this study demonstrated that novel aztreonam-Ca-EDTA or ceftazidime-avibactam-Ca-EDTA combination was significantly effective in eliminating planktonic and mature biofilms in vitro, as well as eradicating CPKp infections in vivo. Both combinations revealed significant therapeutic efficacies in reducing bacterial load in internal organs and protecting treated mice from mortality. Conclusively, this is the first in vitro and in vivo study to demonstrate that novel aztreonam-Ca-EDTA or ceftazidime-avibactam-Ca-EDTA combinations provide favorable efficacy and safety for successful eradication of carbapenemase-producing Klebsiella pneumoniae planktonic and biofilm infections.

Anti-Amyloid-ß Immunotherapy: A Leading Novel Avenue for Alzheimer's Disease.

Alzheimer's disease or senile dementia is principally acknowledged by the gradual accumulation of neurotoxic amyloid- ß protein in the brain and is considered as the initial event of the phenomenon of this asymptomatic ailment. It prompts the decline in cognitive performance, standard psychiatric functioning, and neuronal transmission across the brain. Significant inferences were withdrawn by utilizing the recently introduced disease-modifying anti- amyloid- ß immunotherapy developed after performing the clinical and preclinical controlled trials to cure the neurodegenerative malady. This strategy is worthwhile because of the clinical relevance and specific targeted approach that exhibited the quenched immunotherapeutic effects and encouraged clinical findings. In vitro fabricated, anti- amyloid- ß recombinant monoclonal antibodies are passively employed to promote clearance and antagonize the aggregation and synthesis of neurotoxic and degenerative aggregates of amyloid-ß. Thus, passive immunotherapy has an adequate impact on treating this disorder, and currently, some other monoclonal pharmacological molecules are under clinical trials to defeat this severe exacerbation with more efficacy and clinical benefits. This review compendiously discusses the anti-amyloid-ß immunotherapy, which will provide a more proficient framework to be employed as a potential therapeutic approach.

Overcoming addition of phosphoethanolamine to lipid A mediated colistin resistance in Acinetobacter baumannii clinical isolates with colistin-sulbactam combination therapy.

Overcoming colistin-resistant Acinetobacter baumannii (CoR-AB) has become a major concern due to the lack of effective antibiotics. This study aimed to explore the prevalence of CoR-AB clinical isolates in Thailand, their mechanisms of resistance, and test the efficacy of colistin plus sulbactam against CoR-AB isolates. The colistin resistance rate among carbapenem-resistant A. baumannii was 15.14%. The mcr gene or its variants were not detected in CoR-AB isolates by PCR screening. The lipid A mass spectra of CoR-AB isolates showed the additional [M-H]- ion peak at m/z = 2034 that correlated to the phosphoethanolamine (pEtN) addition to lipid A (N = 27/30). The important amino acid substitutions were found at position S14P, A138T, A227V in PmrB that are associated with overexpression of the pEtN transferase (PmrC) and contributed the pEtN addition. The lipopolysacccharide production genes (lpxACD) were not related to lipid A mass spectra. A colistin plus sulbactam combination exhibited the synergy rate at 86.7% against CoR-AB isolates compare to sulbactam (85.89% resistance) or colistin (15.14% resistance) alone. The excellent synergistic activity of colistin plus sulbactam combination has the potential for the treatment of CoR-AB infections.

High prevalence of mgrB-mediated colistin resistance among carbapenem-resistant Klebsiella pneumoniae is associated with biofilm formation, and can be overcome by colistin-EDTA combination therapy.

The global prevalence of colistin-resistant Klebsiella pneumoniae (ColRkp) facilitated by chromosomal and plasmid-mediated Ara4N or PEtN-remodeled LPS alterations has steadily increased with increased colistin usage for treating carbapenem-resistant K. pneumoniae (CRkp). Our study demonstrated the rising trend of ColRkp showing extensively and pandrug-resistant characteristics among CRkp, with a prevalence of 28.5%, which was mediated by chromosomal mgrB, pmrB, or phoQ mutations (91.5%), and plasmid-mediated mcr-1.1, mcr-8.1, mcr-8.2 alone or in conjunction with R256G PmrB (8.5%). Several genetic alterations in mgrB (85.1%) with increased expressions of Ara4N-related phoPQ and pmrK were critical for establishing colistin resistance in our isolates. In this study, we discovered the significant associations between extensively drug-resistant bacteria (XDR) and pandrug-resistant bacteria (PDR) ColRkp in terms of moderate, weak or no biofilm-producing abilities, and altered expressions of virulence factors. These ColRkp would therefore be very challenging to treat, emphasizing for innovative therapy to combat these infections. Regardless of the underlying colistin-resistant mechanisms, colistin-EDTA combination therapy in this study produced potent synergistic effects in both in vitro and in vivo murine bacteremia, with no ColRkp regrowth and improved animal survival, implying the significance of colistin-EDTA combination therapy as systemic therapy for unlocking colistin resistance in ColRkp-associated bacteremia.

Primer for Designing Main Protease (Mpro) Inhibitors of SARS-CoV-2.

The COVID-19 outbreak has been devastating, with hundreds of millions of infections and millions of deaths reported worldwide. In response, the application of structure-activity relationships (SAR) upon experimentally validated inhibitors of SARS-CoV-2 main protease (Mpro) may provide an avenue for the identification of new lead compounds active against COVID-19. Upon the basis of information gleaned from a combination of reported crystal structures and the docking of experimentally validated inhibitors, four "rules" for designing potent Mpro inhibitors have been proposed. The aim here is to guide medicinal chemists toward the most probable hits and to provide guidance on repurposing available structures as Mpro inhibitors. Experimental examination of our own previously reported inhibitors using the four "rules" identified a potential lead compound, the cathepsin inhibitor GB111-NH2, that was 2.3 times more potent than SARS-CoV-2 Mpro inhibitor N3.

Identification of Alkaloids from Terminalia chebula as Potent SARS- CoV-2 Main Protease Inhibitors: An In Silico Perspective.

Natural compounds in medicinal plants are best remedies for different diseases and are important to develop new drugs. This work was dedicated to understand the role of different natural compounds of Terminalia Chebula, a well-known herbal plant, in the treating of Covid 19. In this article, we have investigated interactions of such natural compounds from Terminalia Chebula with the main protease (Mpro) of the SARS-CoV-2, which is a key component for cleavage of viral polyprotein, and an important target for the development of drugs towards COVID-19. We have performed molecular docking study on 22 different molecules of Terminalia Chebula and proposed that 7 of the natural compounds (triterpenoids and sterols) interacts with a comparable or stronger interactions than the inhibitor N3. Molecular dynamics simulations (100 ns) revealed that 7 Mpro-Terminalia Chebula complexes are stable, conformationally less fluctuated, slightly less compact, and marginally expanded than ligand-free conformation of Mpro. The intermolecular H-bonding and detailed MM/PBSA and MM-GBSA analysis showed Daucosterol interaction to be the most strong, whereas comparable interactions were observed for Arjunetin, Maslinic acid, and Bellericoside. Our study suggested that these natural compounds can act as potent Mpro inhibitors for SARS-CoV-2, and may evolve as promising anti-COVID-19 drugs in the near future.

Exploring the Role of Ubiquitin-Proteasome System in Parkinson's Disease.

Over the last decade, researchers have discovered that a group of apparently unrelated neurodegenerative disorders, such as Parkinson's disease, have remarkable cellular and molecular biology similarities. Protein misfolding and aggregation are involved in all of the neurodegenerative conditions; as a result, inclusion bodies aggregation starts in the cells. Chaperone proteins and ubiquitin (26S proteasome's proteolysis signal), which aid in refolding misfolded proteins, are frequently found in these aggregates. The discovery of disease-causing gene alterations that code for multiple ubiquitin-proteasome pathway proteins in Parkinson's disease has strengthened the relationship between the ubiquitin-proteasome system and neurodegeneration. The specific molecular linkages between these systems and pathogenesis, on the other hand, are unknown and controversial. We outline the current level of knowledge in this article, focusing on important unanswered problems.

Natural and Synthetic Agents Targeting Reactive Carbonyl Species against Metabolic Syndrome.

Reactive carbonyl species (RCS) may originate from the oxidation of unsaturated fatty acids and sugar in conditions of pathology. They are known to have high reactivity towards DNA as well as nucleophilic sites of proteins, resulting in cellular dysfunction. It has been considered that various pathological conditions are associated with an increased level of RCS and their reaction products. Thus, regulating the levels of RCS may be associated with the mitigation of various metabolic and neurodegenerative disorders. In order to perform a comprehensive review, various literature databases, including MEDLINE, EMBASE, along with Google Scholar, were utilized to obtain relevant articles. The voluminous review concluded that various synthetic and natural agents are available or in pipeline research that hold tremendous potential to be used as a drug of choice in the therapeutic management of metabolic syndrome, including obesity, dyslipidemia, diabetes, and diabetes-associated complications of atherosclerosis, neuropathy, and nephropathy. From the available data, it may be emphasized that various synthetic agents, such as carnosine and simvastatin, and natural agents, such as polyphenols and terpenoids, can become a drug of choice in the therapeutic management for combating metabolic syndromes that involve RCS in their pathophysiology. Since the RCS are known to regulate the biological processes, future research warrants detailed investigations to decipher the precise mechanism.

Novel imidazo[1,2-a]pyridine derivatives induce apoptosis and cell cycle arrest in non-small cell lung cancer by activating NADPH oxidase mediated oxidative stress.

AIMS: Imidazo[1,2-a]pyridine-based analogues have recently gained significant interest because of their wide spectrum of biological activities including anti-cancer potential, however the development of targeted therapeutic candidates against non-small cell lung cancer (NSCLC) is of utmost need due to its high prevalence and poor prognosis. Herein, we have aimed to synthesized novel imidazo [1,2-a] pyridine derivatives (IMPA) by coupling with 2-amino-4H-pyran to enhance bioactivity against NSCLC. MAIN METHODS: We have designed and synthesized a series of fifteen novel imidazo [1,2-a] pyridine derivatives through molecular hybridization and studied their anti-cancer activity against in-vitro lung adenocarcinoma and 3D multicellular lung tumor spheroids. KEY FINDINGS: IMPA-2, IMPA-5, IMPA-6, IMPA-8, and IMPA-12 markedly induced cytotoxicity by notably increased NADPH oxidase (NOX) activity, which results in the induction of ROS-mediated apoptosis in A549 lung cancer cells. It caused impairment of mitochondrial membrane potential by increasing pro-apoptotic BAX, and BAK1 expressions, and decreasing anti-apoptotic BCL2 expression, along with the induction of caspase-9/3 activation, however, these attributes were compromised in presence of N-acetyl-L-cysteine (NAC), a free radical scavenger. Increased ROS production by IMPAs also promotes p53 mediated cell cycle arrest through the inactivation of p38MAPK. Reduction of tumor size in IMPAs-treated 3D multicellular lung tumor spheroids gave further validation. SIGNIFICANCE: Beside cytotoxicity, IMPAs also inhibit lung cancer cell invasion and migration, suggesting their applicability in metastatic lung cancer. Therefore, IMPA derivatives could be used as potential anti-cancer agents in treating non-small cell lung cancer.

Determination of potential inhibitors based on isatin derivatives against SARS-CoV-2 main protease (mpro): a molecular docking, molecular dynamics and structure-activity relationship studies.

SARS-COV-2, the novel coronavirus and root of global pandemic COVID-19 caused a severe health threat throughout the world. Lack of specific treatments raised an effort to find potential inhibitors for the viral proteins. The recently invented crystal structure of SARS-CoV-2 main protease (Mpro) and its key role in viral replication; non-resemblance to any human protease makes it a perfect target for inhibitor research. This article reports a computer-aided drug design (CADD) approach for the screening of 118 compounds with 16 distinct heterocyclic moieties in comparison with 5 natural products and 7 repurposed drugs. Molecular docking analysis against Mpro protein were performed finding isatin linked with a oxidiazoles (A2 and A4) derivatives to have the best docking scores of -11.22 kcal/mol and -11.15 kcal/mol respectively. Structure-activity relationship studies showed a good comparison with a known active Mpro inhibitor and repurposed drug ebselen with an IC50 value of -0.67 µM. Molecular Dynamics (MD) simulations for 50 ns were performed for A2 and A4 supporting the stability of the two compounds within the binding pocket, largely at the S1, S2 and S4 domains with high binding energy suggesting their suitability as potential inhibitors of Mpro for SARS-CoV-2.

Unravelling the potential neuroprotective facets of erythropoietin for the treatment of Alzheimer's disease.

During the last three decades, recombinant DNA technology has produced a wide range of hematopoietic and neurotrophic growth factors, including erythropoietin (EPO), which has emerged as a promising protein drug in the treatment of several diseases. Cumulative studies have recently indicated the neuroprotective role of EPO in preclinical models of acute and chronic neurodegenerative disorders, including Alzheimer's disease (AD). AD is one of the most prevalent neurodegenerative illnesses in the elderly, characterized by the accumulation of extracellular amyloid-ß (Aß) plaques and intracellular neurofibrillary tangles (NFTs), which serve as the disease's two hallmarks. Unfortunately, AD lacks a successful treatment strategy due to its multifaceted and complex pathology. Various clinical studies, both in vitro and in vivo, have been conducted to identify the various mechanisms by which erythropoietin exerts its neuroprotective effects. The results of clinical trials in patients with AD are also promising. Herein, it is summarized and reviews all such studies demonstrating erythropoietin's potential therapeutic benefits as a pleiotropic neuroprotective agent in the treatment of Alzheimer's disease.

Multidrug-resistant Neisseria gonorrhoeae infection in heterosexual men with reduced susceptibility to ceftriaxone, first report in Thailand.

The global rapid emergence of azithromycin/ceftriaxone resistant Neisseria gonorrhoeae threatens current recommend azithromycin/ceftriaxone dual therapy for gonorrhea to ensure effective treatment. Here, we identified the first two N. gonorrhoeae isolates with decreased ceftriaxone susceptibility in Thailand. Among 134 N. gonorrhoeae isolates collected from Thai Red Cross Anonymous Clinic, Bangkok, two isolates (NG-083 and NG-091) from urethral swab in male heterosexual patients had reduced susceptibility to ceftriaxone (MICs of 0.125 mg/L). Both were multidrug resistant and strong biofilm producers with ceftriaxone tolerance (MBEC > 128 mg/L). NG-083 and NG-091 remained susceptible to azithromycin (MIC of 1 mg/L and 0.5 mg/L, respectively). Reduced susceptibility to ceftriaxone was associated with alterations in PBP2, PBP1, PorB, MtrR, and mtrR promoter region. NG-083 belonged to sequence type (ST) 7235 and NG-091 has new allele number of tbpB with new ST. Molecular docking revealed ceftriaxone weakly occupied the active site of mosaic XXXIV penicillin-binding protein 2 variant in both isolates. Molecular epidemiology results revealed that both isolates display similarities with isolates from UK, USA, and The Netherlands. These first two genetically related gonococcal isolates with decreased ceftriaxone susceptibility heralds the threat of treatment failure in Thailand, and importance of careful surveillance.

Alkyne-Tagged Apigenin, a Chemical Tool to Navigate Potential Targets of Flavonoid Anti-Dengue Leads.

A flavonoid is a versatile core structure with various cellular, immunological, and pharmacological effects. Recently, flavones have shown anti-dengue activities by interfering with viral translation and replication. However, the molecular target is still elusive. Here we chemically modified apigenin by adding an alkyne moiety into the B-ring hydroxyl group. The alkyne serves as a chemical tag for the alkyne-azide cycloaddition reaction for subcellular visualization. The compound located at the perinuclear region at 1 and 6 h after infection. Interestingly, the compound signal started shifting to vesicle-like structures at 6 h and accumulated at 24 and 48 h after infection. Moreover, the compound treatment in dengue-infected cells showed that the compound restricted the viral protein inside the vesicles, especially at 48 h. As a result, the dengue envelope proteins spread throughout the cells. The alkyne-tagged apigenin showed a more potent efficacy at the EC50 of 2.36 ± 0.22, and 10.55 ± 3.37 µM, respectively, while the cytotoxicities were similar to the original apigenin at the CC50 of 70.34 ± 11.79, and 82.82 ± 11.68 µM, respectively. Molecular docking confirmed the apigenin binding to the previously reported target, ribosomal protein S9, at two binding sites. The network analysis, homopharma, and molecular docking revealed that the estrogen receptor 1 and viral NS1 were potential targets at the late infection stage. The interactions could attenuate dengue productivity by interfering with viral translation and suppressing the viral proteins from trafficking to the cell surface.

Deciphering the focal role of endostatin in Alzheimer's disease.

Alzheimer's disease (AD) is a paramount chronic neurodegenerative condition that has been affecting elderly people since the 1900s. It causes memory loss, disorientation, and poor mental function. AD is considered to be one of the most serious problems that dementia sufferers face. Despite extensive investigation, the pathological origin of Alzheimer's disease remains a mystery. The amyloid cascade theory and the vascular hypothesis, which stresses the buildup of Aß plaques, have dominated research into dementia and aging throughout history. However, research into this task failed to yield the long-awaited therapeutic miracle lead for Alzheimer's disease. Perhaps a hypothetical fragility in the context of Alzheimer's disease was regarded as a state distinct from aging in general, as suggested by the angiogenesis hypothesis, which suggests that old age is one state associated with upregulation of angiogenic growth factors, resulting in decreased microcirculation throughout the body. There has also been evidence that by controlling or inhibiting the components involved in the sequence of events that cause angiogenesis, there is a visible progression in AD patients. In Alzheimer's disease, one such antiangiogenic drug is being used.

Novel α-Aminophosphonates of imatinib Intermediate: Synthesis, anticancer Activity, human Abl tyrosine kinase Inhibition, ADME and toxicity prediction.

An efficient method for the synthesis of a new class of α-aminophosphonates of imatinib derivative has been developed in one-pot Kabachnik-Fields reaction of N-(5-amino-2-methyl phenyl)-4-(3-pyridyl)-2-pyrimidine amine with various aldehydes and diethyl phosphite under microwave irradiation and neat conditions using NiO nanoparticles as an reusable and heterogeneous catalyst, with 96% yield at 450 W within 15 min. All the compounds were evaluated for their in vitro cytotoxicity with various cancer cell lines by MTT assay method. Compounds with halo (4f, -4Br, IC50 = 1.068 ± 0.88 µM to 2.033 ± 0.97 µM), nitro substitution (4 h, -3NO2, IC50 = 1.380 ± 0.94 µM to 2.213 ± 0.64 µM), (4 g, -4NO2, IC50 = 1.402 ± 0.79 µM to 2.335 ± 0.73 µM) and (4i, 4-Cl, 3-NO2, IC50 = 1.437 ± 0.92 µM to 2.558 ± 0.76 µM) were showed better anticancer activity when compared with standard drugs Doxorubicin and Imatinib using MTT assay method. Further in silico target hunting reveals the anticancer activity of the designed compounds by inhibiting human ABL tyrosine kinase and all the designed compounds have shown significant drug-like characteristics.

Kobophenol A Inhibits Binding of Host ACE2 Receptor with Spike RBD Domain of SARS-CoV-2, a Lead Compound for Blocking COVID-19.

In the search for inhibitors of COVID-19, we have targeted the interaction between the human angiotensin-converting enzyme 2 (ACE2) receptor and the spike receptor binding domain (S1-RBD) of SARS-CoV-2. Virtual screening of a library of natural compounds identified Kobophenol A as a potential inhibitor. Kobophenol A was then found to block the interaction between the ACE2 receptor and S1-RBD in vitro with an IC50 of 1.81 ± 0.04 µM and inhibit SARS-CoV-2 viral infection in cells with an EC50 of 71.6 µM. Blind docking calculations identified two potential binding sites, and molecular dynamics simulations predicted binding free energies of -19.0 ± 4.3 and -24.9 ± 6.9 kcal/mol for Kobophenol A to the spike/ACE2 interface and the ACE2 hydrophobic pocket, respectively. In summary, Kobophenol A, identified through docking studies, is the first compound that inhibits SARS-CoV-2 binding to cells through blocking S1-RBD to the host ACE2 receptor and thus may serve as a good lead compound against COVID-19.

A Series of Ferulic Acid Amides Reveals Unexpected Peroxiredoxin 1 Inhibitory Activity with in†vivo Antidiabetic and Hypolipidemic Effects.

Insulin resistance is a major pathophysiological feature in the development of type 2 diabetes (T2DM). Ferulic acid is known for attenuating the insulin resistance and reducing the blood glucose in T2DM rats. In this work, we designed and synthesized a library of new ferulic acid amides (FAA), which could be considered as ring opening derivatives of the antidiabetic PPARγ agonists Thiazolidinediones (TZDs). However, since these compounds displayed weak PPAR transactivation capacity, we employed a proteomics approach to unravel their molecular target(s) and identified the peroxiredoxin 1 (PRDX1) as a direct binding target of FAAs. Interestingly, PRDX1, a protein with antioxidant and chaperone activity, has been implied in the development of T2DM by inducing hepatic insulin resistance. SPR, mass spectrometry-based studies, docking experiments and in vitro inhibition assay confirmed that compounds VIe and VIf bound PRDX1 and induced a dose-dependent inhibition. Furthermore, VIe and VIf significantly improved hyperglycemia and hyperlipidemia in streptozotocin-nicotinamide (STZ-NA)-induced diabetic rats as confirmed by histopathological examinations. These results provide guidance for developing the current FAAs as new potential antidiabetic agents.