Design, Synthesis, and Pharmacological Evaluation of Embelin-Aryl/alkyl Amine Hybrids as Orally Bioavailable Blood-Brain Barrier Permeable Multitargeted Agents with Therapeutic Potential in Alzheimer's Disease: Discovery of SB-1448.

The complex and multifaceted nature of Alzheimer's disease has brought about a pressing demand to develop ligands targeting multiple pathways to combat its outrageous prevalence. Embelin is a major secondary metabolite of Embelia ribes Burm f., one of the oldest herbs in Indian traditional medicine. It is a micromolar inhibitor of cholinesterases (ChEs) and ß-site amyloid precursor protein cleaving enzyme 1 (BACE-1) with poor absorption, distribution, metabolism, and excretion (ADME) properties. Herein, we synthesize a series of embelin-aryl/alkyl amine hybrids to improve its physicochemical properties and therapeutic potency against targeted enzymes. The most active derivative, 9j (SB-1448), inhibits human acetylcholinesterase (hAChE), human butyrylcholinesterase (hBChE), and human BACE-1 (hBACE-1) with IC50 values of 0.15, 1.6, and 0.6 µM, respectively. It inhibits both ChEs noncompetitively with ki values of 0.21 and 1.3 µM, respectively. It is orally bioavailable, crosses blood-brain barrier (BBB), inhibits Aß self-aggregation, possesses good ADME properties, and protects neuronal cells from scopolamine-induced cell death. The oral administration of 9j at 30 mg/kg attenuates the scopolamine-induced cognitive impairments in C57BL/6J mice.

Effect of Myricetin on CYP2C8 Inhibition to Assess the Likelihood of Drug Interaction Using In Silico, In Vitro, and In Vivo Approaches.

Myricetin, a bioflavonoid, is widely used as functional food/complementary medicine and has promising multifaceted pharmacological actions against therapeutically validated anticancer targets. On the other hand, CYP2C8 is not only crucial for alteration in the pharmacokinetics of drugs to cause drug interaction but also unequivocally important for the metabolism of endogenous substances like the formation of epoxyeicosatrienoic acids (EETs), which are considered as signaling molecules against hallmarks of cancer. However, there is hardly any information known to date about the effect of myricetin on CYP2C8 inhibition and, subsequently, the CYP2C8-mediated drug interaction potential of myricetin at the preclinical/clinical level. We aimed here to explore the CYP2C8 inhibitory potential of myricetin using in silico, in vitro, and in vivo investigations. In the in vitro study, myricetin showed a substantial effect on CYP2C8 inhibition in human liver microsomes using CYP2C8-catalyzed amodiaquine-N-deethylation as an index reaction. Considering the Lineweaver-Burk plot, the Dixon plot, and the higher α-value, myricetin is found to be a mixed type of CYP2C8 inhibitor. Moreover, in vitro-in vivo extrapolation data suggest that myricetin is likely to cause drug interaction at the hepatic level. The molecular docking study depicted a strong interaction between myricetin and the active site of the human CYP2C8 enzyme. Moreover, myricetin caused considerable elevation in the oral exposure of amodiaquine as a CYP2C8 substrate via a slowdown of amodiaquine clearance in the rat model. Overall, the potent action of myricetin on CYP2C8 inhibition indicates that there is a need for further exploration to avoid drug interaction-mediated precipitation of obvious adverse effects as well as to optimize anticancer therapy.

Glabridin attenuates paracetamol-induced liver injury in mice via CYP2E1-mediated inhibition of oxidative stress.

CYP2E1 plays a crucial role in the bio-activation of toxic substances leading to liver damage. In this context, CYP2E1 converts paracetamol (PCM) to N-acetyl-p-benzoquinone imine (NAPQI), which is prone to cause hepatotoxicity. Hence, we aimed to explore the protective effect of glabridin on widely used PCM-induced liver injury model in the present study and, after that, correlated with the role of CYP2E1 toward its efficacy. Glabridin was isolated from Glycyrrhiza glabra and characterized before the investigation in an in-vivo mice model of PCM-induced liver injury. Glabridin after oral treatment at 5-20 mg/kg showed a considerable improvement in serum biochemical parameters (ALT and AST) and oxidative stress markers (MDA, GSH, SOD, and catalase) in comparison to only PCM-treatment. Histopathological examination of the liver depicted that glabridin exhibited substantial protection from PCM-induced liver injury compared to the disease control group. Significant down-regulation of CYP2E1 protein and its mRNA expression levels were observed in the glabridin-treated groups compared to PCM-induced respective elevation of CYP2E1. Moreover, activation of NF-κB was significantly inhibited by glabridin. Therefore, glabridin has the potential to protect PCM-induced liver injury through CYP2E1 inhibition-mediated normalization of oxidative stress. Further research is warranted to establish glabridin as a phytotherapeutics for liver protection for which no effective and safe oral drug is available to date.

Glabridin ameliorates methotrexate-induced liver injury via attenuation of oxidative stress, inflammation, and apoptosis.

Despite unprecedented advances in modern medicine, no safe and effective drug is available to date for oral administration to combat drug-induced liver injury, which is a vital concern nowadays. The present study deals with the hepatoprotective effect of pure glabridin, a key phytoconstituent from Glycyrrhiza glabra with mechanistic investigations using an in-vivo methotrexate-induced liver injury model as there is no such precedent. The study was performed in the Swiss mice model where a single dose of methotrexate (40 mg/kg) was given on the 7th day through an intraperitoneal route to induce hepatotoxicity, and glabridin as a test compound was administered orally for eleven consecutive days at 10 to 40 mg/kg. Glabridin markedly improved serum biochemical parameters (SGPT, SGOT), proinflammatory cytokine (TNF-α) level, oxidative stress markers (MDA, GSH, SOD, CAT) as compared to methotrexate alone. Alterations in methotrexate-induced liver architecture were considerably prevented by glabridin treatment as suggested by liver histopathological examination and SEM investigation. Glabridin substantially prevented methotrexate-induced down-regulation of Nrf2, & activation of NF-κB, and caused up-regulation of BAX at different dose levels. Overall, glabridin is found to protect methotrexate-induced hepatotoxicity by improving important factors for oxidative stress, inflammation, and apoptosis.

Amalgamation of in-silico, in-vitro and in-vivo approach to establish glabridin as a potential CYP2E1 inhibitor.

CYP2E1 is directly or indirectly involved in the metabolism of ethanol and endogenous fatty acids but it plays a major role in the bio-activation of toxic substances that produce reactive metabolites leading to hepatotoxicity. Therefore, identification of CYP2E1 inhibitor from bioflavonoids class having useful pharmacological properties has dual benefit regarding avoidance of severe food-drug/nutraceutical-drug interaction and scope to develop a phytotherapeutics through an intended pharmacokinetic interaction.In the present study, we aimed to identify CYP2E1 inhibitor from experimental bioflavonoids which are unexplored for CYP2E1 inhibition till date using in-silico, in-vitro and in-vivo approaches.Results of in-vitro CYP2E1 inhibitory studies using CYP2E1-mediated chlorzoxazone 6-hydroxylation in human liver microsomes showed that glabridin have the highest potential than fisetin, epicatechin, nobiletin, and chrysin to inhibit CYP2E1 enzyme. Mechanistic investigations indicate that glabridin is a competitive CYP2E1 inhibitor. Molecular docking study results demonstrate that glabridin strongly interacted with the active site of human CYP2E1 enzyme. Pharmacokinetics of a CYP2E1 substrate in mice model indicates a significant alteration of chlorzoxazone and 6-hydroxychlorzoxazone plasma levels in the presence of glabridin. Further studies are needed to confirm the results at clinical level.Overall, glabridin is found to be a potential CYP2E1 inhibitor.

Effect of Natural Phenolics on Pharmacokinetic Modulation of Bedaquiline in Rat to Assess the Likelihood of Potential Food-Drug Interaction.

Bedaquiline (TMC-207) is a recently approved drug for the treatment of multidrug-resistant tuberculosis (MDR-TB). Moreover, there is a present and growing concern for natural-product-mediated drug interaction, as these are inadvertently taken by patients as a dietary supplement, food additive, and medicine. In the present study, we investigated the impact of 20 plant-based natural products, typically phenolics, on in vivo oral bedaquiline pharmacokinetics, as previous studies are lacking. Three natural phenolics were identified that can significantly enhance the oral exposure of bedaquiline upon coadministration. We further investigated the possible role of all of the phytochemicals on in vitro P-glycoprotein (P-gp) induction and inhibition and CYP3A4 inhibition in a single platform as bedaquiline is the substrate for both P-gp and CYP3A4. In conclusion, curcumin, CC-I (3',5-dihydroxyflavone-7-O-ß-d-galacturonide-4'-O-ß-d-glucopyranoside), and 6-gingerol should not be coadministered with bedaquiline to avoid untoward drug interactions and, subsequently, its dose-dependent adverse effects.

Intervention of curcumin on oral pharmacokinetics of daclatasvir in rat: A possible risk for long-term use.

Curcumin, a natural diarylheptanoid, is extensively used as a food additive or dietary supplement on the regular basis. It is known to have potential to encumber the drug transporters and hepatic drug metabolizing enzymes that lead to pharmacokinetic interactions with drug or food. Daclatasvir is a new orally acting drug for the treatment of chronic Hepatitis C Virus infections. This is a substrate of P-glycoprotein and CYP3A4 that are involved in the major pharmacokinetic interaction. Hence, the studies' aim is to assess for any possible pharmacokinetic interactions. Pharmacokinetic studies of daclatasvir in presence or absence of curcumin were carried out in Wistar rats following oral administration. Parallelly, the oral pharmacokinetics of daclatasvir was also determined in the presence of ketoconazole or quinidine. Studies revealed that plasma level of daclatasvir was not altered significantly during concomitant single dose administration of curcumin, whereas significantly decreased upon pretreatment for 7 days with curcumin at high dose level. Ketoconazole and quinidine markedly increase daclatasvir exposure following concomitant administration with daclatasvir. It can be concluded that dose adjustment is unlikely to be required for intermittent use of curcumin at low dose but cautious for chronic and concomitant use of curcumin at a high dose.