Discovery of orally bioavailable phenyltetrazolium derivatives for the acute treatment and the secondary prevention of ischemic stroke.

The potential for secondary stroke prevention, which can significantly reduce the risk of recurrent strokes by almost 90%, underscores its critical importance. N-butylphthalide (NBP) has emerged as a promising treatment for acute cerebral ischemia, yet its efficacy for secondary stroke prevention is hindered by inadequate pharmacokinetic properties. This study, driven by a comprehensive structural analysis, the iterative process of structure optimization culminated in the identification of compound B4, which demonstrated exceptional neuroprotective efficacy and remarkable oral exposure and oral bioavailability. Notably, in an in vivo transient middle cerebral artery occlusion (tMCAO) model, B4 substantially attenuated infarct volumes, surpassing the effectiveness of NBP. While oral treatment with B4 exhibited stronger prevention potency than NBP in photothrombotic (PT) model. In summary, compound B4, with its impressive oral bioavailability and potent neuroprotective effects, offers promise for both acute ischemic stroke treatment and secondary stroke prevention.

Molecular docking of curcumin and curcuminoids as human Zn+ dependent histone deacetylase (HDAC) enzyme inhibitors.

Chemotherapy is one of the most well-established and effective cancer treatments available. However, non-tumor-associated damage restrict the treatment's effectiveness and safety. Our growing understanding of cancer epigenetics has resulted in new therapeutic options and the potential of better patient outcomes in recent decades. In cancer, epigenetic changes are widespread, particularly increased expression and activity of histone deacetylases (HDACs). Epi-drugs are chemical agents that modify the structure of DNA and chromatin facilitating disruption of transcriptional and post-transcriptional changes. First generation epi-drugs include HDAC inhibitors (HDACi) (approved to treat hematological malignancies) harbor various adverse effects demanding the discovery and development of potential natural HDACi that might benefit cancer treatment especially in hematological malignancies. Curcumin (diferuloylmethane), a polyphenolic, component of Curcuma longa, is a well-known anti-inflammatory, anti-oxidative, and anti-lipidemic agent and has recently been shown to be a pan HDACi. Yet the potential of other curcuminoids in Curcuma longa as pan HDACi remains unexplored. (i) To virtually screen curcumin and curcuminoids (Desmethoxycurcumin [DMC] & Bisdemethoxycurcumin [BDMC]) against human Histone deacetylase (HDAC) class I, II and IV enzymes in comparison to their pan HDAC inhibition activity with FDA approved human HDACis available in market and also (ii) to predict the drug likeness property and ADME/ toxicity of curcumin, curcuminoids and approved HDACis via computational approach. Homology modelling followed by docking was performed for human HDAC class I, II and IV enzymes with curcumin, Desmethoxycurcumin, Bisdemethoxycurcumin and with 5 reference HDACi compounds Vorinostat (SAHA), Trichostatin A (TSA), Chidamide, Romidepsin, and Panobinostat to understand the protein -ligand interactions and binding efficiencies. Further, the study ligands with low binding energy were predicted for pharmacokinetic properties and Lipinski's rule of 5. Our study revealed that BDMC followed by DMC and curcumin had high inhibitory effect by interacting at the active site of Zn+ HDACs similar to that of the standard HDACi (curcumin, DMC, BDMC, Belinostat, Chidamide, Romidepsin, Panobinostat, Trichostatin A and Vorinostat). Likewise, all of the chosen ligand molecules, with the exception of Romidepsin (refractive index > 130 m3mol-1), adhered to Lipinski's rule of five and none of the natural compounds (curcumin, DMC, BDMC) did report any toxicity and mutagenic property also, the lethal doses (LD50) of all the natural compounds were higher when compared to chemical drugs. BDMC could be a potential pan HDACi than curcumin and DMC owing to high binding affinity among human Zn+ HDACs. The results of our present study can be useful for the design and development of novel compounds having better HDAC inhibitory activity against several types of cancers. Moreover, these findings could be validated with invitro investigations and by clinical trials to evaluate the survival outcomes in cancer patients when treated with the natural HDACi along with standard chemo regimen. Supplementary Information: The online version contains supplementary material available at 10.1007/s40203-024-00221-4.

Synthesis and biological evaluation of the novel chrysin prodrug for non-alcoholic fatty liver disease treatment.

Background: Chrysin (5,7-dihydroxyflavone) is a natural flavonoid that has been reported as a potential treatment for non-alcoholic fatty liver disease (NAFLD). However, extensive phase II metabolism and poor aqueous solubility led to a decrease in the chrysin concentration in the blood after oral administration, limiting its pharmacological development in vivo. Methods: In the present study, we synthesized a novel chrysin derivative prodrug (C-1) to address this issue. We introduced a hydrophilic prodrug group at the 7-position hydroxyl group, which is prone to phase II metabolism, to improve water solubility and mask the metabolic site. Further, we evaluated the ameliorative effects of C-1 on NAFLD in vitro and in vivo by NAFLD model cells and db/db mice. Results: In vitro studies indicated that C-1 has the ability to ameliorate lipid accumulation, cellular damage, and oxidative stress in NAFLD model cells. In vivo experiments showed that oral administration of C-1 at a high dose (69.3 mg/kg) effectively ameliorated hyperlipidemia and liver injury and reduced body weight and liver weight in db/db mice, in addition to alleviating insulin resistance. Proteomic analysis showed that C-1 altered the protein expression profile in the liver and particularly improved the expression of proteins associated with catabolism and metabolism. Furthermore, in our preliminary pharmacokinetic study, C-1 showed favorable pharmacokinetic properties and significantly improved the oral bioavailability of chrysin. Conclusion: Our data demonstrated that C-1 may be a promising agent for NAFLD therapy.

Precision Deuteration in Search of Anticancer Agents: Approaches to Cancer Drug Discovery.

Cancer chemotherapy has been shifted from conventional cytotoxic drug therapy to selective and target-specific therapy after the findings about DNA changes and proteins that are responsible for cancer. A large number of newer drugs were discovered as targeted therapy for particular types of neoplastic disease. The initial discovery includes the development of the first in the category, imatinib, a Bcr-Abl tyrosine kinase inhibitor (TKI) for the treatment of chronic myelocytic leukemia in 2001. But the joy did not last for long as the drug developed a point mutation within the ABL1 kinase domain of BCR-ABL1, which subsequently led to the discovery of many other TKIs. Resistance was observed for newer TKIs a few years after their launching, but the use of TKIs in life-threatening cancer therapy is considered as far better compared with the risks of disease because of its target specificity and hence less toxicity. In search of a better anticancer agent, the physiochemical properties of the lead molecule have been modified for its efficacy toward disease and delay in the development of resistance. Deuteration in the drug molecule is one of such modifications that alter the pharmacokinetic properties, generally its metabolism, as compared with its pharmacodynamic effects. Precision deuteration in many anticancer drugs has been carried out to search for better drugs for cancer. In this review, the majority of anticancer drugs and molecules for which deuteration was applied to get better anticancer molecules were discussed. This review will provide a complete guide about the benefits of deuteration in cancer chemotherapy.

PredPS: Attention-based graph neural network for predicting stability of compounds in human plasma.

Stability of compounds in the human plasma is crucial for maintaining sufficient systemic drug exposure and considered an essential factor in the early stages of drug discovery and development. The rapid degradation of compounds in the plasma can result in poor in vivo efficacy. Currently, there are no open-source software programs for predicting human plasma stability. In this study, we developed an attention-based graph neural network, PredPS to predict the plasma stability of compounds in human plasma using in-house and open-source datasets. The PredPS outperformed the two machine learning and two deep learning algorithms that were used for comparison indicating its stability-predicting efficiency. PredPS achieved an area under the receiver operating characteristic curve of 90.1%, accuracy of 83.5%, sensitivity of 82.3%, and specificity of 84.6% when evaluated using 5-fold cross-validation. In the early stages of drug discovery, PredPS could be a helpful method for predicting the human plasma stability of compounds. Saving time and money can be accomplished by adopting an in silico-based plasma stability prediction model at the high-throughput screening stage. The source code for PredPS is available at https://bitbucket.org/krict-ai/predps and the PredPS web server is available at https://predps.netlify.app.

Recent Updates on the Development of Deuterium-Containing Drugs for the Treatment of Cancer.

Cancer is one of the deadliest diseases in the world. In 2020, 19.3 million cancer cases and 10 million deaths were reported in the world. It is supposed that the prevalence of cancer cases will rise to 28.4 million by 2040. Chemotherapy-based regimens have a narrow therapeutic index, severe adverse drug reactions, and lack metabolic stability. Besides, the metabolism of anticancer produces several non-active and toxic metabolites that reduce exposure of the target site to the parent drug. Therefore, developing better-tolerated and effective new anticancer drugs and modification of the existing anticancer drugs to minimize toxicity and increase efficacy has become a very urgent need. Deuterium incorporation reduces the metabolism of certain drugs that are breakdown by pathways involving hydrogen-carbon bond scission. For example, CYP450 mediated oxidative metabolism of drugs that involves the breakdown of a hydrogen-carbon bond affected by deuteration. Deuterium incorporation into the drug increases the half-life and reduces the dose, which provides better safety and efficacy. Deutetrabenazine is the first deuterated form of tetrabenazine approved to treat chorea associated with Huntington's disease and tardive dyskinesia. The study revealed that Deutetrabenazine has fewer neuropsychiatric side effects with favorable safety than tetrabenazine. The current review highlights the deuterium kinetic isotope effect on drug metabolism, deuterated compound pharmacokinetic property, and safety profile. Besides, this review explains the deuterated anticancer drug development update status.

PEGylated lipid bilayer coated mesoporous silica nanoparticles co-delivery of paclitaxel and curcumin leads to increased tumor site drug accumulation and reduced tumor burden.

Homogeneous PEGylated lipid bilayer coated highly ordered MSNs (PLMSNs) which were systematically optimized and characterized to co-encapsulate paclitaxel (Tax) and curcumin (Cur) were verified to manifest prolonged and enhanced cytotoxic effect against canine breast cancer cells in our previous study. In this article, we took further study of the pharmacokinetic property, cellular uptake, subcellular localization, in vivo distribution and tumor accumulation ability, and treatment efficacy of the drug delivery system. The results revealed that the delivery system could significantly increase the AUC of two drugs, and the anti-tumor effect showed that both intravenous and intratumoral administration group better controlled the tumor weight than that of other groups (P < .05), and the anti-tumor rates were 58.4% and 58.3% respectively. Cell uptake and localization study showed that PLMSNs could effectively carry drugs into cancer cells with sustained release characteristics. The subcellular localization of PLMSNs was mainly in lysosomes and mitochondria. In vivo fluorescence tracing results showed that PLMSNs could be effectively accumulated in the tumor site. The results revealed that the delivery system could effectively reduce the clinical dosage of drugs and reduce its toxic side effects, effectively carry drugs into cancer cells, and exhibit good targeting characteristics for breast cancer.

Identification of highly potent and orally available free fatty acid receptor 1 agonists bearing isoxazole scaffold.

The free fatty acid receptor 1 (FFA1) is being considered to be a novel anti-diabetic target based on its role in amplifying insulin secretion. We have previously identified several series of FFA1 agonists with different heterocyclic scaffolds. Herein, we describe the structural exploration of other heterocyclic scaffolds directed by drug-like physicochemical properties. Further structure-based design and chiral resolution provided the most potent compound 11 (EC50 = 7.9 nM), which exhibited improved lipophilicity (LogD7.4: 1.93), ligand efficiency (LE = 0.32) and ligand lipophilicity efficiency (LLE = 6.2). Moreover, compound 11 revealed an even better pharmacokinetic property than that of TAK-875 in terms of plasma clearance, maximum concentration, and plasma exposure. Although robust agonistic activity and PK profiles for compound 11, the glucose-lowering effects in vivo is not ideal, and the exact reason for in vitro/in vivo difference was worthy for further exploration.

Novel enzyme formulations for improved pharmacokinetic properties and anti-inflammatory efficacies.

Anti-inflammatory enzymes promote the dissolution and excretion of sticky phlegm, clean the wound surface and accelerate drug diffusion to the lesion. They play important roles in treating different types of inflammation and pain. Currently, various formulations of anti-inflammatory enzymes are successfully prepared to improve the enzymatic characteristics, pharmacokinetic properties and anti-inflammatory efficacies. The work was performed by systematically searching all available literature. An overall summary of current research about various anti-inflammatory enzymes and their novel formulations is presented. The original and improved enzymatic characteristics, pharmacokinetic properties, action mechanisms, clinical information, storage and shelf life, treatment efficacies of anti-inflammatory enzymes and their different formulations are summarized. The influencing factors such as enzyme type, source, excipient, pharmaceutical technique, administration route and dosage are analyzed. The combined application of enzymes and other drugs are included in this paper. Anti-inflammatory enzymes were widely applied in treating different types of inflammation and diseases with accompanying edema. Their novel formulations increased enzymatic stabilities, improved pharmacokinetic properties, provided different administration routes, and enhanced anti-inflammatory efficacies of anti-inflammatory enzymes but decreased side effects and toxicity. Novel enzyme formulations improve and expand the usage of anti-inflammatory enzymes.

Novel Polyfunctional Pyridines as Anticancer and Antioxidant Agents. Synthesis, Biological Evaluation and in Silico ADME-T Study.

Two series of novel alkoxylated 2-oxo(imino)-3-pyridinecarbonitriles (structurally-relevant to some reported anticancer pyridines with phosphodiesterase 3A (PDE3A) inhibitory activity) were synthesized and evaluated for their in vitro differential tumor cell growth inhibitory potential against the breast MCF7, hepatocellular Hep-G2, colon CACO-2 cell lines, and a normal human foreskin fibroblast Hs27 cell line. Compounds 8, 16 and 19 displayed recognizable growth inhibitory ability and selectivity towards the breast MCF7 (LC50 19.15, 17.34 and 14.70 µM, respectively) as compared with doxorubicin (LC50 3.94 µM). Meanwhile, compounds 8, 15, 16, and 19 revealed a marginal inhibitory effect on the growth of the normal human foreskin fibroblast Hs27 cell line, beside a distinctive antioxidant potential in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. These four compounds were further assessed for their in vitro inhibition of PDE3A (a current antitumor therapeutic target), where 16 and 19 showed moderate to weak PDE3A inhibitory as compared with milrinone, the positive control. No clear straightforward liaison between the anticancer potential and PDE3A inhibitory activity could be deduced. Computations of the predicted pharmacokinetic properties, toxicity effects (ADME-T), drug-likeness and drug scores for the newly developed compounds showed non-violations of Lipinski's RO5 and Veber's criteria for good bioavailability, with a predicted high safety profile.

A structure-guided optimization of pyrido[2,3-d]pyrimidin-7-ones as selective inhibitors of EGFRL858R/T790M mutant with improved pharmacokinetic properties.

Structural optimization of pyrido[2,3-d]pyrimidin-7-ones was conducted to yield a series of new selective EGFRT790M inhibitors with improved pharmacokinetic properties. One of the most promising compound 9s potently suppressed EGFRL858R/T790M kinase and inhibited the proliferation of H1975 cells with IC50 values of 2.0 nM and 40 nM, respectively. The compound dose-dependently induced reduction of the phosphorylation of EGFR and downstream activation of ERK in NCIH1975 cells. It also exhibited moderate plasma exposure after oral administration and an oral bioavailability value of 16%. Compound 9s may serve as a promising lead compound for further drug discovery overcoming the acquired resistance of non-small cell lung cancer (NSCLC) patients.

Towards Better BBB Passage Prediction Using an Extensive and Curated Data Set.

In the present report, the challenging task of drug delivery across the blood-brain barrier (BBB) is addressed via a computational approach. The BBB passage was modeled using classification and regression schemes on a novel extensive and curated data set (the largest to the best of our knowledge) in terms of log BB. Prior to the model development, steps of data analysis that comprise chemical data curation, structural, cutoff and cluster analysis (CA) were conducted. Linear Discriminant Analysis (LDA) and Multiple Linear Regression (MLR) were used to fit classification and correlation functions. The best LDA-based model showed overall accuracies over 85 % and 83 % for the training and test sets, respectively. Also a MLR-based model with acceptable explanation of more than 69 % of the variance in the experimental log BB was developed. A brief and general interpretation of proposed models allowed the estimation on how 'near' our computational approach is to the factors that determine the passage of molecules through the BBB. In a final effort some popular and powerful Machine Learning methods were considered. Comparable or similar performance was observed respect to the simpler linear techniques. Most of the compounds with anomalous behavior were put aside into a set denoted as controversial set and discussion regarding to these compounds is provided. Finally, our results were compared with methodologies previously reported in the literature showing comparable to better results. The results could represent useful tools available and reproducible by all scientific community in the early stages of neuropharmaceutical drug discovery/development projects.

Design, modeling, expression, and chemoselective PEGylation of a new nanosize cysteine analog of erythropoietin.

BACKGROUND: Recombinant human erythropoietin (rhEPO) is considered to be one of the most pivotal pharmaceutical drugs in the market because of its clinical application in the treatment of anemia-associated disorders worldwide. However, like other therapeutic proteins, it does not have suitable pharmacokinetic properties for it to be administrated at least two to three times per week. Chemoselective cysteine PEGylation, employing molecular dynamics and graphics in in silico studies, can be considered to overcome such a problem. METHODS: A special kind of EPO analog was elicited based on a literature review, homology modeling, molecular dynamic simulation, and factors affecting the PEGylation reaction. Then, cDNA of the selected analog was generated by site-directed mutagenesis and subsequently cloned into the expression vector. The construct was transfected to Chinese hamster ovary/dhfr(-) cells, and highly expressed clones were selected via methotrexate amplification. Ion-immobilized affinity and size exclusion (SE) chromatography techniques were used to purify the expressed analog. Thereafter, chemoselective PEGylation was performed and a nanosize PEGylated EPO was obtained through dialysis. The in vitro biologic assay and in vivo pharmacokinetic parameters were studied. Finally, E31C analog Fourier transform infrared, analytical SE-high-performance liquid chromatography, zeta potential, and size before and after PEGylation were characterized. RESULTS: The findings indicate that a novel nanosize EPO31-PEG has a five-fold longer terminal half-life in rats with similar biologic activity compared with unmodified rhEPO in proliferation cell assay. The results also show that EPO31-PEG size and charge versus unmodified protein was increased in a nanospectrum, and this may be one criterion of EPO biologic potency enhancement. DISCUSSION: This kind of novel engineered nanosize PEGylated EPO has remarkable advantages over rhEPO.